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Biomedical subjects

B B Hoffman

Publications and source records attributed to B B Hoffman.

At least 145 records · Page 8Linked to original sources
PubMed1988

Cardiomyopathy in a rat model of pheochromocytoma. Morphological and functional alterations.

To investigate the cardiac muscle damage observed in pheochromocytoma, New England Deaconness Hospital rats were implanted subcutaneously with a transplantable pheochromocytoma. The tumor was evident 4 weeks after transplantation. Approximately 5-6 weeks after transplant, systolic blood pressure was significantly increased in tumor-bearing animals (183 +/- 13 vs 119 +/- 7 in controls). At this time a cardiomyopathy with the following features was apparent in the tumor-bearing animals: multifocal lesions of enhanced interstitial and replacement fibrosis; granularity of the cytoplasm and contraction band necrosis; and mixed inflammatory infiltrates. Using a morphological scoring system from 0 (no cardiac damage) to 3 (complete involvement of the ventricular cross section studied), the pheochromocytoma animals had a cardiomyopathy score of 1.8 +/- 0.1, which is significantly greater than that found in age- and sex-matched controls: 0.4 +/- 0.1, p less than .001. A significant increase in the wet heart weights (1.28 +/- 0.07 vs. 1.12 +/- 0.04 in controls) was also observed in these animals, indicating the possibility of cardiac hypertrophy in the pheochromocytoma rats. There was a marked decrease in sensitivity to isoproterenol in isolated, electrically driven left atrial strips from pheochromocytoma rats. Isoproterenol's EC50 increased eightfold from 1.5 +/- 0.6 x 10(-8) M in controls to 1.3 +/- 0.4 x 10(-7) M in left atrial strips from the pheochromocytoma rats. However, there was no difference in maximal contractile response to isoproterenol in either the left atrial strips or in right or left ventricular papillary muscle strips. Also, there was no change in responsiveness of either left atrial or right ventricular muscle strips from pheochromocytoma hearts to contraction induced by 3.75 mM calcium chloride. However, the contractile response to calcium was enhanced in left ventricular papillary muscle from tumor-bearing animals (808 +/- 195 vs 372 +/- 101 mg tension in controls, p less than 0.05). These results demonstrate a catecholamine-induced cardiomyopathy in hearts from pheochromocytoma-bearing rats. Furthermore, the results demonstrate a functional beta-adrenergic receptor desensitization in isolated left atrial strips from tumor-bearing rats, whereas maximal contraction of heart muscle, induced by either isoproterenol or calcium chloride, remains intact.

Animals↗
PubMed1988

Mechanism of halothane-induced inhibition of isoproterenol-stimulated lipolysis in isolated rat adipocytes.

The effect of halothane on isoproterenol-stimulated lipolysis was determined in isolated rat epididymal fat cells. The maximal lipolytic response (Emax) activated by isoproterenol was 350 +/- 61 nmol of glycerol/10(5) cells/hr with an EC50 of 5.1 X 10(-9) M. When the adipocytes were simultaneously bubbled with 2.5% halothane, the Emax decreased to 158 +/- 43 nmol of glycerol/10(5) cells/hr and the dose response curve for isoproterenol was shifted to the right (EC50 3.5 X 10(-8) M, p less than 0.05). When lipolysis was maximally stimulated with (-)-isoproterenol (10(-6)M), the inhibitory effect of halothane was found to be both dose dependent (IC50 approximately 2.5%, v/v) and reversible following washout. Neither the nonhydrolyzable cAMP analog, 8-(4-chlorophenylthio) adenosine 3',5'-cyclic monophosphate (2 X 10(-3)M), nor forskolin (10(-6) M) was able to normalize lipolysis in the presence of halothane. The activation of cAMP-dependent protein kinase (EC 2.7.1.37) activity by isoproterenol was not different in halothane-exposed cells when compared to unexposed cells. When control adipocytes were exposed to isoproterenol (10(-6) M), there was a 2.5-fold increase in the activity of hormone-sensitive lipase (EC 3.1.1.3) from 0.64 +/- 0.13 to 1.53 +/- 0.32 pkat (pmol/sec) per mg (p less than 0.005, n = 10). However, in the presence of halothane (2.5%, v/v) isoproterenol stimulation of hormone-sensitive lipase was attenuated by 50% to values of 1.06 +/- 0.23 pkat/mg (p less than 0.01, n = 10). Halothane had no direct inhibitory effect on hormone-sensitive lipase since this enzyme's activity was unaffected when homogenates of isoproterenol-stimulated control cells were incubated with halothane. These studies suggest that halothane impairs the activation of hormone-sensitive lipase by cAMP-dependent protein kinase and in this manner inhibits beta-adrenergic-stimulated lipolysis.

