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Biomedical subjects

B B Hoffman

Publications and source records attributed to B B Hoffman.

At least 127 records · Page 7Linked to original sources

Insulin resistance, glucose intolerance and hyperinsulinemia in patients with hypertension.

Plasma glucose and insulin responses to an oral glucose challenge and insulin-stimulated glucose uptake were measured in 47 age-, weight-, and sex-matched lean white men (16 with normal blood pressure, 14 with untreated hypertension, nine treated with a thiazide diuretic only, and eight treated with combined diuretic and beta-adrenergic antagonist drugs). Following a 75-g glucose dose, plasma glucose and insulin were measured for a three-hour period. In separate studies, insulin-stimulated glucose uptake was estimated by measuring the steady-state plasma glucose (SSPG) and insulin (SSPI) concentrations achieved during the last 30 minutes of a 180-minute continuous infusion of somatostatin, insulin, and glucose (insulin suppression test). Under these conditions endogenous insulin secretion was suppressed, and differences in SSPG concentration allowed comparisons of the ability of exogenous insulin to stimulate disposal of an identical glucose load in different individuals. The results indicated that men with untreated hypertension had significantly elevated plasma glucose (P less than .001) and insulin concentrations (P less than .001) after an oral challenge compared to normal volunteers. Mean SSPG concentrations were also higher (P less than .05) than normal in patients with untreated hypertension.2+ Furthermore, plasma glucose and insulin concentrations after the oral glucose challenge and SSPG concentration during the insulin suppression test were higher in treated than in treated patients than in untreated patients with hypertension. These results confirm earlier observations that untreated patients with hypertension are insulin resistant, hyperglycemic, and hyperinsulinemic compared to a well-matched normotensive control group, and suggest that conventional treatment programs for lowering blood pressure many exaggerated these metabolic defects.

Contraceptives, Oral, Combined↗

Comparison of age-related changes in prostaglandin E1 and beta-adrenergic responsiveness of vascular smooth muscle in adult males.

Aging in humans is associated with a general decline in beta-adrenergic receptor responsiveness. Whether this is a consequence of a defect at the receptor level or along the adenylate cyclase pathway is not known. Using a technique to measure compliance of dorsal hand veins, we investigated the venodilatory response to isoproterenol and prostaglandin E1 (PGE1), which interact with distinct membrane-bound receptors but activate the same adenylate cyclase system. Studies were conducted in 7 young (Y, less than 30 years) and 7 elderly (E, greater than 60 years) healthy male volunteers. Dilatation induced by isoproterenol (mean +/- SD) was 43 +/- 8% in E vs 97 +/- 17% in Y, p = .003. However, PGE, produced complete relaxation in both Y and E subjects (122 +/- 17% vs 97 +/- 19% respectively, p = .270). The sensitivity to PGE1 was not significantly different between the Y and E. Our results demonstrate that PGE1 is a potent venodilator in humans and that the age-related decline in vascular response is specific to beta-adrenoceptor agonists and does not reflect a generalized loss in responsiveness to adenylate cyclase coupled receptors.

Adult↗

Desensitization of alpha 1 adrenoceptor-stimulated glycogen phosphorylase activity in vascular smooth muscle.

Desensitization of alpha 1-adrenoceptor-mediated activation of glycogen phosphorylase was investigated in rabbit aorta. Activation of glycogen phosphorylase by epinephrine was antagonized by the alpha 1-receptor selective antagonist prazosin but not by yohimbine (alpha 2-receptor selective) or by propranolol (beta-receptor antagonist). Preincubation of rabbit aortic ring segments for 5 h with norepinephrine (NE, 10(-5) M) led to a 30-fold loss in sensitivity and a 55% decrease in maximal activation of the enzyme by alpha agonists. Preincubation of aortic ring segments with phenylephrine (10(-5) M) in the presence of propranolol (10(-6) M) also caused desensitization of glycogen phosphorylase activation. The desensitization was heterologous since maximal activation of the enzyme by histamine or KCl was also markedly diminished in segments preincubated with NE. In contrast to these results, catecholamine-induced desensitization to alpha 1-adrenoceptor-mediated smooth muscle contraction in aortic ring segments resulted in loss in sensitivity but not maximal force of contraction on subsequent stimulation by alpha 1 agonists. These results suggest that the mechanism responsible for desensitization of glycogen phosphorylase is distal to receptor activation and may involve attenuation of responses to intracellular Ca2+-dependent enzymes which have limited reserve.

