Biomedical subjects

B B Hoffman

Publications and source records attributed to B B Hoffman.

At least 109 records · Page 6Linked to original sources

PubMed1991

Beta-adrenergic responsiveness in cultured vascular smooth muscle cells and fibroblasts: effect of age.

beta-Adrenergic agonists stimulate cyclic 3',5'-adenosine monophosphate (cAMP) accumulation and relaxation in vascular smooth muscle; both of these responses decline in rat aorta with increasing age. To ascertain whether the deficit in beta-receptor stimulated cAMP accumulation persists in isolated aortic smooth muscle cells, the effect of isoproterenol on cAMP accumulation was measured in cultured vascular smooth muscle cells (VSMC) and vascular fibroblasts taken from young (4-6 weeks) and older (8-12 months) Fischer 344 male rats. Immunofluorescent staining confirmed the identity of VSMC as distinct from fibroblasts. Isoproterenol stimulated cAMP accumulation in a time- and concentration-dependent manner in both cell types; maximal cAMP accumulation induced by beta-adrenergic stimulation in cultured cells was much higher than those seen in the intact aorta. While there was a blunting of cAMP response to isoproterenol in fibroblasts cultured from the older rats, the response in VSMC cultured from the older rats was actually increased compared to the VSMC cultured from the younger rats. In contrast, activation of cAMP accumulation in the cultured cells by forskolin was similar in cells from older and young animals. The results suggest that the blunting in isoproterenol-stimulated cAMP accumulation found in aortas from older animals is not seen in VSMC cultured from these animals; whether this change in the culture reflects removal of some extrinsic factor in the older rats or is a consequence of intrinsic changes in the cells in culture requires further investigation.

Aging↗

PubMed1991

Responsiveness of peripheral veins to vasodilators and the effect of nifedipine on alpha-adrenergic responsiveness in hypertension.

Vasodilators have varying hemodynamic properties that may be important in determining their efficacy for different disorders. We used the dorsal hand vein technique to measure the effects of several vasodilators infused locally and to measure the action of systemically administered nifedipine. The venodilatory effects of hydralazine, verapamil, diazoxide, and nitroglycerin were determined in peripheral veins of healthy subjects. The potency (ED50, the dose producing half-maximal response) was as follows: nitroglycerin (0.0007 micrograms/min) greater than verapamil (6.5 micrograms/min) greater than diazoxide (75 micrograms/min) greater than hydralazine (660 micrograms/min). The effect of oral nifedipine on alpha-adrenergic responsiveness of hand veins was determined. Nifedipine given in therapeutic doses for the treatment of hypertension was associated with a threefold increase in the ED50 for phenylephrine (92 to 277 ng/min; p less than 0.05) and norepinephrine (2.9 to 11.5 ng/min; p less than 0.05). Therapeutic doses of nifedipine are associated with measurable shifts in the dose-response curves to these two alpha-adrenergic agonists in the hand vein. The hand vein technique can be used not only to compare the potency of locally infused drugs but also to measure venous effects of vasoactive drugs at therapeutic concentrations achieved after systemic administration.

Adult↗

PubMed1991

Age-associated differences in beta adrenergic-stimulated lipolysis in adipocytes from Sprague-Dawley and Fischer 344 rats.

We compared the ability of adipocytes isolated from the epididymal fat pads of Sprague-Dawley and Fischer 344 rats of different ages and weights to release glycerol in response to beta-adrenergic stimulation. Twelve-month-old Sprague-Dawley rats weighed approximately three times more than did 2-month-old rats of the same strain (761 +/- 61 g vs 223 +/- 8 g, p less than .001). Basal glycerol release was increased in the adipocytes of the 12-month-old rats (128 +/- 8 nmol/10(5) cells/L compared to the 2-month-old rats 51 +/- 3 nmol/10(5) cells/L). However, the ability of isoproterenol to stimulate glycerol release above basal was markedly decreased in the older and fatter Sprague-Dawley rats (178 +/- 15 nmol/10(5) cells/L vs 482 +/- 20 nmol/10(5) cells/L, p less than .001), and significant correlation coefficients between isoproterenol-stimulated glycerol release and both total body (r = .76, p less than .001) and fat pad (r = .83, p less than .001) weight were seen in Sprague-Dawley rats. Total body weights of 2-month (188 +/- 16 g), 12-month (393 +/- 15 g), and 27-month-old (402 +/- 36 g) Fischer 344 rats were less disparate. Isoproterenol-stimulated glycerol release was similar in the three groups of Fischer 344 rats, and there was no correlation between either total body or fat pad weight and lipolysis in these rats.