Adipose Tissue↗
PubMed1987

Alpha 1 adrenergic receptor mediated polyphosphoinositide breakdown in DDT1-MF2 cells. Lack of evidence of desensitization after prolonged exposure to epinephrine.

The DDT1-MF2 cell line is a transformed smooth muscle cell line which is known to possess both alpha 1 and beta 2 adrenergic receptors. We have utilized these cells to compare the effects of epinephrine pretreatment on the functional capabilities of these two different adrenergic receptors. Pretreatment of the cells grown in suspension with 10(-7) M epinephrine for 6 hr resulted in desensitization of beta receptor stimulated cyclic AMP accumulation. The maximal response to isoproterenol was decreased to 46 +/- 6% of the value in controls (P less than 0.05); there was also a decrease in the sensitivity of the cells to isoproterenol (log EC50 = -6.65 +/- 0.22 vs -7.26 +/- 0.11 in controls, P less than 0.05). Also, there was a decrease in the number of beta receptors from 257 +/- 29 to 163 +/- 22 fmol/mg protein. In contrast, pretreatment with 10(-6) M epinephrine for 6 hr failed to induce a loss of sensitivity in the ability of the alpha 1 receptor agonist phenylephrine to stimulate inositol triphosphate accumulation (log EC50 = -5.59 +/- 0.18 vs -5.42 +/- 0.44 in control cells). A 2-fold increase in basal inositol monophosphate accumulation was observed after epinephrine pretreatment (P less than 0.05); however, there was no change in maximal phenylephrine-stimulated inositol monophosphate accumulation in these cells. There was a small decrease in the alpha 1 receptor number after epinephrine pretreatment (Bmax = 457 +/- 89 fmol/mg protein vs 540 +/- 94 in control cells, P less than 0.05). In contrast to epinephrine pretreatment, pretreatment of cells in suspension with 10(-7) M 12-O-tetradecanoylphorbol-13-acetate (TPA) for 15 min resulted in a nearly complete blunting in the ability of both norepinephrine and phenylephrine to stimulate inositol phosphate accumulation: after norepinephrine stimulation, 774 +/- 34 dpm in TPA-pretreated cells vs 2590 +/- 10 in control cells; inositol monophosphate accumulation after phenylephrine stimulation 576 +/- 25 dpm in TPA-pretreated cells vs 1660 +/- 27 in control cells. Basal levels of inositol monophosphate remained unchanged at 544 +/- 28 dpm vs 505 +/- 31 in TPA-pretreated cells compared to control cells. These data indicate that protein kinase C may exert a negative feedback control on the alpha 1 receptor in these cells and that direct activation of protein kinase C by phorbol esters may have a different effect on the alpha 1 adrenergic receptor system in DDT1-MF2 cells than does prolonged exposure to epinephrine.

Cell Line↗
PubMed1987

A role for insulin in the aetiology and course of hypertension?

It is proposed that abnormalities of glucose and insulin metabolism have a role in both the aetiology and the clinical course of hypertension. There is resistance to insulin-stimulated glucose uptake in patients with hypertension, which is associated with glucose intolerance and hyperinsulinaemia. Hyperinsulinaemia could contribute to hypertension by stimulating the activity of the sympathetic nervous system and kidney sodium and volume reabsorption. Glucose intolerance and hyperinsulinaemia have been identified as risk factors for coronary artery disease, and their presence may help explain why the frequency of this disease has not been reduced by treatment of hypertension. The fact that several antihypertensive drugs deleteriously affect glucose, insulin, and lipid metabolism makes it even more important to consider these factors in the treatment of high blood pressure.

Blood Glucose↗
PubMed1987

In vitro pharmacologic activity of congener derivatives and model conjugates of propranolol and practolol.