Animals↗

Responsiveness of peripheral veins to transdermal and sublingual nitroglycerin in healthy male volunteers.

Nitroglycerin (NTG) is a potent vascular smooth muscle relaxant. With the widespread use of transdermal NTG patches for the prophylaxis of angina, two important issues have arisen: (a) the relative efficacy of transdermal NTG patches compared to other formulations of NTG, and (b) the possibility of development of tolerance to transdermal NTG. We have investigated these two issues by studying the effect of systemically administered NTG (transdermal patches, ointment, and sublingual tablets) on alpha-adrenergic receptor agonist-mediated constriction of human dorsal hand veins. Nitroglycerin patches and ointment (15-60 mg/24 h) applied for 1-4 h did not modify the sensitivity (ED50) to the alpha-adrenergic agonist, phenylephrine. However, sublingual NTG (0.15-0.60 mg) administration caused significant relaxation of partially constricted veins. Following exposure for 24 h to a NTG patch (15 mg/24 h), NTG dose-response curves were not altered suggesting there was no development of tolerance to transdermal NTG. We conclude from our observations that tolerance to transdermal NTG does not appear in veins, possibly due to the low plasma NTG concentrations produced by this preparation. Our results also indicate that high doses of transdermal NTG do not modify phenylephrine-mediated constriction of peripheral veins in humans.

Administration, Cutaneous↗

Responsiveness of superficial hand veins to phenylephrine in essential hypertension. Alpha adrenergic blockade during prazosin therapy.

Patients with essential hypertension show an increase in vascular resistance. It is unclear whether this is caused by structural changes in the arterial wall or by hyperresponsiveness of vascular smooth muscle to endogenous alpha adrenergic agonists. Using the dorsal hand vein compliance technique we compared the changes in diameter of superficial veins in response to phenylephrine, an alpha 1 adrenergic receptor agonist, and to nitroglycerin, a venorelaxant, in patients with essential hypertension and in normotensive subjects. The dose of phenylephrine that produced 50% of maximal venoconstriction (ED50) in the hypertensive subjects was 257 ng/min (geometric mean; log mean +/- SD was 2.41 +/- 0.54). In the control subjects the ED50 was 269 ng/min (geometric mean; log mean was 2.43 +/- 0.43). Maximal response (Emax) for phenylephrine was 84 +/- 13% in the hypertensive subjects and 90 +/- 6% in the control subjects. Differences in the group means of the ED50 (P = 0.92) or the Emax (P = 0.27) were not significant. There were no significant differences in the ED50 (P = 0.54) or the Emax (P = 0.08) for nitroglycerin between the two groups. These results show no evidence for a generalized change in alpha adrenergic responsiveness in hypertension and support the concept that increased blood pressure responses to alpha adrenergic stimulation in hypertensives are due to structural and geometric changes in the arterial wall rather than to an increased responsiveness of postsynaptic alpha adrenergic receptors. The phenylephrine studies were repeated in seven hypertensive patients during treatment with prazosin, an alpha 1 adrenergic antagonist. The mean dose ratio of the shift in phenylephrine ED50 (ED50 during prazosin therapy/ED50 before prazosin therapy) was 6.1. This indicates that small doses of prazosin (1-2 mg) cause significant in vivo shifts in the dose-response relationship of alpha adrenergic agonists. The dorsal hand vein compliance technique is useful in detecting systemic effects of alpha adrenergic antagonists.

Adrenergic alpha-Antagonists↗

Cellular tolerance to adenosine receptor-mediated inhibition of lipolysis: altered adenosine 3',5'-monophosphate metabolism and protein kinase activation.

