David G Johnson

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Scholarly Contributions

Chapters

• Johnson, D. G. (2002). Macrovascular Complications of Diabetes Mellitus. In Winning The Battle Against Diabetes Through Multidisciplinary Strategies(pp 14-18).
• Johnson, D. G., & Bressler, R. (1999). Type 2 Diabetes Mellitus. In Contemporary Endocrinology: Hormone Replacement Therapy(pp 155-167). Totowa, NJ,: Humana Press.
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  Ed. A.W. Meikle
• Johnson, D. G., & Bressler, R. (1996). New pharmacologic approaches. In Diabetes Mellitus, Theory and Practice(pp 1293-1305). East Norwalk, CT: Appleton and Lange, Inc.
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  Johnson DG, Bressler R: New pharmacologic approaches, Chapter 59 in Diabetes Mellitus, Theory and Practice. Ed. Porte D, and Sherwin R, 5th edition. Appleton and Lange, Inc. East Norwalk, CT, 1996, pp 1293-1305.
• Ewy, G. A., & Johnson, D. G. (1992). Drug therapy of hyperlipidemias. In Cardiovascular Drugs and the Management of Heart Disease(pp 419-439). New York, N.Y.: Raven Press.
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  Ed. Ewy GA and Bressler R, Second edition.
• Johnson, D. G., & Bressler, R. (1992). New Pharmacological approaches to therapy of NIDDM. In Diabetes Care(pp 792-805).
• Johnson, D. G., & Bressler, R. (1992). New drugs for the treatment of diabetes mellitus.. In International Textbook of Diabetes Mellitus(pp 797-815). Chicester, U.K: John Wiley & Sons, Ltd.
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  Ed. Alberti KGMM, De Fronzo RA, Keen H, and Zimmet P.
• Johnson, D. G., & Campbell, S. (1992). Hormonal and Metabolic Agents in Geriatric Pharmacology.. In Geriatric Pharmacology(pp 427-450). New York, N.Y.: McGraw Hill.
• Johnson, D. G., & Bressler, R. (1990). New Pharmacologic Approaches. In Diabetes Mellitus, Theory and Practice(pp 887-895).
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  Johnson DG, Bressler R: New Pharmacologic Approaches, Chapter 54 in Diabetes Mellitus, Theory and Practice. Ed. Rifkin H, and Porte D, 4th edition. Elsevier, New York, 1990, pp 887 895.
• Johnson, D. G., Boulton, A. J., Levin, S., & Comstock, J. (1990). A multicentre trial of the aldose-reductase inhibitor, tolrestat, in patients with symptomatic diabetic neuropathy. In Diabetologia(pp 431-437).
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  Boulton AJM, Levin S, Comstock J, and the North American Tolrestat in Neuropathy Research group: A multicentre trial of the aldose-reductase inhibitor, tolrestat, in patients with symptomatic diabetic neuropathy. Diabetologia 33:431-437, 1990.
• Krstenansky, J. L., Trivedi, D., Johnson, D. G., & Hruby, V. J. (1986). Conformational considerations in the design of a glucagon analogue with increased receptor binding and adenylate cyclase potencies. In Journal of the American Chemical Society(pp 1696-1698).
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  . J Amer Chem Soc 108:1696 1698, 1986.
• Johnson, D. G. (1982). Diabetic Ketoacidosis. In Management of Diabetes Mellitus(pp 153-174). Boston, Ma: PSG Inc.
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  editors Bressler, R and Johnson, DG. John Wright
• Johnson, D. G. (1982). Drugs that decrease serum lipids. In Cardiovascular Drugs and the Management of Heart Disease(pp 239-248). New York, N.Y: Raven Press.
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  editors Ewy G. and Bressler R
• Johnson, D. G. (1982). Hormonal and Endocrinologic Agents. In Therapeutics in Elderly Patients(pp 337-344). St. Louis, Mo.
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  editors Conrad K and Bressler R. C.V. Mosby
• Johnson, D. G. (1982). Management of hyperlipidemia.. In Cardiovascular Drugs and the Management of Heart Disease.(pp 647-655). New York, N.Y.: Raven Press.
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  editors Ewy, GA and Bressler, R.
• Johnson, D. G. (1982). Pathophysiology of diabetes mellitus. In Management of Diabetes Mellitus(pp 1-13). Boston, Ma: PSG Inc.
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  editors Bressler, R and Johnson, DG.
• Johnson, D. G., & Bressler, R. (1982). Newer pharmacologic approaches.. In Diabetes Mellitus: Theory and Practice. 3rd edition.(pp 975-985). New York, N.Y.: McGraw Hill Book Co.
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  editors Ellenberg M, Rifkin H.
• Hruby, V. J., Bregman, M. D., Johnson, D. G., Ulichny, C., & Trivedi, D. (1981). In vivo and in vitro studies with glucagon inhibitors.. In Peptides: Synthesis Structure Function(pp 813-816).
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  Proc. Seventh American Peptide Symposium. editors Rich, D.H. and Gross, E
• Bressler, R., & Johnson, D. G. (1979). New pharmacologic approaches to the treatment of diabetes mellitus.. In International Congress Series No. 500. Diabetes(pp 629-634). Amsterdam: Excerpta Medica,.
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  editor WK Waldhause