Adipose Tissue↗

PubMed1991

Desensitization of alpha-adrenergic receptor-mediated smooth muscle contraction: role of the endothelium.

Desensitization of alpha-adrenergic receptor-mediated smooth muscle contraction occur in aortas from New England Deaconess Hospital (NEDH) rats harboring pheochromocytoma (PHEO) and following chronic exposure to the alpha-adrenergic agonist phenylephrine in vitro. Endothelium is known to release an endothelial cell-derived relaxing factor that promotes smooth muscle relaxation. We wondered if the endothelium might contribute to the desensitization of contraction. The role of the endothelium in desensitization was studied using aortic rings with endothelium [E(+)] and with endothelium removed [E(-)]. Maximal phenylephrine (PE)-induced contraction (Emax) for E(+) was 1.7 +/- 0.3 g in controls and 0.4 +/- 0.1 g in PHEO (p less than 0.001), demonstrating desensitization; however, for E(-), Emax was 2.4 +/- 0.2 g in PHEO vs. 2.5 +/- 0.2 g in controls, demonstrating restoration of maximal contraction when the endothelium was removed. However, sensitivity [-log EC50(M)] to PE in E(-) remained significantly lower in PHEO compared to controls (6.94 +/- 0.12 vs. 7.51 +/- 0.14, respectively, p less than 0.001). Similarly, in aortic ring segments desensitized in vitro with phenylephrine, the maximal contraction in phenylephrine-exposed aortas was 60% of that seen in controls. Removal of the endothelium from the vessels pretreated with phenylephrine fully restored the maximal response and sensitivity of these vessels. Treatment of desensitized vessels with hemoglobin (5 x 10(-5) M) restored the maximal contraction and sensitivity to phenylephrine. When the endothelium was removed prior to chronic exposure to phenylephrine, the sensitivity to phenylephrine decreased while the Emax remained similar to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗

PubMed1991

Adrenergic pharmacology in rats harboring pheochromocytoma.

Hypertension and cardiomyopathy are prominent findings in both humans and rats harboring pheochromocytomas, tumors that secrete enormous quantities of catecholamines in an unregulated fashion. We used New England Deaconess Hospital rats harboring pheochromocytomas to investigate the effects of chronic exposure to high concentrations of catecholamines on desensitization of alpha- and beta-adrenergic receptor-mediated responses activated by catecholamines. In addition, rats harboring pheochromocytomas provide a useful model to investigate catecholamine-induced hypertension and cardiomyopathy.

Adrenal Gland Neoplasms↗

PubMed1991

Glucocorticoids induce transcription and expression of the alpha 1B adrenergic receptor gene in DTT1 MF-2 smooth muscle cells.

Steroid hormones modulate physiological processes by a number of mechanisms including regulation of gene expression. We wondered if glucocorticoids might induce expression of alpha 1 adrenergic receptors, which could contribute to the increased sensitivity of vascular smooth muscle to catecholamines that may occur with glucocorticoid excess. We examined the effects of dexamethasone on the expression of the alpha 1B adrenergic receptor gene in DDT1 MF-2 smooth muscle cells. Dexamethasone (10(-6) M) produced a 1.8 +/- 0.2-fold increase in expression of alpha 1B receptors determined with [3H]prazosin. Steady-state values of alpha 1B adrenergic receptor mRNA, analyzed by Northern blotting, increased 2.8 +/- 0.7-fold after 48 h exposure to dexamethasone. This effect of dexamethasone occurred in the presence of the protein synthesis inhibitor cycloheximide. alpha 1B receptor mRNA abundance was also increased by testosterone and aldosterone, whereas beta estradiol and progesterone had no effect. The alpha 1B receptor gene transcription rate, determined in nuclear run-off assays, increased 2.6 +/- 0.6-fold in cells treated with dexamethasone for 24 h. The half-life of the alpha 1B receptor mRNA was unchanged by dexamethasone. These data indicate that glucocorticoids regulate expression of alpha 1B receptors by increasing the rate of transcription of this gene.

Animals↗

PubMed1990

Age-related deficit in beta receptor stimulation of cAMP binding in blood vessels.