Prolonged exposure of many types of cells to drugs or hormones that inhibit the activity of the enzyme adenylate cyclase, such as narcotics and alpha 2-adrenergic agonists, leads to enhanced accumulation of cAMP upon removal of the inhibitory drug. We have found previously that chronic infusion of the adenosine A1 receptor agonist phenylisopropyladenosine (PIA), an inhibitor of adenylate cyclase, into rats leads to enhanced isoproterenol-stimulated cAMP accumulation in adipocytes isolated from these animals. The enhanced cAMP accumulation was associated with an impaired ability of PIA to inhibit lipolysis in these cells. In the present study we have investigated the mechanism of the enhanced cAMP accumulation in adipocytes from PIA-infused rats and the relationship of these changes to the impaired antilipolytic action of the drug. The enhanced isoproterenol-stimulated cAMP accumulation in adipocytes prepared from PIA-infused rats was due to both an increased rate of cAMP synthesis and a decreased rate of cAMP metabolism at high concentrations of cAMP without a change in phosphodiesterase activity. There was heterologous desensitization of the ability of PIA, prostaglandin E1, and nicotinic acid to inhibit cAMP accumulation in the adipocytes from PIA-infused rats; there was an increase in the EC50 of each of these agonists, although maximal inhibition of cAMP accumulation was similar. The relationship between the activation of cAMP-dependent kinase and extent of lipolysis was similar in the two groups of cells. We demonstrated that the explanation for the impaired ability of PIA to decrease the rate of isoproterenol (10(-7) M)-stimulated lipolysis in the cells from the PIA-infused rats was due to the markedly increased concentrations of cAMP in these cells, which led to sufficient activation of the kinase to maintain a high rate of lipolysis even in the presence of PIA. In addition, we found that the changes induced by the PIA infusion were largely reversible over a 2-day period after discontinuing the PIA infusion. These results demonstrate that adipocytes from PIA-infused rats provide an interesting model to investigate the mechanisms of tolerance to inhibitory drugs.

3',5'-Cyclic-AMP Phosphodiesterases↗

Resistance to insulin-stimulated glucose uptake in adipocytes isolated from spontaneously hypertensive rats.

The ability of insulin to stimulate glucose uptake and inhibit catecholamine-induced lipolysis was measured in adipocytes of similar size isolated from SHR and WKY rats. The results indicate that glucose transport was decreased in adipocytes from SHR rats; both basal (19 +/- 2 vs. 32 +/- 2 fmol.cell-1.s-1, P less than .001) and maximal (207 +/- 30 vs. 373 +/- 20 fmol.cell-1.s-1, P less than .01) insulin-stimulated glucose transport were lower in SHR than in WKY rats. In addition, the EC50 of insulin-stimulated glucose uptake was higher (921 +/- 82 vs. 557 +/- 69 pM insulin, P less than .05) in adipocytes from SHR rats than from WKY rats. The ability of phenylisopropyladenosine (PIA) to modulate basal and maximal insulin-stimulated glucose uptake was compared in adipocytes from SHR and WKY rats. These results also demonstrated that glucose uptake was decreased in adipocytes from SHR rats and that PIA similarly enhanced both basal and maximal insulin-stimulated glucose uptake in adipocytes from both groups. Although maximal isoproterenol-stimulated lipolysis was decreased in adipocytes from SHR rats, the ability of insulin to inhibit catecholamine-stimulated lipolysis was at least as great in adipocytes from SHR as from WKY rats. Despite the decrease in insulin-stimulated glucose transport in isolated adipocytes from SHR rats, total number of insulin receptors, their affinity for insulin, and the ability of insulin to stimulate receptor-associated tyrosine kinase activity were similar in adipocytes from SHR and WKY rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

Role of cyclic AMP-dependent protein kinase in the diminished beta adrenergic responsiveness of vascular smooth muscle with increasing age.