Journals/Publications

• Banner, W., Johnson, D. G., Walson, P. D., & Jung, D. (2016). Effects of single large doses of phenytoin on glucose homeostasis--a preliminary report. Journal of clinical pharmacology, 22(2-3), 79-81.
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  The effects of a loading dose of 15 mg/kg phenytoin by iv infusion on the serum levels of insulin, glucagon, and glucose were investigated in five fasting healthy male volunteers between the ages of 23 and 35 years. Serum glucose concentrations rose immediately after the infusion of phenytoin followed by a significant increase in serum insulin values (P less than 0.05). A slight elevation in mean glucagon concentrations after the infusion was not statistically significant. Further studies are indicated to determine whether phenytoin as used in the treatment of status epilepticus may aggravate the hyperglycemia associated with seizures.
• Johnson, D. G. (2016). Identification of enteric hormones with insulin-releasing activity. Life sciences, 28(15-16), 1841-9.
• Jones, P. P., Van Pelt, R. E., Johnson, D. G., & Seals, D. R. (2004). Role of sympathetic neural activation in age- and habitual exercise-related differences in the thermic effect of food. The Journal of clinical endocrinology and metabolism, 89(10), 5138-44.
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  The thermic effect of food (TEF) declines with advancing age in adult humans but is enhanced in the habitually exercising state. The responsiveness of the sympathetic nervous system (SNS) has been implicated in these differences in TEF. We tested the hypotheses that 1) the reduction in TEF with aging is associated with an attenuated SNS response to acute energy intake; and 2) the greater TEF observed in endurance exercise-trained adults is associated with an augmented SNS response. Four groups of healthy men were studied: 16 young and 11 older sedentary men and nine young and 10 older habitually exercising men. Metabolic rate (indirect calorimetry, ventilated hood), skeletal muscle sympathetic nerve activity (MSNA; peroneal microneurography), and plasma norepinephrine and plasma epinephrine concentrations were measured before and for up to 4 h after ingestion of a carbohydrate drink (2.5 g/kg fat-free mass). TEF was approximately 50% greater in young compared with older men (P < 0.05) and approximately 25% greater in exercising compared with sedentary men (P < 0.05). In contrast, the MSNA, plasma norepinephrine, and plasma epinephrine responses were not different among the four groups. Covarying for MSNA did not significantly alter the observed differences in TEF. Habitual exercise status did not affect the age-associated decline in TEF. These findings demonstrate that altered postprandial whole-body and skeletal muscle SNS activation is not an important mechanism mediating either the reduction in TEF with aging or the augmented TEF associated with the exercise-trained state in healthy men. Differences in beta-adrenergic responsiveness to postprandial sympathoadrenal stimulation and/or nonsympathetic adrenergic influences likely explain the age- and habitual exercise-related differences in TEF.
• Bell, C., Seals, D. R., Monroe, M. B., Day, D. S., Shapiro, L. F., Johnson, D. G., & Jones, P. P. (2001). Tonic sympathetic support of metabolic rate is attenuated with age, sedentary lifestyle, and female sex in healthy adults. The Journal of clinical endocrinology and metabolism, 86(9), 4440-4.
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  We recently demonstrated in young adult humans that the sympathetic nervous system contributes to the control of resting metabolic rate via tonic beta-adrenergic receptor stimulation. In the present follow-up study we determined the respective effects of age, habitual exercise status, and sex on this regulatory mechanism. Resting metabolic rate (ventilated hood, indirect calorimetry) was determined in 55 healthy sedentary or endurance exercise-trained adults, aged 18-35 or 60-75 yr (29 men and 26 women), before (baseline) and during the infusion of either a nonselective beta-adrenergic receptor antagonist (propranolol) or saline (control). Relative to baseline values, during beta-adrenergic receptor antagonism resting metabolic rate adjusted for fat-free mass was reduced to a lesser extent in older (mean +/- SE, -130 +/- 46 kJ/d) compared with young (-297 +/- 46) adults, sedentary (-151 +/- 50) compared with endurance exercise-trained (-268 +/- 46) adults, and women (-105 +/- 33) compared with men (-318 +/- 50; all P < 0.01). Reductions in resting metabolic rate during beta-adrenergic receptor antagonism were positively related to higher baseline resting metabolic rate and plasma catecholamine concentrations and negatively related to adiposity (all P < 0.05). Resting metabolic rate was unchanged in response to saline control in all groups. These results provide experimental support for the hypothesis that aging, sedentary living, and female sex are associated with attenuated sympathetic nervous system support of resting metabolic rate in healthy adult humans.
• Monroe, M. B., Seals, D. R., Shapiro, L. F., Bell, C., Johnson, D. G., & Parker Jones, P. (2001). Direct evidence for tonic sympathetic support of resting metabolic rate in healthy adult humans.. American Journal of Physiology, Endocrinology & Metabilism, E740-E744.
• Dailey, G. E., Boden, G. H., Creech, R. H., Johnson, D. G., Gleason, R. E., Kennedy, F. P., Weinrauch, L. A., Weir, M., & D'Elia, J. A. (2000). Effects of pulsatile intravenous insulin therapy on the progression of diabetic nephropathy. Metabolism: clinical and experimental, 49(11), 1491-5.
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  The purpose of this study was to assess the effects of pulsatile intravenous insulin therapy (PIVIT) on the progression of diabetic nephropathy in patients with type 1 diabetes mellitus (DM). This 18-month multicenter, prospective, controlled study involved 49 type 1 DM patients with nephropathy who were following the Diabetes Control and Complications Trial (DCCT) intensive therapy (IT) regimen. Of these, 26 patients formed the control group (C), which continued on IT, while 23 patients formed the treatment group (T) and underwent, in addition to IT, weekly PIVIT. Blood pressure in all patients was maintained below 140/90 mm Hg on antihypertensive medication, preferentially using angiotensin-converting enzyme (ACE) inhibitors. All study patients were seen in the clinic weekly for 18 months, had monthly glycohemoglobin (HbA1c), and every 3 months, 24-hour urinary protein excretion and creatinine clearance (CrCl) determinations. The HbA1c levels declined from 8.61% +/- 0.33% to 7.68% +/- 0.31% (P = .0028) in the T group and from 9.13% +/- 0.36% to 8.19% +/- 0.33% (P = .0015) in the C group during the study period. CrCl declined significantly in both groups, as expected, but the rate of CrCl decline in the T group (2.21 +/- 1.62 mL/min/yr) was significantly less than in the C group (7.69 +/- 1.88 mL/min/yr, P = .0343). We conclude that when PIVIT is added to IT in type 1 DM patients with overt nephropathy, it appears to markedly reduce the progression of diabetic nephropathy. The effect appears independent of ACE inhibitor therapy, blood pressure, or glycemic control.
• Bressler, R., & Johnson, D. G. (1997). Pharmacological regulation of blood glucose levels in non-insulin-dependent diabetes mellitus. Archives of internal medicine, 157(8), 836-48.
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  Non-insulin-dependent diabetes mellitus is a metabolic disease that is common and is characterized by insulin insufficiency and resistance. Measures such as body weight reduction and exercise improve the metabolic defects, but pharmacological therapy is the most frequently used and successful therapy. The sulphonylureas stimulate insulin secretion. Metformin and troglitazone increase disposal and decrease hepatic glucose output without causing hypoglycemia. Acarbose is a dietary aid that spreads the dietary carbohydrate challenge to endogenous insulin over time. These pharmacological agents, either alone or in combination, can improve blood glucose regulation in patients with non-insulin-dependent diabetes mellitus.
• Bressler, R., & Johnson, D. G. (1996). Oral antidiabetic drug use in the elderly. Drugs & aging, 9(6), 418-37.
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  Non-insulin-dependent diabetes mellitus (NIDDM) is a metabolic disease that is common in the elderly, and is characterised by insulin insufficiency and resistance. Measures such as bodyweight reduction and exercise improve the metabolic defects, but pharmacological therapy is the most frequently used and successful therapy. The sulphonylureas stimulate insulin secretion. Metformin and troglitazone increase glucose disposal and decrease hepatic glucose output without causing hypoglycaemia. Acarbose is a dietary aid that spreads the dietary carbohydrate challenge to endogenous insulin over time. These pharmacological agents, either alone or in combination, should improve blood glucose regulation in patients with NIDDM.
• Massett, M. P., Johnson, D. G., & Kregel, K. C. (1996). Cardiovascular and sympathoadrenal responses to heat stress following water deprivation in rats. The American journal of physiology, 270(3 Pt 2), R652-9.
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  This study was designed to characterize the regional and systemic hemodynamic and sympathoadrenal responses to heating after 24 and 48 h of water deprivation in chloralose-anesthetized, male Sprague-Dawley rats (n = 7 per group). Water deprivation produced significant decreases in body weight of 8.1 and 13.7% in the 24- and 48-h groups (P < 0.05), respectively. After water deprivation, rats were exposed to an ambient temperature of 43 degrees C. After correction for body weight differences, heating rates were faster in the 48-h group compared with both euhydrated and 24-h groups. Mean arterial blood pressure (MAP), heart rate, and colonic (Tco) and tail (Ttail) temperatures increased above baseline in all groups during heating. Renal and mesenteric artery blood flow velocities decreased, and vascular resistances increased in response to heating. Compared with euhydrated controls, 48-h water-deprived rats exhibited attenuated pressor (delta MAP = 36 +/- 3 vs. 18 +/- 3 mmHg) and visceral vasoconstrictor (% delta in mesenteric resistance = 122.6 +/- 27.3 vs. 54.9 +/- 6.9%) responses during heating. Tail-skin blood flow estimated from Ttail was also lower at baseline and the onset of heating in water-deprived rats. However, peak Ttail and Tco values were similar across groups. Plasma catecholamines measured in separate groups of rats (n = 6 per group) were significantly higher at baseline and the end of heating in the 48-h group compared with euhydrated and 24-h groups. Despite this exaggerated sympathoadrenal response, the 48-h group exhibited attenuated hemodynamic responses to nonexertional heating compared with euhydrated and 24-h water-deprived rats. These data suggest that cardiovascular and thermoregulatory adjustments can compensate for small changes in hydration state (i.e., 24 h), but more severe levels of hypohydration significantly alter blood pressure and body temperature regulation during heat stress.
• Van Tine, B. A., Azizeh, B. Y., Trivedi, D., Phelps, J. R., Houslay, M. D., Johnson, D. G., & Hruby, V. J. (1996). Low level cyclic adenosine 3',5'-monophosphate accumulation analysis of [des-His1, des- Phe6, Glu9] glucagon-NH2 identifies glucagon antagonists from weak partial agonists/antagonists. Endocrinology, 137(8), 3316-22.
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  [des-His1, des-Phe6,Glu9]Glucagon-NH2 is a newly designed glucagon antagonist. This analog has a binding IC50 of 48 nM (compared to glucagon IC50 of 1.5 nM) and demonstrates pure antagonism in an adenylate cyclase assay. Although the number of glucagon antagonists has grown rapidly recently, closer examination suggested that many of these antagonists retained very low, almost imperceptible levels of cAMP accumulation that were sufficient to elicit an in vivo biological response. To investigate more carefully this secondary biological signal, we measured cAMP accumulation in a revised assay using isolated hepatocytes in the presence of the phosphodiesterase (PDE) inhibitor Rolipram. The PDE inhibitors Rolipram and isobutyl-1-methylxanthine (IBMX) increased the sensitivity of the cAMP accumulation assay from approximately 10-fold for the native hormone to 35-fold above basal levels. On the other hand, amrinone, another PDE inhibitor, did not affect the cAMP accumulation caused by glucagon. The use of PDE inhibitors indicated that three glucagon analogs that had previously been reported to have strong antagonist properties in classical adenylate cyclase assays were actually weak partial agonists in this new assay system. [N alpha-Trinitrophenyl-His1, homo-Arg12]glucagon, [des-amino-His1,D-Phe4,Tyr5, Arg12, Lys17,18,Glu21]glucagon, and [des-His1,Glu9]glucagon-NH2 demonstrated 233%, 21%, and 5.5% cAMP accumulation relative to the native hormone in the presence of 25 microM Rolipram. On the other hand, [des-His1,des-Phe6,Glu9]glucagon-NH2, a newly designed glucagon antagonist, did not activate adenylate cyclase in the presence of Rolipram up to a maximal physiological concentration of 1 microM, indicating that it was a pure antagonist of glucagon-induced adenylate cyclase activity and also the first one in this class. This compound and others were tested in a glycogen phosphorylase assay. As [des-His1,des- Phe6,Glu9]glucagon-NH2 did not activate phosphorylase activity, it was chosen as our candidate for in vivo testing in streptozotocin-induced diabetic rats. An initial dose of 0.75 mg/kg was found to cause the greatest lowering of blood glucose levels (to 63% of the initial levels in 15 min) when the bolus was followed by continuous infusion of 25 micrograms/kgxmin for 1 h.
• Davy, K. P., Johnson, D. G., & Seals, D. R. (1995). Cardiovascular, plasma norepinephrine, and thermal adjustments to prolonged exercise in young and older healthy humans. Clinical physiology (Oxford, England), 15(2), 169-81.
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  We tested the hypothesis that the whole body energy expenditure, plasma norepinephrine, cardiovascular, and internal body temperature adjustments to prolonged submaximal exercise (i.e., 'cardiovascular drift') performed at the same per cent of peak oxygen uptake (per cent VO2peak) under thermoneutral ambient conditions would be smaller in older compared to young non-physically trained men. Healthy young (25 +/- 1 years; VO2max = 49.3 +/- 1.6 ml kg-1 min-1; n = 6) and older (66 +/- 2 years; VO2max = 31.5 +/- 2.3 ml kg-1 min-1; n = 6) untrained men with similar levels of chronic physical activity were studied during pre-exercise standing rest and serially during 45 min of constant load treadmill walking at approximately 65% VO2peak (Ta = approximately 23 degrees C; approximately 40 RH). There were no group differences at rest. From rest to 5 min of exercise, the increases in heart rate were less (P < 0.05), the changes in arterial blood pressure and per cent delta blood volume were not different, and the rise in plasma norepinephrine concentration was greater (P < 0.05) in the older men vs. young controls. Consistent with our hypothesis, the increases in rectal temperature and plasma norepinephrine concentrations from 5 to 45 min of exercise were smaller in the older men (1.06-0.18 vs. 1.46 +/- 0.16 degrees C and 110 +/- 132 vs. 443 +/- 189%, respectively, P < 0.05). In contrast, the progressive increases in VO2, heart rate, and perceived effort, as well as the time-dependent reductions in systolic, mean and diastolic arterial blood pressure and per cent delta blood volume, were not different in the two groups. Thus, the whole body energy expenditure and selected cardiovascular adjustments to prolonged submaximal treadmill exercise performed at the same per cent VO2peak under comfortable ambient conditions are not different in healthy, physical activity-matched young and older men, despite a smaller elevation in internal body temperature in the latter.
• Ng, A. V., Johnson, D. G., Callister, R., & Seals, D. R. (1995). Muscle sympathetic nerve activity during postural change in healthy young and older adults. Clinical autonomic research : official journal of the Clinical Autonomic Research Society, 5(1), 57-60.