Both vascular relaxation and cAMP accumulation mediated by beta adrenergic agonists declines with increasing age. We have developed a method to measure the biologically relevant cAMP bound to the regulatory subunits of cAMP-dependent protein kinase in rat aorta. In homogenates of rat aorta, binding of [3H]cAMP was saturable with a Kd of 8.0 +/- 1.5 nM; the dissociation of [3H]cAMP from the binding sites was comprised of fast and slow components at 4 degrees C. Endogenous cAMP binding in aortas stimulated with isoproterenol (10(-5) M) or forskolin (10(-5) M) was quantitated by radioimmunoassay. Compared to basal values, isoproterenol increased cAMP binding by 37% (P less than 0.05) in aortas from young animals (5-6 weeks) but had essentially no effect on binding in older animals (9-11 months). In contrast, forskolin, which causes full relaxation in aortas from older rats, equally elevated bound cAMP values in aortas in the two age groups. In addition, the ratio of total cAMP binding sites to cAMP-dependent protein kinase catalytic activity was 45% higher in aortas from the older rats, suggesting that there were proportionately more regulatory subunits in those vessels. The deficit in isoproterenol-stimulated cAMP binding in vascular smooth muscle in older animals may in part explain the loss in relaxation mediated by beta adrenergic agonists.

Aging↗

PubMed1990

Effects of a fructose-enriched diet on plasma insulin and triglyceride concentration in SHR and WKY rats.

Significant increases (P less than 0.001) in plasma insulin and triglyceride concentrations and in blood pressure were seen when SHR and WKY rats ate a fructose-enriched diet for 14 days. However, all of the changes were significantly accentuated (P less than 0.02-0.001) in SHR rats. Specifically the increment in plasma insulin concentration following the fructose-enriched diet was 42 +/- 4 microU/ml in SHR as compared to 25 +/- 4 microU/ml in WKY rats (P less than 0.001). Plasma triglyceride concentrations also increased to a greater degree in response to fructose in SHR rats (260 +/- 24 vs. 136 +/- 20 mg/dl, P less than 0.001). Finally, the fructose-induced increase in blood pressure of 29 +/- 4 mm of Hg in SHR rats was greater (P less than 0.02) than that seen in WKY rats (19 +/- 2 mm of Hg). There was no change in plasma glucose concentration in response to the fructose diet. WKY rats gained more weight than did the SHR rats. Thus, although plasma triglyceride and insulin concentration and blood pressure increased when either WKY or SHR rats consumed a fructose enriched diet, the magnitude of these changes was greater in SHR rats.

Animals↗

PubMed1990

Effect of prazosin treatment on HDL kinetics in patients with hypertension.

The effect of prazosin treatment on blood pressure, plasma HDL-cholesterol concentration, and apoprotein-AI/HDL (apoAI/HDL) kinetics was studied in 11 patients with mild hypertension. Blood pressure (mean +/- SEM) fell from 143 +/- 1/96 +/- 1 to 134 +/- 1/86 +/- 1 mm Hg after 4 to 5 months of prazosin treatment (P less than .001), associated with an increase in plasma HDL-cholesterol concentration from 38 +/- 2 to 46 +/- 2 mg/dL (P less than .001). Both the fractional catabolic rate (FCR) and total synthetic rate of apoAI/HDL, which were higher than previous reported values for normal individuals, decreased from 0.36 +/- 0.02 to 0.30 +/- 0.02 L/day and 17.4 +/- 1.1 to 13.8 +/- 1.1 mg/kg/min, respectively. These changes were statistically significant, and the post-treatment values for both variables were now within the normal range. When the decay curve was further analyzed by nonlinear curve fitting, it was shown that the return to normal of the FCR of apoAI/HDL in patients treated with prazosin was accounted for by the decrease of the decay constants of the second [p(2)] and third [p(3)] components of the 125I-AI/HDL disappearance curve. In conclusion, abnormalities in HDL concentration and HDL kinetics exist in patients with very mild hypertension. These defects were significantly improved with prazosin treatment, and this may render the compound of particular clinical benefit in the treatment of patients with mild hypertension.

Apolipoprotein A-I↗

PubMed1990

Decreased responsiveness of superficial hand veins to phenylephrine in black normotensive males.