Beta adrenergic receptor-mediated relaxation of blood vessels declines with age although the mechanism is unknown. We have utilized the mesenteric artery and aorta of young and older rats to investigate this problem. In vessels from 12-month-old rats there was a marked loss in relaxation mediated by beta adrenergic and adenosine receptors compared to younger rats whereas relaxation induced by muscarinic cholinergic receptors, [cyclic AMP (cAMP) independent], was not impaired. Maximal relaxation to forskolin and dibutyryl cAMP were intact in the vessels from older rats. Isoproterenol-stimulated cAMP accumulation and cAMP-dependent protein kinase activation were attenuated markedly in the vessels from the older rats. Maximal forskolin-stimulated cAMP accumulation and cAMP-dependent protein kinase activation were similar in older and young animals. There was an excellent correlation between cAMP-dependent protein kinase activity and relaxation and the relationship was similar in the two age groups. Continuous infusion of the beta adrenergic antagonist timolol for 1 week into older animals partially restored relaxation to beta adrenergic and adenosine receptor agonists in the aorta. These results suggest that the age-related loss of response to beta adrenergic receptor agonist-induced relaxation may be due in part to attenuated activation of cAMP dependent protein kinase and this change may be partially dependent on endogenous catecholamines.

Aging↗

Chronic somatostatin treatment induces enhanced forskolin-stimulated cAMP accumulation in wild-type S49 mouse lymphoma cells but not in protein kinase-deficient mutants.

Many different types of cells exhibit a supersensitivity of adenylate cyclase after chronic treatment with inhibitory drugs; this phenomenon is manifested by enhanced cAMP accumulation upon removal of the inhibitory drug. Acute treatment of wild-type S49 cells with the somatostatin analog SMS 201-995 (SMS) results in inhibition of cAMP accumulation. We have found that chronic SMS treatment of S49 cells results in enhanced isoproterenol- and forskolin-stimulated cAMP accumulation after removal of the SMS. The forskolin-stimulated cAMP synthetic rate was about 57% higher in SMS-pretreated cells (14.22 +/- 1.02 pmol of cAMP/10(6) cells/min) than in untreated control cells (9.08 +/- 0.84 pmol of cAMP/10(6) cells/min). The time course of forskolin-stimulated intracellular cAMP accumulation is complex, with desensitization of cAMP synthesis and marked egress of cAMP from the cells. We have modeled the forskolin-stimulated cAMP time course to a simple function incorporating the initial synthetic rate and rate constants for desensitization and elimination (degradation plus egress). The mathematical modeling suggests that the difference in forskolin-stimulated cAMP time courses between control and SMS-pretreated cells can be explained on the basis of a difference in initial synthetic rates. We tested the hypothesis that the SMS-induced change in forskolin-stimulated cAMP accumulation is triggered by the decrement in the concentration of intracellular cAMP caused by SMS. We studied two independently isolated mutants of S49 cells that are devoid of cAMP-dependent protein kinase activity (kin-). Although SMS acutely inhibits cAMP accumulation in both kin- mutants, neither mutant exhibited an enhanced forskolin-stimulated cAMP synthetic rate after chronic SMS treatment. These results suggest that cAMP-dependent protein kinase is important in the induction of adenylate cyclase supersensitivity in wild-type S49 cells. The mechanistic signal for induction of supersensitivity may be the decreased cAMP accumulation that occurs in response to stimulation of inhibitory receptors, although other hypothetical mechanisms may be invoked.

Adenylyl Cyclase Inhibitors↗

Pharmacokinetic and pharmacodynamic principles of drug therapy in old age. Part 2.

In this Part 2, pharmacodynamic studies which have examined the possibility of true changes in drug "sensitivity" in old age are reviewed. In a variety of organ systems, age-related physiological changes are reflected in altered drug responsiveness in the elderly. Also, a better understanding of different pathophysiological background of disease in this age group leads to a more rational pharmacotherapeutic approach, which is exemplified in the recent drug therapy of hypertension in the elderly.

Aging↗

Pharmacokinetic and pharmacodynamic principles of drug therapy in old age. Part 1.

Changes in pharmacokinetics and pharmacodynamics which occur with aging are reviewed. In Part 1, age-related alterations in pharmacokinetics, which deals with absorption, distribution, metabolism and elimination of drugs, are summarized. Special emphasis is placed on "drug clearance" which conceptual importance for the evaluation of drug elimination has only been recently recognized. Age-related physiological alterations and their influence on major determinants for each organ clearance are discussed.

Aged↗

Venous responsiveness to atrial natriuretic factor in man.