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  Recent evidence suggests that during orthostatic stress the reflex increase in muscle sympathetic nerve activity may be diminished in older adults. To test this hypothesis, we measured muscle sympathetic nerve activity, plasma noradrenaline concentrations, heart rate, and arterial blood pressure in twelve young (mean, 25 years; range, 19-29 years) adults and 14 older (mean 64 years; range, 60-74 years) healthy adults, while supine and during upright sitting. Supine control levels of muscle sympathetic nerve activity were higher in the older subjects (35 +/- 1 vs. 25 +/- 1 bursts/min, p < 0.05), but there were no differences in plasma noradrenaline concentrations, heart rate or arterial pressure. Despite higher supine control levels in the older group, the absolute unit increases in muscle sympathetic nerve activity in response to upright sitting (p < 0.05 vs. control) were not different in the two groups (7 +/- 1 vs. 7 +/- 1 bursts/min), nor were the increases in plasma noradrenaline concentrations. Heart rate did not increase above supine control in response to sitting in either group. Arterial pressure increased slightly (p < 0.05, supine vs. control), but there were no age-related differences. These results indicate that, contrary to recent findings, the reflex increases in muscle sympathetic nerve activity and plasma noradrenaline concentrations and regulation of arterial pressure during this natural orthostatic stress are well preserved in older healthy men and women.
• Ng, A. V., Callister, R., Johnson, D. G., & Seals, D. R. (1994). Endurance exercise training is associated with elevated basal sympathetic nerve activity in healthy older humans. Journal of applied physiology (Bethesda, Md. : 1985), 77(3), 1366-74.
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  We tested the hypothesis that endurance training is associated with altered basal levels of muscle sympathetic nerve activity (MSNA) and responses to acute stress in healthy older adults. MSNA (peroneal microneurography) and plasma norepinephrine (NE) concentrations were measured during supine rest, a cold pressor test, and isometric handgrip (40% maximal voluntary force to exhaustion) in 16 older masters endurance athletes [10 men, 6 women; 66 +/- 1 (SE) yr] and 15 healthy normotensive untrained control subjects (9 men, 6 women; 65 +/- 1 yr). The athletes had higher levels of estimated daily energy expenditure and maximal oxygen uptake and lower levels of resting heart rate and body fat than the control subjects (all P < 0.05). MSNA during supine rest was elevated in the athletes whether expressed as burst frequency (43 +/- 2 vs. 32 +/- 3 bursts/min, respectively; P < 0.05) or burst incidence (75 +/- 4 vs. 52 +/- 5 bursts/100 heartbeats, respectively; P < 0.01). These whole group differences were due primarily to markedly higher levels of MSNA in the athletic vs. untrained women (48 +/- 4 vs. 25 +/- 3 bursts/min, 82 +/- 3 vs. 38 +/- 3 bursts/100 heartbeats, respectively, P < 0.001). In contrast, basal plasma NE concentrations were not significantly different in the athletes vs. control subjects. The MSNA and plasma NE responses to acute stress tended to be greater in the athletes. These findings indicate that vigorous regular aerobic exercise is associated with an elevated level of MSNA at rest and a tendency for an enhanced response to acute stress in healthy normotensive older humans.
• Ng, A. V., Callister, R., Johnson, D. G., & Seals, D. R. (1994). Sympathetic neural reactivity to stress does not increase with age in healthy humans. The American journal of physiology, 267(1 Pt 2), H344-53.
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  Sympathetic nervous system reactivity to stress is though to increase with age in humans. We tested this hypothesis by recording postganglionic sympathetic nerve activity to skeletal muscle (MSNA) (peroneal microneurography) and by measuring plasma norepinephrine concentrations (PNE), heart rate, and arterial pressure before (prestress control) and during cognitive challenge (mental arithmetic and colored word test), thermal stress (i.e., the cold pressor test), and exhaustive isometric handgrip exercise (40% of maximum voluntary force)/postexercise ischemia in 15 older (60-74 yr, mean +/- SE = 64 +/- 1) and 15 young (19-30 yr, mean +/- SE = 25 +/- 1) healthy men and women (8 males, 7 females each). The initial prestress control level of MSNA was higher in the older subjects (P < 0.01 vs. young), but there were no significant differences for PNE, heart rate, or arterial pressure. The MSNA and PNE responses to mental stress were small and not different in the two groups. MSNA and PNE increased markedly in response to the cold pressor test and isometric handgrip exercise/post exercise ischemia in both groups. The absolute unit increases in MSNA were similar in the two groups, but the relative (percentage) increases were actually smaller in the older subjects (P < 0.05 vs. young) due to their elevated baseline levels. The stress-evoked increases in arterial pressure were similar in the groups, but the older subjects tended to demonstrate smaller increases in heart rate. In general, no gender differences were noted in either age group. These findings fail to support the long-held concept that stress-induced sympathetic nervous system stimulation becomes exaggerated with age. Thus, sympathetic neural hyperreactivity does not appear to be a fundamental property of the aging process in humans.
• Tsai, A., Cowan, M. R., Johnson, D. G., & Brannon, P. M. (1994). Regulation of pancreatic amylase and lipase gene expression by diet and insulin in diabetic rats. The American journal of physiology, 267(4 Pt 1), G575-83.
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  Although insulin has been proposed to mediate the dietary regulation of pancreatic amylase, its interaction with diet in the regulation of amylase and lipase is not well understood and was examined in diabetic rats fed diets high in carbohydrate (HC), protein (HP), or fat (HF) and treated with insulin. Diabetes, independent of diet, decreased amylase content (97%; P < 0.0001) and mRNA (90%; P < 0.0001), but insulin only restored amylase content and mRNA to respective dietary control values. Diabetes, independent of diet, also increased lipase mRNA 1.6-fold (P < 0.004) but interacted (P < 0.0003) with diet on lipase content, resulting in opposite effects in HC- (increased 202%) and HF-diabetic rats (decreased 40%). Insulin partially restored lipase content and mRNA to respective dietary control values. Diet, independent of diabetes, regulated amylase content (P < 0.0001) and mRNA (P < 0.0003), which were three- to fourfold greater in HC- than in HF-fed rats, and lipase content (P < 0.001) and mRNA [rat pancreatic lipase 1 (rPL-1), P < 0.04; rPL-3, P < 0.0001], which were 1.8-fold greater in HF- than in HC- or HP-fed rats. Insulin failed to stimulate maximal amylase gene expression in HP- or HF-fed diabetic rats, suggesting that it is necessary, but not sufficient, for this dietary regulation. Differential regulation of lipase activity and mRNA by diet and insulin raises the possibility that lipase gene expression is regulated by a complex interaction of diet and insulin.
• Hruby, V. J., Gysin, B., Trivedi, D., & Johnson, D. G. (1993). New glucagon analogues with conformational restrictions and altered amphiphilicity: effects on binding, adenylate cyclase and glycogenolytic activities. Life sciences, 52(10), 845-55.
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  In an effort to obtain highly potent glucagon antagonists, we have investigated glucagon (1) structure-function relationships utilizing the following design principles: (1) structural changes known to lead to partial agonist activities; (2) conformational restrictions; (3) changes in the conformational probabilities of the primary sequence; and (4) increased amphiphilicity. In this report we present the total synthesis, purification, receptor binding, adenylate cyclase activity, in vivo glycogenolytic activity and CD spectrum of the following four glucagon analogues: [Ahx17,18]glucagon (2), [D-Phe4,Tyr5, 3,5-diiodo-Tyr10,Arg12,Lys17,18,Glu21]glucagon (3), [Asp9,Lys12,Lys17,18,Glu21]glucagon 4, and [Glu15,Lys17,18]glucagon 5. Compound 2 binds exclusively to the high affinity receptor and compound 3 was a highly potent antagonist with respect to adenylate cyclase activity. Analog 4 showed distinct biphasic binding (IC50 5.6 nM and 630 nM), with only the low affinity binding leading to adenylate cyclase activity. Furthermore in analogue 5 receptor binding and adenylate cyclase activity were dissociated by a factor of 5. The results are consistent with a multistep binding mechanism in which glucagon interacts first nonspecifically with the anisotropic interphase of the cell membrane, followed by a conformational transition which occurs in the sequences 10-14 and 15-18 when the membrane bound peptide binds to its receptor.
• Kregel, K. C., Johnson, D. G., & Seals, D. R. (1993). Tissue-specific noradrenergic activity during acute heat stress in rats. Journal of applied physiology (Bethesda, Md. : 1985), 74(4), 1988-93.
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  The purpose of this study was to determine whether nonexertional heat stress alters the behavior of internal organ and skeletal muscle sympathetic nervous system (SNS) activity in unrestrained conscious rats. Norepinephrine (NE) synthesis was blocked with alpha-methyl-p-tyrosine, and the rate of decline in tissue NE concentration after synthesis blockade was used to estimate SNS activity in the left ventricle, kidney, liver, adrenal gland, and soleus and extensor digitorum longus muscles of the hindlimb. Male Sprague-Dawley rats (250-320 g) were maintained in thermoneutral control conditions (ambient temperature = 24 degrees C, n = 10) or exposed to an ambient temperature of 42 degrees C until a colonic temperature (Tc) of 39.5 or 41.0 degrees C (n = 10 each) was attained. During heating, as Tc rose from control levels (approximately 38 degrees C) to 41.0 degrees C, mean arterial pressure and heart rate increased from 120 +/- 3 to 141 +/- 3 mmHg and from 381 +/- 4 to 420 +/- 5 beats/min, respectively (P < 0.05). There was a strong trend for increased NE turnover rates in the left ventricle, liver, and adrenal gland in NE synthesis-blocked rats attaining a Tc of 39.5 degrees C compared with the normothermic values, whereas the turnover rate in the kidney was significantly elevated at this level of hyperthermia (126%) vs. the control condition. In animals heated to a Tc of 41.0 degrees C, the NE turnover rate was markedly increased in the left ventricle (590%), kidney (531%), liver (262%), and adrenal gland (602%) compared with normothermic control values.(ABSTRACT TRUNCATED AT 250 WORDS)
• Ng, A. V., Callister, R., Johnson, D. G., & Seals, D. R. (1993). Age and gender influence muscle sympathetic nerve activity at rest in healthy humans. Hypertension, 21(4), 498-503.
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  Muscle sympathetic nerve activity at rest increases with age in humans. The respective influences of the aging process per se and gender on this increase and whether age and gender effects on muscle sympathetic nerve activity can be identified with plasma norepinephrine concentrations, however, have not been established. To examine these issues, nine young women (aged 24 +/- 1 years; mean +/- SEM), eight young men (aged 26 +/- 1 years), seven older women (aged 63 +/- 1 years), and eight older men (aged 66 +/- 1 years) were studied. All were healthy, normotensive (blood pressure < 140/90 mm Hg), nonobese (< 20% above ideal weight), unmedicated, nonsmokers engaged in minimal to recreational levels of chronic physical activity. Arterial blood pressure (manual sphygmomanometry, brachial artery), heart rate, muscle sympathetic nerve activity (peroneal microneurography), and antecubital venous plasma norepinephrine concentrations (radioenzymatic assay) were determined during quiet supine resting conditions. Body weight was higher in men, but there were no age-related differences, whereas estimated body fat (sum of skinfolds) was higher in women and in the older groups (p < 0.05). Estimated daily energy expenditure, arterial blood pressure, and heart rate were not different among the groups. Both muscle sympathetic nerve activity burst frequency and burst incidence at rest were progressively higher in the young women, young men, older women, and older men (10 +/- 1 versus 18 +/- 2 versus 25 +/- 3 versus 39 +/- 5 bursts/min and 16 +/- 1 versus 30 +/- 4 versus 40 +/- 3 versus 61 +/- 6 bursts/100 heartbeats, respectively; all p < 0.05 versus each other).(ABSTRACT TRUNCATED AT 250 WORDS)
• Taylor, J. A., Hand, G. A., Johnson, D. G., & Seals, D. R. (1992). Augmented forearm vasoconstriction during dynamic exercise in healthy older men. Circulation, 86(6), 1789-99.
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  We tested the hypothesis that the nonactive limb vasoconstriction evoked during large-muscle dynamic exercise becomes augmented with aging in humans.
• Taylor, J. A., Hand, G. A., Johnson, D. G., & Seals, D. R. (1992). Sympathoadrenal-circulatory regulation of arterial pressure during orthostatic stress in young and older men. The American journal of physiology, 263(5 Pt 2), R1147-55.
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  Our purpose was to test the hypothesis that human aging alters sympathoadrenal-circulatory control of arterial blood pressure during orthostasis. Plasma catecholamine and hemodynamic adjustments to two different forms of orthostatic stress, lower body suction (-10 to -50 mmHg) and standing, were determined in 14 young (26 +/- 1 yr) and 13 older (64 +/- 1) healthy, normally active men. During quiet supine rest, cardiac output tended to be lower and systemic vascular resistance higher in the older men, but no other differences were observed. On average, arterial blood pressure was well maintained during both forms of orthostasis in the two groups; the older men actually demonstrated better maintenance of pressure (P < 0.05) and a lesser incidence of orthostatic hypotension than the young men during lower body suction. Despite a blunted reflex tachycardia during orthostatic stress (P < 0.05), cardiac output tended to decrease less in the older men because of a smaller decline in stroke volume (P < 0.05, suction only), whereas the reflex increases in systemic vascular resistance were not different in the two groups. The whole forearm vasoconstrictor response tended to be attenuated in the older men during lower body suction, but was identical in the two groups with standing. Forearm skin vascular resistance was unaltered during lower body suction in both groups. Orthostasis-evoked increases in antecubital venous plasma norepinephrine concentrations were similar in the young and older men, whereas little or no increases in plasma epinephrine concentrations were observed in either group.(ABSTRACT TRUNCATED AT 250 WORDS)
• Kregel, K. C., Overton, J. M., Johnson, D. G., Tipton, C. M., & Seals, D. R. (1991). Mechanism for pressor response to nonexertional heating in the conscious rat. Journal of applied physiology (Bethesda, Md. : 1985), 71(1), 192-6.
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  The purpose of this study was to determine the systemic hemodynamic mechanism(s) underlying the pressor response to nonexertional heat stress in the unrestrained conscious rat. After a 60-min control period [ambient temperature (Ta) 24 degrees C], male Sprague-Dawley rats (260-340 g) were exposed to a Ta of 42 degrees C until a colonic temperature (Tc) of 41 degrees C was attained. As Tc rose from control levels (38.1 +/- 0.1 degrees C) to 41 degrees C, mean arterial blood pressure (carotid artery catheter, n = 33) increased from 124 +/- 2 to 151 +/- 2 mmHg (P less than 0.05). During this period, heart rate increased (395 +/- 5 to 430 +/- 6 beats/min, P less than 0.05) and stroke volume remained unchanged. As a result, ascending aorta blood flow velocity (Doppler flow probe, n = 8), used as an index of cardiac output, did not change from control levels during heating, but there was a progressive Tc-dependent increase in systemic vascular resistance (+30% at end heating, P less than 0.05). This systemic vasoconstrictor response was associated with decreases in blood flow (-31 +/- 9 and -21 +/- 5%) and increases in vascular resistance (94 +/- 16 and 53 +/- 8%; all P less than 0.05) in the superior mesenteric and renal arteries (n = 8 each) and increases in plasma norepinephrine (303 +/- 37 to 1,237 +/- 262 pg/ml) and epinephrine (148 +/- 28 to 708 +/- 145 pg/ml) concentrations (n = 12, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
• Seals, D. R., Johnson, D. G., & Fregosi, R. F. (1991). Hyperoxia lowers sympathetic activity at rest but not during exercise in humans. The American journal of physiology, 260(5 Pt 2), R873-8.
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  The primary aim of this study was to determine the influence of systemic hyperoxia on sympathetic nervous system behavior at rest and during submaximal exercise in humans. In seven healthy subjects (aged 19-31 yr) we measured postganglionic sympathetic nerve activity to skeletal muscle (MSNA) in the leg, antecubital venous norepinephrine concentrations, heart rate, and arterial blood pressure during normoxic rest (control) followed by 3- to 4-min periods of either hyperoxic (100% O2 breathing) rest, normoxic exercise (rhythmic handgrips at 50% of maximum force), or hyperoxic exercise. During exercise, isocapnia was maintained by adding CO2 to the inspirate as necessary. At rest, hyperoxia lowered MSNA burst frequency (12-42%) and total activity (6-42%) in all subjects; the average reductions were 25 and 23%, respectively (P less than 0.05 vs. control). Heart rate also decreased during hyperoxia (6 +/- 1 beats/min, P less than 0.05), but arterial blood pressure was not affected. During hyperoxic compared with normoxic exercise, there were no differences in the magnitudes of the increases in MSNA burst frequency or total activity, plasma norepinephrine concentrations, or mean arterial blood pressure. In contrast, the increase in heart rate during hyperoxic exercise (13 +/- 2 beats/min) was less than the increase during normoxic exercise (20 +/- 2 beats/min; P less than 0.05). We conclude that, in healthy humans, systemic hyperoxia 1) lowers efferent sympathetic nerve activity to skeletal muscle under resting conditions without altering venous norepinephrine concentrations and 2) has no obvious modulatory effect on the nonactive muscle sympathetic nerve adjustments to rhythmic exercise.