Previous studies in our laboratory suggested that synthetized derivatives of isoproterenol and histamine could create agonists more potent and receptor and/or tissue selective than the parent compound. In the present study we have evaluated the hypothesis that our results with isoproterenol and histamine derivatives could be extended to include beta-adrenergic antagonists. With this purpose in mind, fourteen derivatives of propranolol and practolol were synthesized and tested in four in vitro systems. The congeners and conjugates were tested using biologic assays (blocking of cAMP accumulation) and/or radioligand binding assays in S-49 lymphoma cells and in rat adipocytes, heart and lung which contain beta 1 and/or beta 2 receptors. Our results indicate that structural modifications distant from the pharmacophore alter the pharmacologic profile of the parent compound. The relative potencies of the derivatives were dependent upon several key factors including the length of the methylene spacer chain and the nature of the substituents on the aromatic ring. The presence of a spacer group with four methylenes resulted in the most active compound in each series when tested on S-49 cells. The derivatives with a paramethyl toluidide group were more potent than the derivatives with a trifluoromethyl toluidide group. The dipeptide derivatives were more potent on adipocyte than S-49 cells, suggesting a preference for beta 1 receptors. Some of the same modifications that led to altered potency and which resulted in an increased receptor and/or tissue selectivity using the progenitors isoproterenol or histamine did extrapolate to the beta blockers. Our data suggest that alterations in receptor and/or tissue selectivity must be imparted by the carrier moiety of the drug and may be related to the biochemical microenvironment of the receptors.

Adipose Tissue↗
PubMed1987

Absence of age-related changes in venous responsiveness to nitroglycerin in vivo in humans.

We have previously demonstrated a progressive loss in the ability of the beta-receptor agonist isoproterenol to relax veins with increasing age. In this study the influence of age on the responsiveness of medium-sized veins to local infusions of nitroglycerin was studied in two groups of 15 healthy male volunteers using the dorsal hand vein compliance technique. A dorsal hand vein was preconstricted with submaximally effective doses of phenylephrine and a dose-response curve with nitroglycerin was established. The nitroglycerin dose that caused a 50% venodilation ranged from 0.7 to 22.4 ng/min (geometric mean 3.6 ng/min) in the younger group (aged 19 to 29 years; mean +/- SD 23 +/- 3 years) and from 0.2 to 17.9 ng/min (geometric mean 3.6 ng/min) in the older subjects (aged 50 to 74 years; mean +/- SD 63 +/- 7 years) (P = 0.49 between geometric means). The mean (+/- SD) maximal venodilation, based on the pretreatment baseline, was 103% +/- 65% in the younger and 125% +/- 64% in the older subjects (P = 0.18). These results indicate that there is no age-related change in venous responsiveness to nitroglycerin.

Adult↗
PubMed1987

Stimulation and inhibition of lipolysis in isolated rat adipocytes: evidence for age-related changes in responses to forskolin and PGE1.

The ability of a number of hormones to activate cellular responses in a variety of cells declines with age. The mechanisms responsible for these alterations are complex and incompletely understood. Rat adipocytes have served as an important model to study blunted responses to stimulatory hormones which function by activating cAMP accumulation. We have previously found that the blunted lipolytic response of adipocytes from older rats to the beta adrenergic receptor agonist isoproterenol appeared to be due to a lessened ability of isoproterenol to activate cAMP accumulation. Further, the blunted response to isoproterenol was apparently caused by an accentuated inhibition of lipolysis, mediated by adenosine receptors activated by endogenously released adenosine. The present studies were designed to test and extend those conclusions. We have utilized forskolin to augment the cAMP accumulation that occurs in the presence of isoproterenol. Isoproterenol-activated lipolysis was greater in adipocytes from 2 month old rats compared with those from 12 month old rats (603 +/- 32 vs 450 +/- 29 nmol/10(5) cells/hr, P less than 0.01). However, in the presence of forskolin (10(-6) M), there was no significant difference in the response to isoproterenol between the two groups (646 +/- 23 vs 615 +/- 29 nmoles/10(5) cells/hr). As we had seen previously, the adenosine receptor agonist phenylisopropyladenosine more effectively inhibited lipolysis in the adipocytes from older rats. We now also find that PGE1 more efficaciously inhibits lipolysis in the cells from older rats. These data confirm that diminished cAMP accumulation in adipocytes from older rats appears to be a rate-limiting alteration in the regulation of lipolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1987

Effects of thyroid hormone on beta-adrenergic responsiveness of aging cardiovascular systems.

We have compared the effects of beta-adrenergic stimulation on the heart and peripheral vasculature of young (2-mo-old) and older (12-mo-old) rats both in the presence and absence of triiodothyronine (T3)-induced hyperthyroidism. The hemodynamic consequences of T3 treatment were less prominent in the aged hyperthyroid rats compared with young hyperthyroid rats (both in intact and pithed rats). There was a decrease in sensitivity of chronotropic responsiveness to isoproterenol in older pithed rats, which was apparently reversed by T3 treatment. The number and affinity of myocardial beta-adrenergic receptor sites measured by [125I]cyanopindolol were not significantly different in young and older control rats; also, beta-receptor density increased to a similar extent in both young and older T3-treated rats. The ability of isoproterenol to relax mesenteric arterial rings, markedly blunted in older rats, was partially restored by T3 treatment without their being any change in isoproterenol-mediated relaxation in the arterial preparations from young rats. The number and affinity of the beta-adrenergic receptors measured in the mesenteric arteries was unaffected by either aging or T3 treatment. The data suggest that effects of thyroid hormone and age-related alterations of cardiovascular responsiveness to beta-adrenergic stimulation are interrelated in a complex fashion with a net result that the hyperkinetic cardiovascular manifestations in hyperthyroidism are attenuated in the older animals.