Essential hypertension is more prevalent among blacks than whites although the explanation is unknown. It is possible that an altered vascular adrenoceptor responsiveness in blacks may play a role in the etiology of this racial difference. To test this hypothesis, we have compared the diameter changes in superficial veins in response to phenylephrine, an alpha-adrenergic agonist, and to isoproterenol, a beta-adrenergic agonist, in black and white young normotensive males using the dorsal hand vein compliance technique. The maximal venoconstriction after phenylephrine (Emax) was 92 +/- 9% (mean +/- SD) in the whites but only 74 +/- 12% in the blacks (p = 0.00046). The ED50 of phenylephrine was 342 ng/min (geometric mean) in whites and 245 ng/min in blacks (p = 0.50). The Emax and ED50 for isoproterenol-mediated venodilation was not significantly different between the racial groups. These results indicate a decreased maximal responsiveness to alpha-adrenergic stimulation in normotensive blacks. How these changes relate to cardiovascular alterations in hypertensive blacks requires further study.

Adolescent↗

PubMed1990

Effect of temazepam on blood pressure regulation in healthy elderly subjects.

1. Blood pressure regulation was studied in 12 healthy elderly subjects after double-blind randomised administration of placebo, 15 mg and 30 mg temazepam at 10.00 h and 22.00 h. 2. Supine and standing heart rate and blood pressure were measured after daytime administration and supine measurements were obtained during sleep. 3. Temazepam caused a fall in systolic blood pressure and an increase in heart rate after morning administration. These changes were greater in the standing position and were dose-dependent; for standing blood pressure and heart rate 1 h after administration there was a 7 mm Hg fall and 6 beats min-1 increase after 15 mg temazepam and a 10 mm Hg fall and 8 beats min-1 increase after 30 mg temazepam. Temazepam magnified the fall in systolic blood pressure and increase in heart rate that occurred with standing. Temazepam enhanced the fall in systolic blood pressure that occurred during sleep (mean +/- s.d.; placebo: -23 +/- 10 mm Hg, 15 mg temazepam: -31 +/- 13 mm Hg, 30 mg temazepam: -36 +/- 14 mm Hg). 4. These changes in blood pressure regulation caused by temazepam may have clinical importance in some elderly individuals.

Aged↗

PubMed1990

Decreased cyclic AMP degradation in NG 108-15 neuroblastoma X glioma hybrid cells and S49 lymphoma cells chronically treated with drugs that inhibit adenylate cyclase.

The increase in hormone-stimulated cyclic AMP accumulation observed in a variety of intact cells after chronic pretreatment with drugs that inhibit adenylate cyclase activity has been attributed to an increase in adenylate cyclase activity following withdrawal of the inhibitory drug. In NG 108-15 mouse neuroblastoma X rat glioma hybrid cells (NG cells) chronically treated with the muscarinic cholinergic agonist carbachol, we have found a significant decrease in the apparent degradation rate constant for cyclic AMP, in addition to an increase in the prostaglandin E1 (PGE1)-stimulated cyclic AMP synthesis rate in intact cells. In carbachol-pretreated NG cells that were stimulated with a maximally effective dose of PGE1, and that accumulated steady-state cyclic AMP concentrations fourfold or more higher than in control cells, the apparent rate constant for degradation was about 53% lower than the value for control cells. In carbachol-pretreated cells stimulated with a submaximal dose of PGE1 to yield a steady-state cyclic AMP concentration comparable to control cells, the apparent rate constant was 31% lower than the value for control cells. In S49 mouse lymphoma cells (S49 cells) chronically treated with an analog of the inhibitory agonist somatostatin, the first-order rate constant for cyclic AMP degradation in intact cells following isoproterenol stimulation was 29% lower than the value for control cells. Despite these changes in the kinetics of cyclic AMP degradation in intact NG cells and S49 cells, there was either no change or a minimal change (less than 10%) in phosphodiesterase activities assayed in extracts of cells chronically exposed to inhibitory drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗

PubMed1990

Captopril improves hypertension and cardiomyopathy in rats with pheochromocytoma.