• Seals, D. R., Johnson, D. G., & Fregosi, R. F. (1991). Hypoxia potentiates exercise-induced sympathetic neural activation in humans. Journal of applied physiology (Bethesda, Md. : 1985), 71(3), 1032-40.
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  Our purpose was to test the hypothesis that hypoxia potentiates exercise-induced sympathetic neural activation in humans. In 15 young (20-30 yr) healthy subjects, lower leg muscle sympathetic nerve activity (MSNA, peroneal nerve; microneurography), venous plasma norepinephrine (PNE) concentrations, heart rate, and arterial blood pressure were measured at rest and in response to rhythmic handgrip exercise performed during normoxia or isocapnic hypoxia (inspired O2 concn of 10%). Study I (n = 7): Brief (3-4 min) hypoxia at rest did not alter MSNA, PNE, or arterial pressure but did induce tachycardia [17 +/- 3 (SE) beats/min; P less than 0.05]. During exercise at 50% of maximum, the increases in MSNA (346 +/- 81 vs. 207 +/- 14% of control), PNE (175 +/- 25 vs. 120 +/- 11% of control), and heart rate (36 +/- 2 vs. 20 +/- 2 beats/min) were greater during hypoxia than during normoxia (P less than 0.05), whereas the arterial pressure response was not different (26 +/- 4 vs. 25 +/- 4 mmHg). The increase in MSNA during hypoxic exercise also was greater than the simple sum of the separate responses to hypoxia and normoxic exercise (P less than 0.05). Study II (n = 8): In contrast to study I, during 2 min of exercise (30% max) performed under conditions of circulatory arrest and 2 min of postexercise circulatory arrest (local ischemia), the MSNA and PNE responses were similar during systemic hypoxia and normoxia. Arm ischemia without exercise had no influence on any variable during hypoxia or normoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
• Taylor, J. A., Hand, G. A., Johnson, D. G., & Seals, D. R. (1991). Sympathoadrenal-circulatory regulation during sustained isometric exercise in young and older men. The American journal of physiology, 261(5 Pt 2), R1061-9.
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  The aim of this study was to test the hypothesis that the arterial blood pressure, vasoconstrictor, and sympathoadrenal adjustments to sustained submaximal isometric exercise become augmented with advancing age in humans. Fourteen young (26 +/- 1 yr) and 14 older (66 +/- 1 yr) healthy males performed isometric handgrip exercise at 30% of maximal voluntary force until exhaustion (inability to maintain target force). Maximal handgrip force was quite similar in the young and older subjects (402 +/- 20 vs. 392 +/- 20 N, respectively). The two groups did not differ significantly on any variable at rest. During sustained handgrip to exhaustion, peak levels of both perceived exertion and contracting forearm electromyographic activity were similar in the young and older men, suggesting equivalent voluntary efforts. Exercise time was not different in the two groups (315 +/- 27 s in young vs. 339 +/- 17 s in older men). Throughout exercise the increases in arterial blood pressure were very similar in the young and older subjects. Heart rate increased less (P less than 0.05), but stroke volume (impedance cardiography) tended to decrease less (not significant) in the older men; thus the increases in cardiac output were not different in the two groups. During the latter portion of exercise, systemic vascular resistance tended to increase in both the young and older men, with no significant group differences. The blood flow responses in the whole calf (venous occlusion plethysmography) and the calf skin (laser-Doppler velocimetry) were similar in the young and older subjects, as were the corresponding increases in vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
• Kregel, K. C., Johnson, D. G., Tipton, C. M., & Seals, D. R. (1990). Arterial baroreceptor reflex modulation of sympathetic-cardiovascular adjustments to heat stress. Hypertension, 15(5), 497-504.
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  The purpose of this study was to determine if the arterial baroreceptor reflexes modulate the sympathocirculatory responses to acute heat stress. To address this, arterial pressure, heart rate, mesenteric and renal blood flow velocity (Doppler flow probes), arterial plasma norepinephrine, and colonic temperature were measured before and during whole body heating (42 degrees C ambient temperature) in groups of conscious, unrestrained rats with (sham) or without (sinoaortic deafferentation) intact arterial baroreceptor reflexes. Heating was stopped when a colonic temperature of 41 degrees C was attained. Baseline levels of arterial pressure were similar in the two groups, whereas heart rate was elevated in deafferented versus sham-operated rats (p less than 0.01). The increases above baseline for both arterial pressure (73 +/- 4 vs. 27 +/- 2 mm Hg) and heart rate (127 +/- 10 vs. 33 +/- 5 beats/min) were threefold to fourfold greater at the end of heating in the deafferented versus the sham group (p less than 0.01). Declines in mesenteric and renal blood flow were similar in the two groups during heating; however, deafferented rats had greater increases in both mesenteric and renal vascular resistance (p less than 0.05). Plasma norepinephrine was elevated at baseline in deafferented versus sham rats and increased in both groups during heating (p less than 0.01). The magnitude of the increase in plasma norepinephrine from baseline to 41 degrees C was fivefold greater in the deafferented versus the sham rats (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
• Kregel, K. C., Johnson, D. G., Tipton, C. M., & Seals, D. R. (1990). Cardiovascular-sympathetic adjustments to nonexertional heat stress in mature and senescent Fischer 344 rats. Journal of applied physiology (Bethesda, Md. : 1985), 69(6), 2043-9.
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  The purpose of this study was to test the hypothesis that the cardiovascular-sympathetic nervous system adjustments during nonexertional heat stress are exaggerated in senescent (S, 24 mo) vs. mature (M, 12 mo) conscious unrestrained Fischer 344 rats. During two separate trials (48 h apart), each animal was exposed to an ambient temperature (Ta) of 42 degrees C until a colonic temperature (Tco) of 41 degrees C was attained and then cooled at a Ta of 26 degrees C until Tco returned to the initial control level. Trial 1: heart rate (HR), mean arterial blood pressure (MAP), and arterial plasma concentrations of norepinephrine (NE), epinephrine (E), and lactate (La) were similar between the S and M groups during the baseline (control) period. The absolute increases in HR, MAP, NE, and E from the control period to the end of heating were of similar magnitudes between groups; however, La increased more in the S than M animals (P less than 0.05). During recovery, the declines toward control levels for all variables were similar or even more rapid in the S vs. M animals (P less than 0.05). Trial 2: the changes in HR and MAP during heating were similar to those observed in trial 1 in both groups. Generally, NE and E control levels were elevated in both groups compared with those in trial 1. The absolute increases in NE during heating were similar to trial 1 in both groups, whereas E increased to a greater extent than in trial 1 in the S animals (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
• Rowell, L. B., Johnson, D. G., Chase, P. B., Comess, K. A., & Seals, D. R. (1989). Hypoxemia raises muscle sympathetic activity but not norepinephrine in resting humans. Journal of applied physiology (Bethesda, Md. : 1985), 66(4), 1736-43.
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  The experimental objective was to determine whether moderate to severe hypoxemia increases skeletal muscle sympathetic nervous activity (MSNA) in resting humans without increasing venous plasma concentrations of norepinephrine (NE) and epinephrine (E). In nine healthy subjects (20-34 yr), we measured MSNA (peroneal nerve), venous plasma levels of NE and E, arterial blood pressure, heart rate, and end-tidal O2 and CO2 before (control) and during breathing of 1) 12% O2 for 20 min, 2) 10% O2 for 20 min, and 3) 8% O2 for 10 min--in random order. MSNA increased above control in five, six, and all nine subjects during 12, 10, and 8% O2, respectively (P less than 0.01), but only after delays of 12 (12% O2) and 4 min (8 and 10% O2). MSNA (total activity) rose 83 +/- 20, 260 +/- 146, and 298 +/- 109% (SE) above control by the final minute of breathing 12, 10, and 8% O2, respectively. NE did not rise above control at any level of hypoxemia; E rose slightly (P less than 0.05) at one time only with both 10 and 8% O2. Individual changes in MSNA during hypoxemia were unrelated to elevations in heart rate or decrements in blood pressure and end-tidal CO2--neither of which always fell. We conclude that in contrast to some other sympathoexcitatory stimuli such as exercise or cold stress, moderate to severe hypoxemia increases leg MSNA without raising plasma NE in resting humans.
• Johnson, D. G. (1988). New drugs for people with type II diabetes. Diabetes Forecast, 64.
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  Diabetes Forecast 40:64, 1988.
• McKee, R. L., Hruby, V. J., Trivedi, D. B., Johnson, D. G., Gandolfi, A. J., Krumdieck, C. L., & Brendel, K. (1988). Perifused precision-cut liver slice system for the study of hormone-regulated hepatic glucose metabolism. Journal of pharmacological methods, 19(4), 339-54.
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  A nonrecirculatory perfusion system for precision-cut rat liver slices has been developed and utilized for investigating hormone-regulated hepatic glucose metabolism. In this system, slices are cultured in a highly controlled environment and exhibit excellent retention of viability as judged by their maintenance of intracellular potassium and glycogen contents. Using this system, the complex physiological phenomenon of hormone-regulated glycogenolysis was investigated at both extra- and intracellular sites. Specifically, the sensitive responses of intracellular cyclic AMP (cAMP) production, activation of cyclic AMP-dependent protein kinase, and production of glucose upon glucagon stimulation have been measured. The maximal responses observed for these parameters were either equal to or greater than those previously reported for either isolated hepatocytes or perfused livers, demonstrating the sensitivity of this technique. Upon dose-response examination of glucagon challenge, it was observed that high doses of glucagon (greater than 16 nM) stimulate glucose production by activating the cAMP-second messenger cascade. In contrast, low doses (less than 4 nM) stimulate this process without production of intracellular cAMP or activation of cAMP-dependent protein kinase, suggesting the operation of cAMP-independent messenger. Since this system permits measurements of parameters common to many cellular processes, this methodology is suitable for addressing both pharmacological and toxicological questions.
• Brendel, K., McKee, R. L., Hruby, V. J., Johnson, D. G., Gandolfi, A. J., & Krumdieck, C. L. (1987). Precision cut tissue slices in culture: a new tool in pharmacology. Proceedings of the Western Pharmacology Society, 30, 291-3.
• Conrad, K. A., Fagan, T. C., Mayshar, P., Davis, T. P., & Johnson, D. G. (1987). Antihypertensive effects of parenteral nicardipine alone and in combination with captopril. Clinical pharmacology and therapeutics, 42(1), 113-8.
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  We studied the safety and efficacy of intravenous nicardipine alone and in combination with oral captopril. Sixteen patients with essential hypertension received a single oral dose of captopril, 50 mg, to be certain that excessive hypotension would not occur. Nicardipine was given intravenously as a 2 mg bolus, followed by an infusion at a rate designed to lower the supine diastolic blood pressure at least 10 mm Hg; then oral captopril, 50 mg, or placebo was given. The next week, nicardipine was again infused, but the alternate oral treatment was given. Intravenous nicardipine reduced blood pressure from 156 +/- 15/101 +/- 5 mm Hg (mean arterial blood pressure 120 +/- 6 mm Hg) to 140 +/- 11/88 +/- 4 mm Hg (mean arterial blood pressure 105 +/- 5 mm Hg). When captopril was added to nicardipine, the mean arterial blood pressure fell an additional 8 mm Hg but the heart rate did not increase. The combination of angiotensin-converting enzyme inhibition and calcium channel blockage produces additive antihypertensive effects without additional reflex tachycardia.
• Gysin, B., Johnson, D. G., Trivedi, D., & Hruby, V. J. (1987). Synthesis of two glucagon antagonists: receptor binding, adenylate cyclase, and effects on blood plasma glucose levels. Journal of medicinal chemistry, 30(8), 1409-15.
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  In diabetes mellitus, hyperglycemia is often associated with elevated levels of glucagon in the blood. This suggests that glucagon is a contributing factor in the metabolic abnormalities of diabetes mellitus. A glucagon-receptor antagonist would provide direct evidence for glucagon's role in diabetes mellitus. On the basis of careful consideration of conformational, amphiphilic, and structural factors, we have synthesized two new glucagon analogues with antagonist biological activities by using solid-phase methodology. These two new analogues, [Asp3,D-Phe4,Ser5,Lys17,18,Glu21]glucagon (2) and [D-Phe4,Tyr5,3,5-I2-Tyr10,Arg12,Lys17,18,G lu21]glucagon (3) had IC50 values 5.4% and 50% those of glucagon, respectively, and showed no measurable adenylate cyclase activity. When tested in normal rats, 2 lowered plasma glucose levels and suppressed glucagon-mediated hyperglycemia 105 +/- 8%, back to basal levels. Analogue 3, which lowered the basal adenylate cyclase activity in rat liver plasma membranes, increased plasma glucose levels at very high concentration in vivo and inhibited glucagon-mediated hyperglycemia in normal rats by 50%. However, neither of the new glucagon antagonists lowered the plasma glucose levels of diabetic animals. The data would suggest these new glucagon-receptor antagonists may have two actions: (a) in normal rats they can act as standard glucagon-receptor inhibitors of glucagon-mediated glycogenolysis; (b) in diabetic rats, however, because of the low levels of glycogen in the liver, the antagonists apparently have little or no antagonist effect or enhancement on glucagon-mediated glucose production.
• Johnson, D. G. (1987). Lipid metabolism and therapy of hyperlipidemia. American Association for Clinical Chemistry, 1-4.
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  Am Assoc Clin Chem Endo 5:1 4, 1987.
• Lee, R. W., Gay, R. G., Moffett, C., Johnson, D. G., & Goldman, S. (1987). Atrial natriuretic peptide levels during development of chronic heart failure after myocardial infarction in rats. Life sciences, 40(20), 2025-30.
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  Serum levels of atrial natriuretic peptide (ANP) are elevated in chronic heart failure presumably due to dilatation of the left atrium resulting from increases in intracardiac pressures. To define the time course of changes in serum ANP levels and to determine the relationship to left ventricular end-diastolic pressure, rats were subjected to coronary artery ligation to produce myocardial infarction and left ventricular failure. Atrial natriuretic peptide levels were measured weekly for four weeks thereafter. In rats with myocardial infarction and elevation of left ventricular end-diastolic pressure there was no change in ANP levels at 7 and 14 days. However, at day 21 and 28, ANP levels were elevated more than 3 fold. There was a correlation between ANP levels and left ventricular end-diastolic pressures. There was no correlation between ANP levels and right atrial pressures or serum sodium concentrations. We conclude that the chronic elevation of left ventricular end-diastolic pressure is required to produce an increase in ANP after myocardial infarction which results in chronic heart failure.
• Gysin, B., Trivedi, D., Johnson, D. G., & Hruby, V. J. (1986). Design and synthesis of glucagon partial agonists and antagonists. Biochemistry, 25(25), 8278-84.