The venorelaxant effect of atrial natriuretic factor in man was studied using the dorsal hand vein technique. Infusion of met-ANF to preconstricted veins at doses up to 240 ng min-1 in 11 healthy male subjects caused only minimal venorelaxation. Atrial natriuretic factor is unlikely to have a significant venorelaxant effect at physiological doses in man.

Adolescent↗

Lowering of plasma glucose in diabetic rats by antilipolytic agents.

Both nicotinic acid (NA) and the adenosine receptor agonist phenylisopropyladenosine (PIA) are potent antilipolytic agents. We have evaluated the ability of these compounds to lower plasma glucose concentration in 450-g male diabetic rats. Diabetes was induced by intravenous streptozotocin, and the rats were studied 7-10 days later. Mean (+/- SE) fasting glucose decreased 4 h after subcutaneous injections of PIA at 0 and 2 h. A similar change in plasma glucose level was also seen in rats injected with NA. The decrease in the concentration of plasma glucose in both instances was preceded by marked sustained reductions in plasma free fatty acid (FFA) concentrations; FFA decreased in PIA-injected rats and in response to NA. With injection of normal saline, neither plasma glucose nor FFA concentrations decreased in diabetic rats. There was no change in the plasma insulin concentration of rats that had hypoglycemic responses to PIA or NA. In vitro glucose uptake was determined in isolated adipocytes, and both PIA and NA were shown to increase basal and maximal insulin-stimulated glucose uptake. The stimulating effect of the two compounds was similar, and the magnitude of the effect was comparable in adipocytes from either normal or diabetic rats. As a result, neither NA nor PIA could restore the defects in glucose transport to normal in adipocytes from diabetic rats. Insulin-stimulated glucose uptake was assessed in vivo by determining the steady-state glucose response of diabetic rats to a continuous infusion of insulin and glucose and was found to be significantly enhanced in response to NA compared with NaCl.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

Attenuation of fructose-induced hypertension in rats by exercise training.

This study was initiated to see if the insulin resistance, hyperinsulinemia, and hypertension that follow feeding normotensive Sprague-Dawley rats a fructose-rich diet could be prevented by letting rats run spontaneously in exercise wheel cages. Blood pressure in sedentary rats increased from (mean +/- SEM) 125 +/- 2 to 148 +/- 3 mm Hg in response to 2 weeks of a high fructose diet, and this increment was significantly (p less than 0.001) attenuated in exercising rats (from 121 +/- 1 to 131 +/- 2 mm Hg). In addition, mean (+/- SEM) plasma insulin concentration was lower in fructose-fed rats allowed to run spontaneously (44 +/- 2 vs 62 +/- 5 microU/ml; p less than 0.01). Finally, resistance to insulin-stimulated glucose uptake was assessed by determining the steady state plasma glucose response to a continuous glucose and exogenous insulin infusion during a period in which endogenous insulin secretion was suppressed. The results of these studies indicated that the mean (+/- SEM) steady state plasma glucose concentration was significantly lower in the exercise-trained rats (127 +/- 5 vs 168 +/- 6 mg/dl; p less than 0.001), despite the fact that the steady state plasma insulin levels were also lower in rats allowed to run spontaneously (75 +/- 4 vs 90 +/- 5 microU/ml; p less than 0.05). Thus, the ability of exercise-trained rats to stimulate glucose disposal was enhanced as compared with that of sedentary rats fed the same fructose-rich diet. These data demonstrate that the insulin resistance, hyperinsulinemia, and hypertension produced in normotensive rats by feeding them a high fructose diet can be attenuated if rats are allowed to run spontaneously.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Mechanism for desensitization of beta-adrenergic receptor-stimulated lipolysis in adipocytes from rats harboring pheochromocytoma.