Hypertension and cardiomyopathy are prominent findings in humans and rats harboring pheochromocytomas, tumors that can secrete enormous quantities of catecholamines. We have previously found that alpha- and beta-adrenergic receptor antagonists may ameliorate the hypertension and cardiomyopathy found in New England Deaconess Hospital rats implanted with pheochromocytoma. The present studies were designed to determine the possible action of the angiotensin converting enzyme inhibitor captopril on these changes in rats harboring pheochromocytomas. Rats were implanted with transplantable pheochromocytomas and treated with captopril dissolved in the drinking water (1 mg/ml) for 4-6 weeks. Systolic blood pressure was monitored by using the tail-cuff technique. In the rats with pheochromocytoma, blood pressure progressively increased to 184 +/- 3 mm Hg after the tumor was implanted. However, in rats with pheochromocytoma treated with captopril in the drinking water before the development of hypertension, blood pressure did not increase (137 +/- 3 mm Hg). In rats with pheochromocytoma with established hypertension, captopril normalized the systolic blood pressure. Plasma norepinephrine was markedly elevated to a similar extent in both groups compared with unimplanted control rats. Plasma renin activities were slightly lower in rats with pheochromocytoma compared with unimplanted control rats. Treatment with captopril of rats with pheochromocytoma did not modify contraction of isolated rings of thoracic aorta exposed in vitro to either phenylephrine or angiotensin II. Treatment with captopril markedly attenuated the cardiomyopathy induced by pheochromocytoma. These results demonstrate that captopril prevents the development of hypertension despite markedly elevated concentrations of catecholamines. In addition, captopril attenuates catecholamine-induced cardiomyopathy in pheochromocytoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗

PubMed1990

Activation of muscarinic cholinergic receptors in mouse neuroblastoma x rat glioma hybrid cells: rapid induction of enhanced capacity of prostaglandin E1 receptors to stimulate cyclic AMP accumulation.

Many cells develop an adaptive increase in the capacity of adenylate cyclase to synthesize cyclic AMP (cAMP) after prolonged (hours or days) exposure to drugs which initially inhibit enzyme activity. Recent evidence suggests that adaptive increases in cAMP responses can be induced within minutes by inhibitory drugs. We have investigated the kinetics for induction and decay of this phenomenon in mouse neuroblastoma x rat glioma hybrid cells. The muscarinic cholinergic agonist carbachol induced an increase in prostaglandin E1-stimulated cAMP accumulation within 2 min of pretreatment with carbachol; the increase was 70 to 100% above control values after exposure to carbachol for 30 min. Enhanced cAMP responsiveness decayed with a half-life of about 8 min after removal of carbachol. Pretreatment with carbachol for 30 hr led to an enhanced cAMP response which decayed in two components, a rapid component and an additional, more stable component which persisted for at least 2 hr after withdrawal of carbachol. Pertussis toxin prevented these effects of carbachol. Prevention of carbachol-induced inhibition of cAMP accumulation below basal concentrations with a phosphodiesterase inhibitor did not prevent the ability of carbachol to acutely induce augmented prostaglandin E1-stimulated cAMP accumulation. Mouse neuroblastoma x rat glioma hybrid cells exhibit an enhanced cAMP response after both acute and chronic exposure to a muscarinic cholinergic agonist although these processes decay with different time courses. The signal for this acutely induced adaptation does not appear to be the decrease in cellular cAMP concentration resulting from inhibition of adenylate cyclase but does require a pertussis toxin-sensitive substrate.

Adenylate Cyclase Toxin↗

PubMed1989

Hypertension as a disease of carbohydrate and lipoprotein metabolism.

Patients with untreated hypertension have been shown to be resistant to insulin-stimulated glucose uptake and both hyperinsulinemic and hypertriglyceridemic when compared with matched control groups with normal blood pressure. In addition, insulin resistance, hyperinsulinemia, and hypertriglyceridemia have been demonstrated in rat models of hypertension, including spontaneously hypertensive rats and Sprague-Dawley rats fed a fructose-enriched diet, and the defect in insulin-stimulated glucose uptake in these experimental models can also be shown at the cellular level. Furthermore, experimental interventions that prevent insulin resistance and/or hyperinsulinemia from developing in fructose-fed rats also greatly attenuate the increase in blood pressure. Finally, endogenous hyperinsulinemia and hypertriglyceridemia have been identified as factors that increase the risk of coronary artery disease, and may contribute to the increased prevalence of ischemic heart disease in patients with high blood pressure. The fact that past antihypertensive treatment has not focused on these metabolic abnormalities, and, indeed, may have exacerbated them, could help explain why it has been difficult to show that lowering blood pressure decreases risk of coronary artery disease. These observations raise the possibility that abnormalities of carbohydrate and lipoprotein metabolism may play a role in both the etiology and the clinical course of hypertension.

Carbohydrate Metabolism↗

PubMed1989

Effect of prazosin treatment on carbohydrate and lipoprotein metabolism in patients with hypertension.