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  The hyperglycemia and ketosis of diabetes mellitus are generally associated with elevated levels of glucagon in the blood. This suggests that glucagon is a contributing factor in the metabolic abnormalities of diabetes mellitus. A glucagon-receptor antagonist might provide important evidence for glucagons's role in this disease. In this work we describe how we combined structural modifications that led to glucagon analogues with partial agonist activity to give glucagon analogues that can act as competitive antagonists of glucagon-stimulated adenylate cyclase activity. Using solid-phase synthesis methodology and preparative reverse-phase high-performance liquid chromatography, we synthesized the following seven glucagon analogues and obtained them in high purity: [D-Phe4,Tyr5,Arg12]glucagon (2); [D-Phe4,Tyr5,Lys17,18]glucagon (3); [Phe1,Glu3,Lys17,18]glucagon (4); [Glu3,Val5,Lys17,18]glucagon (5); [Asp3,D-Phe4,Ser5,Lys17,18]glucagon (6); I4-[Asp3,D-Phe4,Ser5,Lys17,18]glucagon (7); [Pro3]glucagon (8). Purity was assessed by enzymatic total hydrolysis, by chymotryptic peptide mapping, and by reverse-phase high-performance liquid chromatography. The new analogues were tested for specific binding, for their effect on the adenylate cyclase activity in rat liver membranes, and for their effect on the blood glucose levels in normal rats relative to glucagon. Analogues showing no adenylate cyclase activity were examined for their ability to act as antagonists by displacing glucagon-stimulated adenylate cyclase dose-response curves to the right (higher concentrations). The binding potencies of the new analogues relative to glucagon (= 100) were respectively 1.0 (2), 1.3 (3), 3.8 (4), 0.4 (5), 1.3 (6), 5.3 (7), and 3 (8). Glucagon analogues 3-5 and 8 were all weak partial agonists with EC50 values of 500 (3), 250 (4), 1600 (5), and 395 nM (8), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
• Henriksen, E. J., Tischler, M. E., & Johnson, D. G. (1986). Increased response to insulin of glucose metabolism in the 6-day unloaded rat soleus muscle. The Journal of biological chemistry, 261(23), 10707-12.
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  Hind leg muscles of female rats (85-99 g) were unloaded by tail cast suspension for 6 days. In the fresh-frozen unloaded soleus, the significantly greater concentration of glycogen correlated with a lower activity ratio of glycogen phosphorylase (p less than 0.02). The activity ratio of glycogen synthase also was lower (p less than 0.001), possibly due to the higher concentration of glycogen. In isolated unloaded soleus, insulin (0.1 milliunit/ml) increased the oxidation of D-[U-14C]glucose, release of lactate and pyruvate, incorporation of D-[U-14C]glucose into glycogen, and the concentration of glucose 6-phosphate more (p less than 0.05) than in the weight-bearing soleus. At physiological doses of insulin, the percent of maximal uptake of 2-deoxy-D-[1,2-3H]glucose/muscle also was greater in the unloaded soleus. Unloading of the soleus increased by 50% the concentration of insulin receptors, due to no decrease in total receptor number during muscle atrophy. This increase may account for the greater response of glucose metabolism to insulin in this muscle. The extensor digitorum longus, which generally shows little response to unloading, displayed no differential response of glucose metabolism to insulin.
• McKee, R. L., Pelton, J. T., Trivedi, D., Johnson, D. G., Coy, D. H., Sueiras-Diaz, J., & Hruby, V. J. (1986). Receptor binding and adenylate cyclase activities of glucagon analogues modified in the N-terminal region. Biochemistry, 25(7), 1650-6.
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  In this study, we determined the ability of four N-terminally modified derivatives of glucagon, [3-Me-His1,Arg12]-, [Phe1,Arg12]-, [D-Ala4,Arg12]-, and [D-Phe4]glucagon, to compete with 125I-glucagon for binding sites specific for glucagon in hepatic plasma membranes and to activate the hepatic adenylate cyclase system, the second step involved in producing many of the physiological effects of glucagon. Relative to the native hormone, [3-Me-His1,Arg12]glucagon binds approximately twofold greater to hepatic plasma membranes but is fivefold less potent in the adenylate cyclase assay. [Phe1,Arg12]glucagon binds threefold weaker and is also approximately fivefold less potent in adenylate cyclase activity. In addition, both analogues are partial agonists with respect to adenylate cyclase. These results support the critical role of the N-terminal histidine residue in eliciting maximal transduction of the hormonal message. [D-Ala4,Arg12]glucagon and [D-Phe4]glucagon, analogues designed to examine the possible importance of a beta-bend conformation in the N-terminal region of glucagon for binding and biological activities, have binding potencies relative to glucagon of 31% and 69%, respectively. [D-Ala4,Arg12]glucagon is a partial agonist in the adenylate cyclase assay system having a fourfold reduction in potency, while the [D-Phe4] derivative is a full agonist essentially equipotent with the native hormone. These results do not necessarily support the role of an N-terminal beta-bend in glucagon receptor recognition. With respect to in vivo glycogenolysis activities, all of the analogues have previously been reported to be full agonists.(ABSTRACT TRUNCATED AT 250 WORDS)
• Smith, P. F., Krack, G., McKee, R. L., Johnson, D. G., Gandolfi, A. J., Hruby, V. J., Krumdieck, C. L., & Brendel, K. (1986). Maintenance of adult rat liver slices in dynamic organ culture. In vitro cellular & developmental biology : journal of the Tissue Culture Association, 22(12), 706-12.
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  Adult rat liver slices were maintained for 20 h in a novel organ culture system with minimal loss of viability and function. Potassium and adenosine triphosphate levels were maintained at in vivo levels, following an initial recovery period (2 to 4 h), for up to 20 h. Protein synthesis and secretion were linear for 20 and 16 h, respectively. In addition, the liver slices synthesized glycogen between 4 and 12 h in culture. Finally, the liver slices were hormonally responsive during the 20 h culture period as exemplified by glucagon-stimulated glucose production. This system provides a simple and effective method for the culture and biochemical maintenance of adult rat liver for 20 h with minimal loss of biochemical function.
• Smith, P. F., Thompson, W. J., de Haën, C., Halonen, M., Palmer, J. D., & Johnson, D. G. (1986). Bronchodilator activity of a nonxanthine phosphodiesterase inhibitor; 2,4-diamino-5-cyano-6-bromopyridine (compound I). The Journal of pharmacology and experimental therapeutics, 237(1), 114-9.
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  The ability of 2,4-diamino-5-cyano-6-bromopyridine (compound 1) to inhibit bronchiolar smooth muscle constriction was examined in isolated rings of rabbit primary bronchi and intrapulmonary bronchioles. After carbachol-induced constriction these tissue were significantly relaxed by either compound I or 1-methyl-3-isobutylxanthine (MIX) in a similar dose-dependent manner with 50 to 80% relaxation occurring at 100 microM of either compound. Compound I also attenuated the constrictor response of bronchial rings to histamine and significantly reduced the tension generated by horseradish peroxidase in sensitized tissues responding to this antigen. In addition, both compound I and MIX were found to inhibit the soluble cyclic AMP phosphodiesterase activity of rabbit bronchioles. Finally, both compound I and MIX caused a nearly 2-fold, time-dependent increase in cyclic AMP levels in isolated rabbit intrapulmonary bronchioles. The similarities of both the in vitro tissue responses to these compounds and the phosphodiesterase inhibitory properties suggest that the ability of compound I to reduce constrictor-induced tension generation in bronchial smooth muscle is related to the inhibition of cyclic nucleotide phosphodiesterases and the consequent elevation of cyclic AMP.
• Fagan, T. C., Johnson, D. G., & Grosso, D. S. (1985). Metronidazole-induced gynecomastia. JAMA, 254(22), 3217.
• Escourrou, P., Johnson, D. G., & Rowell, L. B. (1984). Hypoxemia increases plasma catecholamine concentrations in exercising humans. Journal of applied physiology: respiratory, environmental and exercise physiology, 57(5), 1507-11.
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  To determine whether plasma catecholamine concentrations (a measure of sympathetic nervous activity [SNA]) rise above normoxic levels during exercise with hypoxemia, we exercised seven men for 15 min at three loads that required from 40 to 88% of maximal O2 uptake (VO2max). Subjects breathed room air on one day and 11-12% O2 on another with relative work loads corrected for the 24% fall in VO2max during hypoxemia. Hypoxemia caused large increments in norepinephrine (NE) concentration (radioenzyme technique) to 1.21 +/- 0.20 ng/ml (mean +/- SE), 2.79 +/- 0.38, and up to 5.90 +/- 0.75 (hypoxemia) compared with 0.89 +/- 0.06, 1.66 +/- 0.16, and 3.95 +/- 0.39 in normoxia at the three loads, respectively (P less than 0.001). Epinephrine (E) concentration approximately doubled (P less than 0.001) in hypoxemia at each load when compared with normoxic levels (i.e., 0.10 +/- 0.01 ng/ml, 0.23 +/- 0.03, and 0.46 +/- 0.06 in normoxia). However, hypoxemia did not significantly alter linear relationships between log plasma NE concentration and either heart rate (HR) or percent VO2max utilized, or between HR and percent VO2max. Thus NE concentration, like HR, appeared to reflect relative severity of exercise and overall SNA in both hypoxemia and normoxia. Above 40% VO2max during hypoxemia, circulating NE and E far exceeded levels known to have direct vasoconstrictor and metabolic effects in normoxic humans, but hypoxemia may blunt vasoconstriction in some regions.
• Johnson, D. G., & Bressler, R. (1984). New pharmacologic approaches to the treatment of diabetes. Special topics in endocrinology and metabolism, 6, 163-92.
• Johnson, D. G., & Korc, M. (1984). Diabetes mellitus: diagnostic evaluation and management.. Endocrine, 24-32.
• Korc, M., & Johnson, D. G. (1984). Glycosylated hemoglobin, Methodology and interpretation.. Endocrine, 1-8.
• Martinez-Torres, C., Cubeddu, L., Dillmann, E., Brengelmann, G. L., Leets, I., Layrisse, M., Johnson, D. G., & Finch, C. (1984). Effect of exposure to low temperature on normal and iron-deficient subjects. The American journal of physiology, 246(3 Pt 2), R380-3.
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  Twenty-one Venezuelan peasants were segregated into three groups on the basis of measurements of iron status: seven normal subjects, six iron-deficient subjects with normal hemoglobin and eight iron-deficient subjects with a hemoglobin concentration of less than 9 g/dl. All subjects were placed in a water bath at an initial temperature of 36 degrees C. The water temperature was then rapidly lowered to 28 degrees C, and observations were made over the period of 1 h. Mean oral temperature of the first group fell 0.2, the second group 0.5, and the third group 0.9 degrees C. Mean plasma norepinephrine levels in both groups of iron-deficient subjects were significantly higher at 36 degrees C and during cold exposure compared with control subjects. Oxygen consumption was also significantly increased in both groups of iron-deficient subjects after cold exposure.
• de Haën, C., Nist, B. J., Hansen, R. S., Johnson, D. G., & Thompson, W. J. (1984). 2,4-Diamino-5-cyano-6-halopyridines: a new class of cyclic AMP phosphodiesterase inhibitors with therapeutic potential. Biochemical pharmacology, 33(13), 2109-13.
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  2,4-Diamino-5-cyano-6-halopyridines have been described previously as oral insulinotropic agents and have been found recently to have bronchodilatory properties. In the present report the synthesis of the iodo compound is newly described, and it is established that HI- or HBr-mediated condensation and cyclization of malononitrile in 1,2-dichloroethane yield selectively the 5-cyanopyridine derivatives. The pyridine derivatives were found to constitute a new class of potent cyclic AMP phosphodiesterase inhibitors. Inhibition of purified dog kidney cyclic AMP phosphodiesterase was of the mixed type. Since cyclic AMP phosphodiesterase inhibitors are known to enhance glucose-induced insulin secretion and to activate glucose production by the liver, the finding that the pyridine derivatives described here inhibited cyclic AMP phosphodiesterase opens new avenues of interpretation for their insulinotropic action as well as for the paradoxical lack of improvement of glucose disposal by elevation of insulin after oral drug administration. Cyclic AMP phosphodiesterase inhibition also has the potential of explaining the bronchodilatory effects of these drugs.
• Grosso, D. S., Boyden, T. W., Pamenter, R. W., Johnson, D. G., Stevens, D. A., & Galgiani, J. N. (1983). Ketoconazole inhibition of testicular secretion of testosterone and displacement of steroid hormones from serum transport proteins. Antimicrobial agents and chemotherapy, 23(2), 207-12.
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  In vivo perfusion of canine testes with ketoconazole inhibited the stimulation of testosterone production by human chorionic gonadotropin in a dose-dependent manner. Ketoconazole also selectively displaced steroids from serum-binding globulins. Dihydrotestosterone and estradiol binding to sex hormone-binding globulin were inhibited by ketoconazole. Cortisol binding to corticosteroid-binding globulin was unaffected. The concentrations of ketoconazole that inhibited human chorionic gonadotropin stimulation of testicular androgen production and displaced sex steroids from sex hormone-binding globulin were in the range of blood levels found in patients on higher therapeutic dosage regimens. Suppression of testicular testosterone synthesis and displacement of estrogens from sex hormone-binding globulin may decrease the androgen/estrogen ratio of the blood and contribute to the development of gynecomastia that has been reported in some ketoconazole-treated patients.
• Escourrou, P., Freund, P. R., Rowell, L. B., & Johnson, D. G. (1982). Splanchnic vasoconstriction in heat-stressed men: role of renin-angiotensin system. Journal of applied physiology: respiratory, environmental and exercise physiology, 52(6), 1438-43.
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  We conducted a two-part study to determine whether the renin-angiotensin system contributes to the rise in splanchnic vascular resistance (SVR) during heat stress (rectal temperature was raised 1 degree C). In experiment 1 (control) seven men on a normal salt diet were directly heated (water-perfused suits) for 40-50 min. Arterial pressure (85 Torr) was unchanged; plasma renin activity (PRA) rose from 102 to 239 ng angiotensin I.100 ml-1.3 h-1; and SVR increased 73% (from 63 to 109 units). Experiment 2 was a repetition of experiment 1 on the same subjects, except that propranolol (10 mg iv) was given at the onset of heating to block renin release. Propranolol attenuated the rise in heart rate and reduced mean arterial pressure from 82 to 72 Torr; it blocked the rise in PRA with heating in two subjects, reduced it in three, but increased it in two. Although changes in SVR paralleled those in PRA in three subjects, SVR still rose 60% (from 58 to 99 units) after PRA rise was blocked. In both experiments, plasma norepinephrine concentration rose indicating increased sympathetic nervous activity. During mild heat stress, increased PRA is not a major factor in the increase of SVR.
• Johnson, D. G., Goebel, C. U., Hruby, V. J., Bregman, M. D., & Trivedi, D. (1982). Hyperglycemia of diabetic rats decreased by a glucagon receptor antagonist. Science (New York, N.Y.), 215(4536), 1115-6.
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  The glucagon analog [l-N alpha-trinitrophenylhistidine, 12-homoarginine]-glucagon (THG) was examined for its ability to lower blood glucose concentrations in rats made diabetic with streptozotocin. In vitro, THG is a potent antagonist of glucagon activation of the hepatic adenylate cyclase assay system. Intravenous bolus injections of THG caused rapid decreases (20 to 35 percent) of short duration in blood glucose. Continuous infusion of low concentrations of the inhibitor led to larger sustained decreases in blood glucose (30 to 65 percent). These studies demonstrate that a glucagon receptor antagonist can substantially reduce blood glucose levels in diabetic animals without addition of exogenous insulin.
• Orlander, P., & Johnson, D. G. (1982). Endocrinologic problems in the aged. Otolaryngologic clinics of North America, 15(2), 439-49.
• DeFelice, R., Johnson, D. G., & Galgiani, J. N. (1981). Gynecomastia with ketoconazole. Antimicrobial agents and chemotherapy, 19(6), 1073-4.
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  Three of forty men developed bilateral gynecomastia upon ketoconazole treatment. Symptoms abated despite continued therapy. This appears to be a direct drug effect on breast tissue.
• Marques, P. R., Illner, P., Williams, D. D., Gren, W. L., Kendall, J. W., Davis, S. L., Johnson, D. G., & Gale, C. C. (1981). Hypothalamic control of endocrine thermogenesis. The American journal of physiology, 241(6), E420-7.