Prolonged stimulation of beta-adrenergic receptors with catecholamines leads to desensitization of their ability to activate cAMP accumulation. However, little is known about the relationship between these changes and possible alterations in physiological responses. We have used isolated adipocytes prepared from NEDH rats harboring pheochromocytomas, a norepinephrine-secreting tumor, to address this question. As expected, there was a decrease in the ability of isoproterenol to maximally activate cAMP accumulation in adipocytes from rat harboring pheochromocytoma [323 +/- 107 vs. 707 +/- 145 pmol/10(5) cells.min (mean +/- SD) in controls]. This change was associated with an increase in the EC50 of isoproterenol for activation of cAMP-dependent protein kinase (5.8 X 10(-8) vs. 2.4 X 10(-8) M in controls) and a decrease in maximal activation of the kinase (38 +/- 16% vs. 77 +/- 14% in controls). For lipolysis there was a loss in sensitivity to isoproterenol but no change in maximal lipolytic rate in the adipocytes from rats harboring pheochromocytoma. For both groups there was a similar relationship between kinase activation and lipolysis; maximal lipolysis had already occurred for protein kinase-A activity ratios less than 30%. Therefore, the blunted cAMP response in adipocytes from rats harboring pheochromocytoma did not impair the maximal lipolytic rate. These results demonstrate that adipocytes can efficiently maintain maximal lipolysis in a desensitized state because of considerable reserve in the biochemical cascade leading to the lipolytic response. In addition, our findings demonstrate that there are no regulatory changes induced by prolonged exposure to catecholamines that are distal to cAMP accumulation.

Adipose Tissue↗

Additive hypoglycemic effects of drugs that modify free-fatty acid metabolism by different mechanisms in rats with streptozocin-induced diabetes.

In this study the effect of two drugs [etomoxir and nicotinic acid (NA)] on plasma glucose, free-fatty acid (FFA), and triglyceride (TG) concentrations was determined in rats with streptozocin (STZ)-induced diabetes. The two compounds modify FFA metabolism by different mechanisms, etomoxir (ethyl-2-[6-(4-cholorophenoxyl)-hexyl]oxirane-2-carboxylate) by inhibiting hepatic fatty acid oxidation, and NA by inhibiting lipolysis in adipose tissue. Diabetes was induced in male Sprague-Dawley rats, weighing approximately 400 g, by STZ injection (30 mg/kg i.v.), and the metabolic effects of the two drugs were studied 7-10 days later. The acute administration of either etomoxir or NA lowered plasma glucose concentrations in diabetic rats by approximately 150 mg/dl (P less than .001) in 4 h. However, the two drugs differed dramatically in their effects on plasma FFA and TG concentrations. Specifically, etomoxir produced striking increases in plasma FFA and TG concentrations, whereas NA administration caused a marked decrease. However, when NA was given in conjunction with etomoxir, NA prevented the increase in plasma FFA and TG concentration seen with etomoxir; the combination of NA and etomoxir approximately doubled the decrease in plasma glucose concentration produced by NA or etomoxir when given alone. Because plasma insulin concentrations did not change in response to either drug, whether administered singly or in combination, these metabolic effects do not result from a change in insulin secretion. These results suggest that modulation of FFA metabolism at the level of the adipocyte or the liver can have dramatic effects on carbohydrate and lipid metabolism.

Adipose Tissue↗

Alpha-1 adrenergic receptors in the nonfailing and failing human heart.

We examined alpha-1 adrenergic receptor density in ventricular myocardium from nonfailing and failing human hearts, utilizing the alpha-1 radioligand [125I]IBE2254. The alpha-1 receptor population comprised a relatively small portion of the total adrenergic receptors, 14.6 +/- 1.9%. However, in failing human ventricular myocardium the alpha-1 adrenergic receptor population constituted a much greater portion, 27.3 +/- 2.1% (P less than .01). The reason for the increased proportion of alpha-1 adrenergic receptors was not that the total concentration of alpha-1 receptors was increased, but instead was due to selective down-regulation of the beta-1 adrenergic receptor population. Beta-2 adrenergic receptors behaved similarly to alpha-1 adrenergic receptors in the failing human heart, and were increased in proportion and unchanged in total number. Additionally, the ability of alpha-1 stimulation to increase the incorporation of label from [3H]inositol into inositol phosphates was examined in tissue homogenates. Maximal doses of norepinephrine produced only marginal stimulation of phosphatidylinositol hydrolysis, in contrast to a more substantial response produced by muscarinic stimulation. We conclude that human ventricular myocardium contains alpha-1 adrenergic receptors that 1) are of relatively low density, 2) are unchanged in density by heart failure and 3) mediate relatively low-level stimulation of phosphatidylinositol hydrolysis.

Carbachol↗