This study evaluated the effect of prazosin in controlled mild hypertension and evaluated select metabolic changes that occurred with prazosin monotherapy. Various aspects of glucose, insulin, and lipid metabolism were studied before and after approximately 10 weeks of prazosin treatment in 12 patients with mild hypertension. Prazosin was well tolerated and induced a significant decrease (p less than 0.001) in both systolic and diastolic blood pressures, without any change in body weight. Plasma concentrations of glucose, free fatty acid, and lactate, which were measured hourly from 8 A.M. to 4 P.M. following meals consumed at 8 A.M. and noon, did not change with prazosin treatment. However, the plasma insulin response from 8 A.M. to 4 P.M. decreased significantly (p less than 0.001) following prazosin treatment. In addition, fasting plasma triglyceride and cholesterol concentrations were significantly lower (p less than 0.05) in prazosin-treated persons, as were postprandial triglyceride concentrations (p less than 0.001). Lower total plasma triglyceride and cholesterol concentrations were accounted for by decreases in very low-density lipoprotein cholesterol and triglyceride and low-density lipoprotein cholesterol and triglyceride, whereas both high-density lipoprotein triglyceride and high-density lipoprotein cholesterol concentrations increased following prazosin treatment. Finally, although both apolipoprotein A1 and apolipoprotein B concentrations decreased in association with prazosin treatment, the decrease in apolipoprotein B was much greater in magnitude, leading to an increase in the ratio of apolipoprotein A1 to apolipoprotein B. In this study, treatment of mild hypertension with prazosin led to lower blood pressures and changes in insulin and lipoprotein metabolism that are important in this patient population.

Adult↗

PubMed1989

Responsiveness of superficial hand veins to adrenergic stimuli in patients with cystic fibrosis.

1. The basic biochemical defect of cystic fibrosis (CF) remains undetermined, but impaired function of the beta-adrenoceptor-mediated adenosine 3':5'-cyclic monophosphate (cyclic AMP)-dependent regulatory pathway in secretory cells is likely to be involved in the pathophysiology of the disease. 2. We have compared responsiveness to beta-adrenergic stimulation in vivo by infusing isoprenaline locally into peripheral veins of CF patients and control subjects; the dorsal hand vein technique was used to measure the vascular response to isoprenaline. 3. CF patients required significantly higher doses of isoprenaline for half-maximal dilatation of the preconstricted veins (ED50) than controls (geometric mean: 44.5 ng/min in CF patients compared with 14.8 ng/min in controls; P less than 0.05). Maximal venodilatation was 74 +/- 30% of baseline in CF patients compared with 94 +/- 50% in controls (NS between groups). 4. The clinical score of CF patients was uncorrelated with the ED50 of isoprenaline. Thus the decreased beta-adrenergic responsiveness does not seem to be related to the severity of the disease. 5. Our results indicate a defect in the cyclic-AMP-dependent pathway in vascular smooth muscle cells of CF patients. Whether this is associated with the CF gene defect itself requires further study.

Adult↗

PubMed1989

Impaired insulin-mediated inhibition of lipolysis and glucose transport with aging.

Regulation of hormone action with aging has been extensively studied; adipocytes provide an interesting model for some of these questions. We have compared the ability of insulin to stimulate glucose uptake and suppress lipolysis in adipocytes isolated from two month and twelve month-old rats. The ability of insulin to stimulate maximal glucose transport was decreased in adipocytes from the older rats (P less than 0.001); as well, insulin's EC50 was also higher (P less than 0.01) in these cells. Furthermore, these defects were present when insulin-stimulated glucose transport was measured in the presence or absence of adenosine deaminase which metabolizes endogenously released adenosine. Endogenously released adenosine is a stimulator of glucose transport and an inhibitor of lipolysis. Maximal suppression of isoproterenol-induced lipolysis by insulin was similar when adipocytes isolated from the two age groups were incubated in the absence of adenosine deaminase. However, maximal insulin-mediated suppression of lipolysis was found to be significantly decreased (P less than 0.001) in adipocytes isolated from older rats when the experiments were done in the presence of adenosine deaminase; also, insulin's EC50 was increased in these cells under these conditions (P less than 0.001). These results emphasize the importance of the adenosine receptor in modulating the response of isolated adipocytes to insulin, particularly for lipolysis, and document the presence of age-associated defects in insulin regulation of both glucose transport and lipolysis.

Adipose Tissue↗