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  Hypothalamic and ruminal cooling raised serum thyrotropin (TSH), adrenocorticotropin (ACTH), norepinephrine (NE), and glucose in conscious goats in 20 degree C ambient temperature. Cooling of the preoptic anterior hypothalamus (POAH) for 2 h initially evoked shivering and vasoconstriction, leading to 1.5 degree C rise in rectal temperature (Tr). Pituitary-thyroid activation by POAH cooling was shown by peak rises in TSH of 60% at 40 min, in triiodothyronine (T3) of 54% at 80 min, and in thyroxine (T4) of 40% at 140 min. At 60 min, ACTH and NE peaked at 57 and 65%, respectively. TSH, ACTH, and NE declined during the 2nd h of POAH cooling as Tr plateaued; when POAH cooling was stopped, these hormones fell below basal level as vasodilation and panting restored Tr to normal. In contrast to the core hyperthermia evoked by POAH cooling, ruminal intubation with O degree C water (1 liter/10 kg) led to general hypothermia, Tpoah and Tr falling 1.6 degree C at 40 min. Pituitary-thyroid responses were less but ACTH and NE more, compared with POAH cooling. TSH peaked at 37% at 20 min, T3 at 55% at 60 min, and T4 at 18% at 200 min. ACTH peaked at 250% at 30 min and NE at 120% at 20 min. Thermosensitive neurons in the POAH seem to mediate more sensitive and complete control over TSH than over ACTH, or NE release, whereas extrahypothalamic core thermosensitivity (e.g., brain stem, spinal cord, abdomen) may influence ACTH and NE more than TSH release.
• Villar, H. V., Johnson, D. G., Lynch, P. J., Pond, G. D., & Smith, P. H. (1981). Pattern of immunoreactive glucagon in portal, arterial and peripheral plasma before and after removal of glucagonoma. American journal of surgery, 141(1), 148-52.
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  Gel fractionation of portal, arterial and peripheral plasma glucagon levels was performed before and after the successful removal of a glucagonoma. A 47 year old woman had symptoms of dermatitis, weight loss, anemia and diabetes mellitus over a 16 year period. Removal of the alpha-cell tumor corrected all of her symptoms. Gel filtration of portal, arterial and peripheral blood showed two peaks of glucagon radioimmunoassay activity, a higher molecular weight glucagon with a molecular weight of 9,000 and a 3,500 dalton glucagon. Five minutes after tumor removal, the higher molecular weight glucagon had disappeared completely from the arterial and peripheral blood but not from the portal vein.
• Dillman, E., Gale, C., Green, W., Johnson, D. G., Mackler, B., & Finch, C. (1980). Hypothermia in iron deficiency due to altered triiodothyronine metabolism. The American journal of physiology, 239(5), R377-81.
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  Iron-deficient rats become hypothermic and have an excessive catecholamine response when exposed to an ambient temperature of 4 degrees C. This is not due to changes in body insulation, since thickness is unaltered, since differences persist after removal of hair, and since cutaneous vasoconstriction is intact. On the other hand, oxygen consumption of iron-deficient animals at 4 degrees C is reduced, 39 +/- 3 ml . kg-1 . min-1 compared to 63 +/- 2 in control animals. Thyroxine (T4) values at 4 degrees C were 4.34 +/- 0.20 microgram/dl sera as compared to control values of 3.6 +/- 0.32. Triiodothyronine (T3) values of iron-deficient animals in the cold were 48 +/- 6.8 ng/dl as compared to 72 +/- 5.6 in control animals. Treatment of iron-deficient animals with iron was shown to normalize the plasma T3 response at 4 degrees C within 6 days. Thyroidectomized iron-deficient animals injected with T3 did not show hypothermia at 4 degrees C, whereas thyroidectomized iron-deficient animals injected with T4 showed hypothermia, increased catecholamines, and decreased T3 levels as compared to non-iron-deficient animals similarly treated. It is proposed that iron deficiency impairs conversion of T4 to T3 and that this is primarily responsible for the hypothermia observed.
• Johnson, D. G., & Bressler, R. (1980). Preoperative management of the diabetic patient. Contemporary anesthesia practice, 3, 39-45.
• Johnson, D. G., & Conley, V. (1980). Postinhibitory overshoot of insulin release by gastric inhibitory polypeptide. Life sciences, 27(24), 2373-80.
• Werner, P. L., Benson, J. W., Brodsky, J. B., Hollander, P. M., Asplin, C. M., Johnson, D. G., & Palmer, J. P. (1980). Comparison of glucagon responses to 2-deoxy-D-glucose and hypoglycemia in man. The American journal of physiology, 239(3), E227-31.
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  2-Deoxy-D-glucose (2DG), by competitive inhibition of glucose utilization, produces a state of intracellular glucopenia with resultant activation of both the sympathetic and parasympathetic branches of the autonomic nervous system. We have investigated the relationship between the activation of the autonomic nervous system caused by this drug and glucagon secretion. Subjects experienced symptoms identical to those observed during true hypoglycemia and demonstrated a marked rise in both gastric acid secretion and urinary epinephrine excretion. Mean immunoreactive glucagon (IRG) levels rose only slightly post-2DG (maximal mean increment, 18 pg/ml). Insulin-induced hypoglycemia, although eliciting a similar increase in urinary epinephrine excretion, was followed by a severalfold increase in IRG. Thus, although hypoglycemia and 2DG induced similar discharge of the autonomic nervous system, the glucagon response to hypoglycemia was much greater. These observations provide strong evidence that marked increases in sympathetic and parasympathetic discharge in man are weak alpha-cell stimuli and further support the hypothesis that the rise in IRG that occurs during hypoglycemia is not mediated primarily via the autonomic nervous system.
• Chait, A., Brunzell, J. D., Johnson, D. G., Benson, J. W., Werner, P., Palmer, J. P., Albers, J. J., Ensinck, J. W., & Bierman, E. L. (1979). Reduction of plasma triglyceride concentration by acute stress in man. Metabolism: clinical and experimental, 28(5), 553-61.
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  Three different forms of stress all resulted in acute reduction of plasma triglyceride concentrations. Pyrogen reactions in two hypertriglyceridemic men resulted in the lowering of very-low-density lipoprotein (VLDL) triglyceride levels by 93% and 73% due to decreased secretion of this lipoprotein into plasma. More modest reductions in plasma triglycerides were observed after 2-deoxyglucose-induced intracellular glucopenia and insulin-induced hypoglycemia. With hypoglycemia, the lowering of plasma triglyceride concentration correlated significantly with the stimulation of urinary epinephrine output (r = 0.86) but with neither the urinary norepinephrine response nor with the increase in plasma immunoreactive glucagon levels. To further test whether these changes in plasma triglyceride levels were mediated via the sympathetic nervous system, hypoglycemia was evoked by insulin in subjects with traumatic spinal cord transactions. Two such subjects, who demonstrated sympathetic stimulation in response to hypoglycemia, had evidence of reduced VLDL secretion into plasma, while in two who had no evidence of an adrenergic response. VLDL secretion was not inhibited. Thus, acute lowering of plasma triglyceride concentrations by certain forms of stress appears to be mediated via the sympathetic nervous system.
• Dillmann, E., Johnson, D. G., Martin, J., Mackler, B., & Finch, C. (1979). Catecholamine elevation in iron deficiency. The American journal of physiology, 237(5), R297-300.
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  Iron-deficient rats have increased blood and urinary catecholamines regardless of whether anemia is or is not present. The catecholamine response in both iron-deficient and control animals is largely temperature dependent, showing little difference at the isothermic temperature of 30 degrees C but a two- to threefold increase in iron-deficient animals over controls at lower temperatures. The iron-deficient rat is unable to maintain body temperature at 4 degrees C and this is independent of anemia or of food intake. When animals are run on the treadmill for 4 h, body temperatures increase but the difference observed at 4 degrees C between iron-deficient and control animals persists. The underlying abnormality in temperature regulation and in catecholamine response disappeared after 6 days of iron therapy.
• Johnson, D. G. (1979). The pathogenesis of diabetes mellitus. Arizona medicine, 36(10), 766-70.
• Johnson, D. G., & de Haën, C. (1979). 2,4-Diamino-5-cyano-6-halopyridines and analogues. A new family of insulin secretogogues that resemble glucose in hydrogen bonding possibilities. Molecular pharmacology, 15(2), 287-93.
• Marques, P. R., Williams, D. D., Shen, L., Johnson, D. G., Baylink, D. J., & Gale, C. C. (1979). Parathyroid hormone release is not associated with acute sympathetic arousal in goats. Endocrine research communications, 6(1), 57-70.
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  Physiological activation of the sympathetic adrenomedullary (SAM) axis following both thermal and non thermal stress was assessed by changes in serum norepinephrine, glucose and/or protein as well as indices of peripheral blood flow. The occurrence of elevated serum parathyroid hormone (PTH) did not reliably reflect SAM activation as might be predicted from pharmacological studies that document a beta adrenergic receptor mechanism in the parathyroid gland that mediates catecholamine stimulated release of PTH into the circulation. The beta agonist isoproterenol at 1 microgram/min for 60 min did produce a transient increase in serum PTH at 20 min. Overall, the data raise doubts about the physiological significance of the adrenergic receptor in the parathyroid gland. Significant increases in serum PTH of 67% and 109% above basal respectively were seen following ruminal loading with cold and thermoneutral water. Associated with the PTH change were increased serum phosphorus and elevated or constant serum protein and serum total calcium.
• Fujimoto, W. Y., Ensinck, J. W., Merchant, F. W., Williams, R. H., Smith, P. H., & Johnson, D. G. (1978). Stimulation by gastric inhibitory polypeptide of insulin and glucagon secretion by rat islet cultures. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.), 157(1), 89-93.
• Jacobs, T. P., Henry, D. P., Johnson, D. G., & Williams, R. H. (1978). Epinephrine and dopamine beta-hydroxylase secretion from bovine adrenal. The American journal of physiology, 234(6), E600-5.
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  The perfusate of the isolated, acetylcholine-stimulated bovine adrenal was studied for epinephrine (E) concentration and dopamine beta-hydroxylase (DBH) activity. Analysis of single stimuli showed that DBH disappeared from the perfusate with a t1/2 of 19.1-29.0 min. whereas E disappeared with a t1/2 of 0.78-1.0 min. Stimulation every 5 min over 105 min caused a gradual decline in E concentration to 36% of its initial value, whereas DBH activity reached a plateau after the second stimulus and thereafter remained unchanged. The decline in E was not influenced by addition of catecholamine precursors and biosynthetic cofactors to the medium and was not accompanied by a shift in the ratios of E and norepinephrine (NE) in the perfusate. Inhibitors of DBH activity were not detected in the perfusate and nonexocytotic leakage of DBH into the perfusate did not occur. These results document the temporal dissociation of the appearance and disappearance of DBH and E after a single stimulus and the progressive dissociation of DBH and E secretion under conditions of prolonged perfusion with rapid and repetitive stimulation. Possible explanations of these observations are offered.
• Jacobs, T. P., Johnson, D. G., & Williams, R. H. (1978). Epinephrine secretion from the perfused adrenal gland produced by scorpion toxin. Toxicology and applied pharmacology, 46(2), 405-9.
• Benson, J. W., Johnson, D. G., Palmer, J. P., Werner, P. L., & Ensinck, J. W. (1977). Glucagon and catecholamine secretion during hypoglycemia in normal and diabetic man. The Journal of clinical endocrinology and metabolism, 44(3), 459-64.
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  To examine the role of catecholamines in glucopenia-induced glucagon secretion, urinary epinephrine and norepinephrine and plasma immunoreactive glucagon (IRG) were measured during insulin-induced hypoglycemia in normal and insulin-dependent diabetic-man. Despite equivalent levels of hypoglycemia the mean plasma IRG increment in diabetes was only 15% of normals. The increases in epinephrine and norepinephrine were comparable in diabetics and normals; thus, the blunted response in plasma IRG to the stimulus of low blood sugar in diabetics cannot be explained by a generalized defect in catecholamine secretion. It is suggested that an alpha-cell glucoreceptor defect may account for the abnormal response to glucopenia in diabetics. To evaluate the possibility that impaired sensitivity to circulating catecholamines could explain the alpha cell dysfunction in diabetics, exogenous epinephrine was infused in normals and insulin-dependent diabetics. Elevated plasma IRG during epinephrine infusion was observed in only 50% of normals. The diabetics were hyperresponsive; mean increment in plasma IRG 3 times that of normals. The data demonstrate enhanced rather than impaired sensitivity to catecholamines in diabetes mellitus.
• Chideckel, E. W., Goodner, C. J., Koerker, D. J., Johnson, D. G., & Ensinck, J. W. (1977). Role of glucagon in mediating metabolic effects of epinephrine. The American journal of physiology, 232(5), E464-70.
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  In order to separate direct effects of epinephrine on fuel metabolism from those mediated by glucagon, epinephrine (0.1 microng/kg-min) was infused for 120 min in 18- and 65-h fasted, nonanesthetized baboons with and without a concomitant somatostatin infusion. At both stages of fasting, epinephrine stimulated glucagon, secretion, and this was blocked by somatostatin. At 18 h, with epinephrine alone, glucose rose early and remained elevated throughout the infusion. In the glycogen-depleted 65-h fasted animals, there was attenuation of the early glucose rise, with glucose reaching a maximum level at 100-120 min. With somatostatin blockade of glucagon release in the 18-h fasted animals, a pattern of attenuated early glucose rise similar to that of the 65-h fasted animals occurred. Somatostatin also inhibited this early glycogenolytic response when the epinephrine dose was increased fivefold. The behavior of FFA, glycerol, and beta-hydroxybutyrate was unchanged by the addition of somatostatin to epinephrine at either stage of fasting. Thus, glucagon mediates the early glycogenolytic response to epinephrine, but not the delayed hyperglycemia and probably not the lipolysis.
• Illner, P., Marques, P., Williams, D. D., Steiner, R. A., Green, W. L., Davis, S. L., Kendall, J. W., Johnson, D. G., & Gale, C. C. (1977). Endocrine responses to ruminal cooling in goats. The Pharmacology of Thermoregulation Third International Symposium, 58-61.
• Johnson, D. G., Hayward, J. S., Jacobs, T. P., Collis, M. L., Ackerson, J. D., & Williams, R. H. (1977). Plasma norepinephrine responses of man in cold water. Journal of Applied Physiology, 216.
• Johnson, D. G., Hayward, J. S., Jacobs, T. P., Collis, M. L., Eckerson, J. D., & Williams, R. H. (1977). Plasma norepinephrine responses of man in cold water. Journal of applied physiology: respiratory, environmental and exercise physiology, 43(2), 216-20.
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  The hypothermic stress of immersion in cold water stimulates release of norepinephrine from the sympathetic nervous system. The speed and pattern of this response was studied in six healthy men by serial measurements of plasma norepinephrine concentrations before, during, and after 60 min of immersion in 10 degrees C water. After immersion for 2 min, the mean norepinephrine concentration was increased from 359+/-32 (basal) to 642+/-138 pg/ml and rose gradually to a maximum of 1.171+/-226 pg/ml after 45 min of immersion. Metabolic rate increased approximately threefold during the immersion period. After rewarming in warm water (40 degrees C), the subjects showed a transient peak in plasma norepinephrine followed by a rapid decrease to basal levels after 30 min. The fall in plasma norepinephrine after approximately 8 min of rewarming occurred despite persistent depression of the core temperature and coincided with a sudden decrease in metabolic rate and cessation of body shivering. These results suggest that the sympathetic nervous response to cold can be activated or suppressed very quickly and is dependent on the skin temperature.
• Smith, P. H., Merchant, F. W., Johnson, D. G., Fujimoto, W. Y., & Williams, R. H. (1977). Immunocytochemical localization of a gastric imhibitory polypeptide-like material within A-cells of the endocrine pancreas. The American journal of anatomy, 149(4), 585-90.
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  In rat pancreatic islets, the glucagon-producing A-cells also contain a GIP-like material as revealed by the peroxidase-antiperoxidase immunocytochemical technique. Control studies showed that this dual staining was not due to the cross-reactivity of anti-GIP with glucagon. It is concluded either that the A-cells synthesize a GIP-like peptide or that it is taken up from the circulation.
• Williams, D. D., Illner, P., Marques, P., Steiner, R. A., Green, W. L., Davis, S. L., Kendall, J. W., Johnson, D. G., & Gale, C. C. (1977). Endocrine responses to cooling of the hypothalamus in goats. The Pharmacology of Thermoregulation Third International Symposium, 62-63.
• Johnson, D. G. (1976). The important role of insulin therapy in 1976. Hospital Formulary, 11, 184.
• Johnson, D. G., & Ensinck, J. W. (1976). Stimulation of glucagon secretion by scorpion toxin in the perfused rat pancreas. Diabetes, 25(8), 645-9.
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  Toxin from the scorpion Leiurus quinquestriatus was used to release norepinephrine from sympathetic nerve endings in the perfused rat pancrease. Addition of toxin, 10 mug./ml., to perfusate containing 0.3 mg./ml. glucose caused a large increase in release of norepinephrine and glucagon. Glucagon secretion was suppressed by perfusate containing 3.0 mg./ml. glucose but still responded to stimulation with scorpion toxin. Atropine, 10 muM, had no effect on either norepinephrine or glucagon release in response to scorpion toxin. The release of glucagon was blocked by 100 muM propranolol, 10 muM phentolamine, or 30 muM phenoxybenzamine. Somatostatin, 55nM, did not affect the release of norepinephrine by scorpion toxin but totally inhibited the glucagon response. These results suggest that pharmacologic stimulation of the adrenergic nerve endings in the rat pancreas can elicit a rapid release of glucagon. This response can be prevented by appropriate concentrations of either alpha or beta adrenergic blocking agents or somatostatin.
• Johnson, D. G., Henry, D. P., Moss, J., & Williams, R. H. (1976). Inhibition of insulin release by scorpion toxin in rat pancreatic islets. Diabetes, 198.
• Johnson, D. G., Henry, D. P., Moss, J., & Williams, R. H. (1976). Inhibition of insulin rlease by scorpion toxin in rat pancreatic islets. Diabetes, 25(3), 198-201.
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  Toxin purified from venom of the scorpion Leiurus quinquestriatus was used to release the norepinephrine from adrenergic nerve terminals in isolated pancreatic islets perifused in vitro. Addition of toxin (10 mug./ml) to the perifusion medium caused a sixfold increase in release of norepinephrine in the presence or absence of 3 X 10(-5) M phenoxybenzamine. During 20 minutes of stimulation with toxin, the pancreatic islets released an average of 15 pg. of norepinephrine per islet, which represented 20 per cent of the normal content of norepinephrine in islets. Insulin secretory rates in response to either 1.0 or 3.0 mg./ml. glucose were inhibited similarly by scorpion toxin. Addition of phenoxybenzamine abolished the inhibition of insulin release caused by scorpion toxin. Phenoxybenzamine alone did not affect release of insulin. Neither the enhanced release of norepinephrine nor the decreased release of insulin was reversed by a 20-minute wash-out period after infusion of toxin. These results indicate that the sympathetic nerve terminals in the rat pancreatic islet contain considerable amounts of norepinephrine that can be released by scorpion toxin. The norepinephrine released from sympathetic nerve endings in the pancreatic islet can inhibit release of insulin through an alpha-adrenergic action that is blocked by phenoxybenzamine.
• Palmer, J. P., Henry, D. P., Benson, J. W., Johnson, D. G., & Ensinck, J. W. (1976). Glucagon response to hypoglycemia in sympathectomized man. The Journal of clinical investigation, 57(2), 522-5.
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  Hypoglycemia stimulates immunoreactive glucagon (IRG) secretion and increases the activity of the sympathetic nervous system. To ascertain if the augmented alpha cell activity evoked by glucopenia is mediated by the adrenergic nervous system, the glucagon response to insulin-induced hypoglycemia of five subjects with neurologically complete cervical transections resulting from trauma, thereby disrupting their hypothalamic sympathetic outflow, was compared to six healthy volunteers. In addition to clinical neurological evaluation, completeness of sympathectomy was verified by failure to raise plasma norepinephrine levels during hypoglycemia compared to the two- and threefold increase observed in controls. Total IRG response (IRG area above basal 0-90 min) and peak IRG levels achieved were the same in the quadriplegics and the controls. Although the glucagon rise tended to be slower, and the peak levels attained occurred later in the quadriplegic patients than in the controls, this response was appropriate for their sugar decline, which was slower and reached the nadir later than in the control subjects. These observations that the glucagon release during insulin-induced hypoglycemia is normal in subjects whose hypothalamic sympathetic outflow has been interrupted provide strong evidence that the sympathetic nervous system does not mediate the glucagon response to hypoglycemia.
• Thompson, W. J., Johnson, D. G., & Williams, R. H. (1976). Hormonal regulation of pancreatic islet adenyl cyclase. Biochemistry, 15(8), 1658-63.
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  Adenyl cyclase activity of rat pancreatic islet membrane was increased by secretin, pancreozymin, and isoproterenol, while ACTH, glucagon, growth hormone, and insulin had no effect. Both secretin and isoproterenol activations were enhanced by prostaglandin E1 (PGE1) and GTP. Isoproterenol activation was additive with PGE1, as was that of secretin with PGE1, but only in the presence of GTP. Secretin activation in the presence of PGE1 and GTP was equivalent to NaF stimulation. Kinetic analysis indicated that secretin and GTP increased the maximum velocity of the adenyl cyclase and tended to decrease the apparent affinity of the enzyme for ATP. Glucagon activation of islet membrane adenyl cyclase was dependent upon prior treatment of the membrane preparation with EGTA and the use of inhibitors of proteolytic enzymes during the collagenase digestion phase of islet preparation. These results suggest that hormonal regulation of insulin secretion may be affected by PGE1 and guanine nucleotide modulation of the adenyl cyclase activation process.
• Thompson, W. J., Johnson, D. G., & Williams, R. H. (1976). Hormonal regulation of pancreatic islet adenyl cyclase. Biochemistry, 1658.
• Hayes, J. R., Johnson, D. G., Koerker, D., & Williams, R. H. (1975). Inhibition of gastrin release by somatosatin in vitro. Endocrinology, 96(6), 1374-6.
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  An in vitro system which uses perifused pieces from the antrum of rat stomach has been used to study the effect of dihydrosomatostatin on gastrin release. The gastrin concentration in fractions of the perfusate was measured by radioimmunoassay. Dihydrosomatostatin (2 x 10-7M) had no effect on basal gastrin levels but virtually abolished the biphasic response seen with argine stimulation. The study demonstrates close functional similarities between G cells and pancreatic islet cells.
• Henry, D. P., Johnson, D. G., Starman, B. J., & Williams, R. H. (1975). Kinetic characterization of rat serum dopamine-beta-hydroxylase using a simplified radioenzymatic assay. Life sciences, 17(7), 1179-86.
• Henry, D. P., Starman, B. J., Johnson, D. G., & Williams, R. H. (1975). A sensitive radioenzymatic assay for norepinephrine in tissues and plasma. Life sciences, 16(3), 375-84.
• Johnson, D. G., Ensinck, J. W., Koerker, D., Palmer, J., & Goodner, C. J. (1975). Inhibition of glucagon and insulin secretion by somatostatin in the rat pancreas perfused in situ. Endocrinology, 96(2), 370-4.
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  Perfusion of growth hormone inhibitory factor (somatostatin) into rat pancreas inhibited secretion of glucagon and insulin into medium containing 5.5 mM glucose. A 15-min infusion of arginine (20 mM) greatly increased glucagon and insulin secretion. When perfused simultaneously with arginine, somatostatin (55 nM) abolished the increase in glucagon secretion. The acute phase of insulin secretion in response to arginine was attenuated by somatostatin, and subsequent secretion was decreased to control levels. Pretreatment for 5 min with somatostatin blocked even acute-phase insulin secretion in response to arginine. Somatostatin did not affect basal or glucose-stimulated secretion of insulin from rat pancreatic islets isolated by the collagenase technique. Arginine-stimulated secretion of insulin was enhanced by somatostatin in isolated islets. These results demonstrate a direct effect of somatostatin on the pancreas to inhibit secretion of glucagon and insulin. The failure of somatostatin to inhibit insulin secretion in pancreatic islets may be due to alterations in the beta cells produced by the isolation procedure. It is also possible that the effect of somatostatin on insulin secretion may be mediated indirectly.
• Johnson, D. G., Thompson, W. J., & Williams, R. H. (1974). Regulation of adenylyl cyclase from isolated pancretic islets by prostaglandins and guanosine 5'-triphosphate. Biochemistry, 13(9), 1920-4.
• Thompson, W. J., Johnson, D. G., Lavis, V. R., & Williams, R. H. (1974). Effects of secretin on guanyl cyclase of various tissues. Endocrinology, 94(1), 276-8.
• Cramer, H., Johnson, D. G., Hanbauer, I., Silberstein, S. D., & Kopin, I. J. (1973). Accumulation of adenosine 3',5'-monophosphate induced by catecholamines in the rat superior cervical ganglion in vitro. Brain research, 53(1), 97-104.
• Johnson, D. G., Fujimoto, W. Y., & Williams, R. H. (1973). Enhanced release of insulin by prostaglandins in isolated pancreatic islets. Diabetes, 22(9), 658-63.
• Johnson, D. G., Weise, V. K., Hanbauer, I., Silberstein, S. D., & Kopin, I. J. (1973). Dopamine-beta-hydroxylase activity during sympathetic reinnervation of rat iris in organ culture. Neurobiology, 3(2), 88-90.
• Maengwyn-Davies, G. D., Johnson, D. G., Thoa, N. B., Weise, V. K., & Kopin, I. J. (1973). Influence of isolation and of fighting on adrenal tyrosine hydroxylase and phenylethanolamine-N-methyltransferase activities in three strains of mice. Psychopharmacologia, 28(4), 339-50.
• Hanbauer, I., Johnson, D. G., Silberstein, S. D., & Kopin, I. J. (1972). Pharmacological and kinetic properties of uptake of ( 3 H)-norepinephrine by superior cervical ganglia of rats in organ culture. Neuropharmacology, 11(6), 857-62.
• Johnson, D. G., Silberstein, S. D., Hanbauer, I., & Kopin, I. J. (1972). The role of nerve growth factor in the ramification of sympathetic nerve fibres into the rat iris in organ culture. Journal of neurochemistry, 19(9), 2025-9.
• Kopin, I. J., Silberstein, S. D., Johnson, D. G., Hanbauer, I., & Jacobowitz, D. M. (1972). Sympathetic reinnervation of the rat iris in vitro. Advances in biochemical psychopharmacology, 6, 89-92.
• Silberstein, S. D., Johnson, D. G., Hanbauer, I., Bloom, F. E., & Kopin, I. J. (1972). Axonal sprouts and ( 3 H)norepinephrine uptake by superior cervical ganglia in organ culture. Proceedings of the National Academy of Sciences of the United States of America, 69(6), 1450-5.
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  Superior cervical ganglia from adult rats maintained in organ culture show a progressive increase in the rate of uptake of [(3)H]norepinephrine. The enhanced uptake of norepinephrine is a consequence of the development of axonal sprouts. Formation of axonal sprouts, which appear to have many of the properties of sympathetic nerve endings, is inhibited by colchicine and vinblastine, presumably because of the interaction of these drugs with neurotubular protein.
• Thoa, N. B., Johnson, D. G., & Kopin, I. J. (1972). Inhibition of norepinephrine biosynthesis by -methyl amino acids in the guinea-pig vas deferens. The Journal of pharmacology and experimental therapeutics, 180(1), 71-7.
• Johnson, D. G., Gorden, P., & Kopin, I. J. (1971). A sensitive radioimmunoassay for 7S nerve growth factor antigens in serum and tissues. Journal of neurochemistry, 18(12), 2355-62.
• Johnson, D. G., Thoa, N. B., & Kopin, I. J. (1971). Inhibition of norepinephrine biosynthesis by chlorpromazine in the guinea-pig vas deferens. The Journal of pharmacology and experimental therapeutics, 177(1), 146-54.
• Johnson, D. G., Thoa, N. B., Weinshilboum, R., Axelrod, J., & Kopin, I. J. (1971). Enhanced release of dopamine- -hydroxylase from sympathetic nerves by calcium and phenoxybenzamine and its reversal by prostaglandins. Proceedings of the National Academy of Sciences of the United States of America, 68(9), 2227-30.
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  Dopamine-beta-hydroxylase (EC 1.14.2.1), an enzyme localized in sympathetic synaptic vesicles, was released together with norepinephrine during in vitro stimulation of the hypogastric nerve that innervates the vas deferens of the guinea pig. Stimulation of the nerve in the presence of high concentrations of calcium (7.5 mM) or phenoxybenzamine caused a marked increase in the amounts of the enzyme and norepinephrine released into the bath. The augmentation of release of dopamine-beta-hydroxylase by 7.5 mM calcium or phenoxybenzamine was reversed by prostaglandin E(2). These findings suggest that the release of the sympathetic neurotransmitter, norepinephrine, occurs by a process of exocytosis in which the vesicular content of soluble dopamine-beta-hydroxylase is also released. The depolarization-induced exocytosis, which is stimulated by calcium, may be affected by prostaglandin E(2) or phenoxybenzamine through inhibition or enhancement of the actions of calcium in the release process.
• Kopin, I. J., Silberstein, S. D., Johnson, D. G., Hanbauer, I., & Jacobwitz, D. M. (1971). Sympthetic reinnervation of the rat iris in vitro. Third International Society for Neurochemistry.
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  Raven Press (New York),
• Silberstein, S. D., Johnson, D. G., Jacobowitz, D. M., & Kopin, I. J. (1971). Sympathetic reinnervation of the rat iris in organ culture. Proceedings of the National Academy of Sciences of the United States of America, 68(6), 1121-4.
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  Reinnervation of sympathetically denervated rat iris by superior cervical ganglion cells has been demonstrated to occur in vitro. Return of [(3)H]norepinephrine uptake by irises incubated in contact with ganglia was associated with the reappearance of nerve fibers containing catecholamines that were demonstrable by fluorescent histochemistry. The reinnervating neurons appeared to follow the same general pattern of innervation seen in the normal iris, but the density of the neural plexus was much greater. Nerve growth factor influenced the rate and extent of innervation of the iris but not of neuronal growth within the ganglion.
• Thoa, N. B., Johnson, D. G., & Kopin, I. J. (1971). Selective release of newly synthesized norepinephrine in the guinea pig vas deferens during hypogastric nerve stimulation. European journal of pharmacology, 15(1), 29-35.
• Thoa, N. B., Johnson, D. G., Kopin, I. J., & Weiner, N. (1971). Acceleration of catecholamine formation in the guinea-pig vas deferens after hypogastric nerve stimulation: roles of tyrosine hydroxylase and new protein synthesis. The Journal of pharmacology and experimental therapeutics, 178(3), 442-9.
• Weinshilboum, R. M., Thoa, N. B., Johnson, D. G., Kopin, I. J., & Axelrod, J. (1971). Proportional release of norepinephrine and dopamine- -hydroxylase from sympathetic nerves. Science (New York, N.Y.), 174(4016), 1349-51.
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  Dopamine-beta-hydroxylase(DBH), the enzyme that catalyzes the conversion of dopamine to norepinephrine, is localized in the vesicles containing catecholamine in sympathetic nerves. This enzyme is released with norepinephrine when the nerves to the guinea pig vas deferens are stimulated in vitro, and the amount of enzyme discharged increases as the length of stimulation periods increases. The amount of DBH released is proportional to the amount of norepinephrine released, and the ratio of norepinephrine to DBH discharged into the incubation medium is similar to that in the soluble portion of the contents of the synaptic vesicles from the vas deferens. These data are compatible with the release of the neurotransmitter norepinephrine and DBH from symnpathetic nerves by a process of exocytosis.
• Galton, V. A., Valtin, H., & Johnson, D. G. (1966). Thyroid function in the absence of vasopressin. Endocrinology, 78(6), 1224-9.
• Johnson, D. G. (1966). The effect of cold exposure on the catecholamine excretion of rats treated with decaborane. Acta physiologica Scandinavica, 129.
• Johnson, D. G. (1965). Adrenomedullary response to 2-deoxyglucose in the hypothyroid, euthyroid, and hyperthyroid rat. Acta physiologica Scandinavica, 65(4), 337-43.

Others

• Davy, K. P., Johnson, D. G., & Seals, D. R. (1995, January). Cardiovascular, plasma norepinephrine, and thermal adjustments to prolonged exercise in young and older healthy humans.. Clinical Physiology.
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  Clin Physiol, 1995. Revised January 9, 2006
• Ng, A. V., Johnson, D. G., Callister, R., & Seals, D. R. (1995, January). Muscle sympathetic nerve activity during postural change in healthy young and older adults. Clinical Autonomic Research.
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  Clin Auto Res 5(1):57-60, 1995.
• Johnson, D. G. (1994, January). Endocrine Emergencies in the Intensive Care Unit. American Society Hospital Pharmacists.
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  American Society Hospital Pharmacists. Abstr. SPG-29. 1994
• Kregel, K. C., Johnson, D. G., Tipton, C. M., & Seals, D. R. (1992, January). Regional norepinephrine depletion during nonexertional heating in the conscious rat.. "Federation proceedings"[Journal].
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  Fed Proc 1992.
• Taylor, J. A., Hand, G. A., Johnson, D. G., & Seals, D. R. (1992, January). Augmented forearm vasoconstriction during dynamic exercise in healthy older men. Circulation.
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  Circulation, 1992.
• Johnson, D. G. (1991, January). Biguanides: try them again for the first time.. International Diabetes Federation.
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  International Diabetes Federation, Washington, DC, 1991.
• Taylor, J. A., Hand, G. A., Johnson, D. G., & Seals, D. R. (1991, January). Sympathetic-vasoconstrictor adjustments to submaximal isometric exercise in young and older men.. American College of Sports Medicine.
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  Am College Sports Medicine, 1991.
• Seals, D. R., Reiling, M. J., & Johnson, D. G. (1990, Janauary). Peak sympathetic nerve activity during fatiguing isometric exercise in humans.. Society for Neuroscience.
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  Soc Neurosci 1990
• Fagan, T. C., Conrad, K. A., Mackie, M. J., Johnson, D. G., Mazzu, A. L., & Burkholder, D. E. (1989, January). Effects of meals and nitrendipine on serum glucose, insulin, glucagon and norepinephrine IV.. World Conference on Clinical Pharmacology and Therapeutics 1989..
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  World Conference on Clinical Pharmacology and Therapeutics 1989.
• Goodby, C. S., Ritenbaugh, C., & Johnson, D. G. (1989, January). Population differences in insulin response to oral glucose tolerance test under two different diet conditions.. Federation of American Societies for Experimental Biology.
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  FASEB Journal V.3:A539 (abst.1823), 1989.
• Jaspan, J., Malone, J., Nikolai, T., Rand, L., Gitelman, H., Raskin, P., Johnson, D. G., McRae, J., & Bergman, M. (1989, January). Clinical response to sorbinil (S) in painful diabetic neuropathy (DN).. Diabetes.
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  Diabetes 38 (Suppl 2):14A (abst. 56), 1989.
• Kregel, K. C., Tipton, C. M., & Johnson, D. G. (1989, January). Arterial baroreflexes modulate the sympathetic cardiovascular and thermal adjustments to heat stress in the conscious rat. Circulation.
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  Circ 80:II 290, 1989.
• McKee, R. L., Brendel, K., Trivedi, D., Zechel, C., Johnson, D. G., & Hruby, V. J. (1987, January). Activities of glucagon antagonists on normal and diabetic liver: evidence for cAMP independent events.. Tenth American Peptide Symposium.
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  Tenth American Peptide Symposium (abst.), 1987.
• Johnson, D. G., Pelton, J. T., Ayres, E., & Hruby, V. (1985, January). Inhibition of glucagon and insulin release by synthetic analogs of somatostatin. XII Congress of the International Diabetes Federation. Diabetes Research and Clinical Practice.
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  XII Congress of the International Diabetes Federation. Diabetes Res and Clin Pract E.9. Suppl 1:705, 1985.
• Johnson, D. G., Pelton, J. T., Ayres, E., & Hruby, V. (1985, January). Inhibition of glucagon and insulin release by synthetic analogs of somatostatin.. Clinical Research.
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  Clin Res 33:102A, 1985.
• Johnson, D. G., McCreary, J. M., Thompson, W. J., & DeHaen, C. (1984, Janury). Inhibition of pancreatic islet phosphodiesterase by 2,4 diamino 5 cyano 6 bromo pyridine.. Advanced Cyclic Nucleotide Research Protein Phosphorylation.
  More info

  Adv. Cyclic Nucleotide Res. Protein Phosphorylation 16:419, 1984.
• Escourrou, P., Rowell, L. B., Johnson, D. G., & Blackmon, J. R. (1983, January). Plasma catecholamines, hepatic function and blood flow during hypoxia and exercise in humans.. "Federation proceedings"[Journal].
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  Fed Proc 42:4722 (abst.), 1983.
• Johnson, D. G., Smith, P., Thompson, W. J., & DeHaen, C. (1983, January). Bronchodilator activity of a non xanthine phosphodiesterase inhibitor, 2,4 diamino 5 cyano 6 bromopyridine. Clinical Research.
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  Clin Res 31:20A, 1983
• Orlander, P. R., Johnson, D. G., & Hruby, V. (1982, January). Effects of a glucagon receptor antagonist on insulin release in the perfused rat pancreas. Clinical Research.
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  Clin Res 30:102A, 1982.
• Hruby, V. J., Bregman, M. D., Johnson, D. G., Ulichny, C., & Trivedi, D. (1981, January). In vivo and in vitro studies with glucagon inhibitors.. Seventh American Peptide Symposium..
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  Seventh American Peptide Symposium. 1981.
• Johnson, D. G., & Conley, V. K. (1981, January). Stimulation of gastrin secretion by scorpion toxin in the perfused rat antrum.. Clinical Research.
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  Clin. Res 29:85A, 1981
• Johnson, D. G., Dickerson, R., Rutala, P., & Bressler, R. (1980, January). Clinical evaluation of pirogliride in patients with maturity onset diabetes. Clinical Research.
• Ulichny, C., Johnson, D. G., Hruby, V., Bregman, M., & Trivedi, D. (1981, January). Effect of glucagon inhibitor on blood glucose in diabetic rats. Diabetes.
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  Diabetes 30:1981.
• Banner, W., Johnson, D. G., Walson, P., & Jung, D. (1980, January). Effects of phenytoin on glucose homeostasis.. World Conference on Clinical Pharmacology and Therapeutics..
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  World Conference on Clinical Pharmacology and Therapeutics. (Abst 0728), 1980.
• Johnson, D. G., & DeHaen, C. (1980, January). : Potentiation of insulin release by 2, 4 diamino 5 cyano 6 halopyridines.. "Federation proceedings"[Journal].
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  Fed Proc 39: (Abst 2919), 1980
• Johnson, D. G., Dickerson, J., Rutala, P., & Bressler, R. (1980, January). Pirogliride in maturity onset diabetes.. World Conference on Clinical Pharmacology and Therapeutics..
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  World Conference on Clinical Pharmacology and Therapeutics. (Abst 0138), 1980.
• Johnson, D. G., Villar, H. V., Smith, P. H., & Brown, J. C. (1980, January). Immunoreactive gastric inhibitory polypeptide in a glucagonoma.. Diabetes.
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  Diabetes 29:107 (Abst 419), 1980.
• Villar, H. V., Johnson, D. G., Lynch, P. L., Pond, G. D., & Smith, P. H. (1980, January). Successful removal of glucagonoma after 16 year history of symptoms.. Society for Surgery of the Alimentary Tract. 21st Meeting.
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  Society for Surgery of the Alimentary Tract. 21st Meeting (Abst 227), 1980.
• Dillmann, E., Gale, C., Green, W., Johnson, D. G., & Finch, C. A. (1979, January). Tissue effects of iron deficiency.. 4th International Conference on Proteins of Iron Metabolism (Abst).
• Dillmann, E., Gale, C., Green, W., Johnson, D. G., Mackler, B., & Finch, C. (1979, January). Abnormal thermoregulation due to an impaired T4 to T3 conversion in iron deficiency.. Clinical Research.
• Johnson, D. G., & Conley, V. (1979, January). Gastric inhibitory polypeptide can mediate post inhibitory overshoot of insulin release.. Diabetes.
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  Diabetes 28:406 (Abst 247), 1979.
• Johnson, D. G., & DeHaen, C. (1979, January). 2,4 diamino 5 cyano 6 halopyridines: a new class of insulin secretagogues.. Clinical Research.
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  Clin Res 27:85A, 1979
• Dillmann, E., Johnson, D. G., Martin, J., & Finch, C. (1978, January). Catecholamines and thermogenesis in iron deficiency.. Blood.
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  Blood 52 (Suppl 1):79, (Abstr 14) 1978.
• Smith, P. H., Merchant, F. W., Johnson, D. G., & Williams, R. H. (1978, January). Immunocytochemical localization of pancreatic and intestinal cells containing gastric inhibitory polypeptide (GIP). The Anatomical Record.
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  Anat Rec 190:154, 1978.
• Fujimoto, W. Y., Ensinck, J. W., Johnson, D. G., Merchant, F. W., & Smith, P. (1977, January). Gastric inhibitory polypeptide (GIP), cholecystokinin (CCK), secretin (S) effects on in vitro insulin and glucagon secretion.. Diabetes.
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  Diabetes 26 (Suppl 1):177, 1977.
• Fujimoto, W. Y., Merchant, F. W., Smith, P. H., Johnson, D. G., & Williams, R. H. (1977, January). Gastric inhibitory peptide stimulates insulin secretion from neonatal rat pancreatic monolayer cultures.. Clinical Research.
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  Clin Res 25:159A, 1977.
• Johnson, D. G., Merchant, F. W., Smith, P. H., Fujimoto, W. Y., & Williams, R. H. (1977, January). Binding and action of gastric inhibitory polypeptide in the endocrine pancreas of the rat.. "Federation proceedings"[Journal].
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  Fed Proc 36:299, 1977.
• Marques, P. R., Williams, D. D., Illner, P., Steiner, R., Shen, L., Johnson, D. G., Baylink, D. J., & Gale, C. C. (1977, January). Acute cold stress in goats: Assessment of endogenous catechols in the physiological regulation of parathyroid hormone.. 6th Parathyroid Conference.
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  6th Parathyroid Conference, Vancouver, Canada 75, 1977
• Smith, P. H., Merchant, F. W., Johnson, D. G., Fujimoto, F. Y., & William, R. H. (1977, January). Immunocytochemical localization of gastric inhibitory polypeptide in the pancreatic islet A cells of rats and humans.. The Anatomical Record.
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  Anat Rec 187:717, 1977.
• Benson, J., Johnson, D. G., Palmer, J., & Werner, P. (1976, January). Glucagon and catecholamine secretion in response to hypoglycemia in diabetes. Clinical Research.
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  Clin Res 24:115A, 1976
• Ensinck, J. W., Laschansky, E., Knoeber, M., Johnson, D. G., Benson, J., & Goodner, C. J. (1976, January). Distribution of somatostatin (S) measured by radioimmunoassay. Clinical Research.
  More info

  Clin Res 24:155A, 1976.
• Johnson, D. G., Hayward, J. S., Jacobs, T. P., Collis, M. L., Eckerson, J. D., & Williams, R. H. (1976, January). Plasma norepinephrine responses of man in cold water. Clinical Research.
  More info

  Clin Res 23:362A, 1976.
• Johnson, D. G., & Ensinck, J. W. (1975, January). Stimulation of glucagon secretion by scorpion toxin in the perfused rat pancreas.. Diabetes.
  More info

  Diabetes 24:68, 1975.
• Johnson, D. G., Henry, D. P., Moss, J., & Williams, R. H. (1975, January). Inhibition of insulin secretion by scorpion toxin.. Federation proceedings"[Journal].
  More info

  Fed Proc 34:2951, 1975
• Chen, M., Smith, P. H., Woods, S. C., Johnson, D. G., & Porte, Jr, D. (1974, January). Direct inhibitory effects of somatostatin on dog pancreatic endocrine function in vivo. Diabetes.
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  Diabetes 23:78, 1974.
• Henry, D. P., Johnson, D. G., & Williams, R. H. (1974, January). Kinetic studies of dopamine B hydroxylase in rat serum.. Federation proceedings"[Journal].
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  Fed Proc 33:1615, 1974.
• Johnson, D. G., Ensinck, J. W., Koerker, D., Palmer, J., & Goodner, C. J. (1974, January). Inhibition of glucagon and insulin secretion by somatostatin in the rat pancreas perfused in situ.. Diabetes.
  More info

  Diabetes 23:374, 1974
• Johnson, D. G., Henry, D. P., Ensinck, J. W., Aagaard, G. N., & Williams, R. H. (1974, January). Abnormal synthesis of norepinephrine in idiopathic orthostatic hypotension.. Clinical Research.
  More info

  Clin Res 22 (3):557A, 1974.
• Johnson, D. G. (1973, January). Modulatory control of sympathetic neurotransmission by prostaglandins.. Transactions of the American Society for Neurochemistry.
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  Transactions of the American Society for Neurochemistry 4:56, 1973.
• Johnson, D. G., Thompson, W. J., & Williams, R. H. (1973, January). Stimulation of adenyl cyclase from isolated pancreatic islets by prostaglandins. Federation proceedings"[Journal].
  More info

  Fed Proc 32:3293, 1973.
• Thompson, W. J., Johnson, D. G., & Williams, R. H. (1973, January). Modulation of the hormonal stimulation of adenyl cyclase from isolated pancreatic islets by guanosine triphosphate.. Diabetes.
  More info

  Diabetes 22:34, 1973.
• Cramer, H., Johnson, D. G., Silberstein, S. D., & Kopin, I. J. (1971, January). Effects of catecholamines on cyclic AMP levels in rat superior cervical ganglia in vitro. Pharmacologist.
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  Pharmacologist 13:365, 1971 13:365, 1971
• Hanbauer, I., Johnson, D. G., Silberstein, S. D., & Kopin, I. J. (1971, January). Enhanced (3 H) norepinephrine uptake in superior cervical ganglia in organ culture. Pharmacologist.
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  Pharmacologist 13:71, 1971
• Johnson, D. G., Gorden, P., & Kopin, I. J. (1971, January). Nerve growth factor determination by a sensitive radioimmunologic assay in mouse serum and tissues. Federation proceedings"[Journal].
  More info

  Fed Proc 31:1172, 1971.
• Johnson, D. G., Stromberg, P., Fujimoto, W. Y., & Williams, R. H. (1971, January). Enhanced release of insulin by prostaglandins in isolated pancreatic islets.. Diabetes.
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  Diabetes 21:21, 1971.
• Johnson, D. G., Thoa, N. B., & Kopin, I. J. (1971, January). Chlorpromazine inhibition of norepinephrine biosynthesis in the guinea pig vas deferens. Federation proceedings"[Journal].
  More info

  Fed Proc 29:943, 1971.
• Maengwyn Davies, G. D., Johnson, D. G., Thoa, N. B., Weise, V. K., & Kopin, I. J. (1971, January). Effect of fighting on adrenal medullary enzymes in mice. Pharmacologist.
  More info

  Pharmacologist 13:621, 1971.
• Silberstein, S. D., Johnson, D. G., Hanbauer, I., & Kopin, I. J. (1971, January). Sympathetic reinnervation of the rat iris in organ culture.. Pharmacologist.
  More info

  Pharmacologist 13:69, 1971.
• Weinshilboum, R., Johnson, D. G., Thoa, N. B., Axelrod, J., & Kopin, I. J. (1971, January). Proportional release of dopamine B hydroxylase (DBH) and norepinephrine (NE) during sympathetic nerve stimulation.. Pharmacologist.
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  . Pharmacologist 13:213, 1971.