Aging↗
PubMed1987

Fructose-induced insulin resistance and hypertension in rats.

To determine if hypertension could be produced in normal rats by feeding them a fructose-enriched diet, Sprague-Dawley rats were fed either normal chow or a diet containing 66% fructose as a percentage of total calories for approximately 2 weeks. At the end of this period systolic blood pressure had increased from 124 +/- 2 to 145 +/- 2 (SEM) mm Hg in the fructose-fed rats, whereas no change occurred in the control group. In addition, hyperinsulinemia and hypertriglyceridemia were associated with hypertension in fructose-fed rats. The addition of clonidine to the drinking water inhibited fructose-induced hypertension, but not the increase in plasma insulin or triglyceride concentration seen in fructose-fed rats. Thus, the metabolic changes associated with fructose-induced hypertension are unlikely to be secondary to an increase in sympathetic activity. Whether or not this is also true of the hypertension remains to be clarified.

Animals↗
PubMed1987

Desensitization of postjunctional alpha 1- and alpha 2-adrenergic receptor-mediated vasopressor responses in rat harboring pheochromocytoma.

Prolonged stimulation of tissues by adrenergic agonists may lead to diminished responsiveness of the tissues to subsequent activation by catecholamines; this phenomenon has been termed desensitization or tachyphylaxis. We have examined the in vivo consequences of prolonged stimulation of vascular alpha-adrenergic receptors in rats harboring pheochromocytoma, a tumor that secretes catecholamines. In both early (3-4 weeks after implantation) and late (6-7 weeks after implantation) stages of tumor development, New England Deaconess Hospital rats with transplanted pheochromocytomas developed hypertension and tachycardia and had plasma dopamine and norepinephrine concentrations markedly greater than controls. In both these stages of pheochromocytoma, pressor responses to several vasoconstrictors were examined after pithing. Rats with the tumor were found to become progressively subsensitive to alpha-adrenergic agonists. In the early phase of pheochromocytoma, loss in sensitivity was found for both alpha 1- and alpha 2-adrenergic agonists, whereas responsiveness to the nonadrenergic vasoconstrictors Arg-vasopressin and angiotensin-II was intact (homologous desensitization). However, in the later stage of pheochromocytoma, pressor responses to all these vasoconstrictive agents and also to stimulation of the complex sympathetic outflow were found to be subsensitive (heterologous desensitization). In plasma membranes prepared from mesenteric arteries of early stage tumor-bearing rats, [3H]prazosin binding sites were significantly decreased to 150 +/- 12 fmol/mg vs. 234 +/- 19 fmol/mg in controls. [3H]Yohimbine binding sites were not significantly altered. Our results show that both postjunctional alpha 1- and alpha 2-adrenergic receptor-mediated vasopressor responses can be specifically attenuated in the presence of chronically elevated endogenous catecholamine levels produced by pheochromocytoma and that each alpha-receptor subtype may be differently regulated in the development of desensitization.

Angiotensins↗
PubMed1987

Observations in New England Deaconess Hospital rats harboring pheochromocytoma.

Pheochromocytomas are rare tumors, typically found in the adrenal medulla, which may secrete large quantities of catecholamines such as dopamine, norepinephrine, and epinephrine. Pheochromocytomas are usually associated with hypertension, which may be severe. Relatively little is known about the cardiovascular manifestations of pheochromocytoma because of the rarity of the disease and the difficulty of ethically studying patients with this explosive and potentially lethal disease. New England Deaconess rats (a Wistar-derived strain) harbor a transplantable pheochromocytoma which has many features reminiscent of the human disease. These rats develop markedly elevated concentrations of norepinephrine that are associated with severe hypertension, desensitization of alpha and beta adrenergically mediated responses, and catecholamine-induced cardiomyopathy. This paper briefly reviews work undertaken in the author's laboratory on the mechanisms of these alterations in the cardiovascular system of rats harboring pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed1987

Effects of adrenergic receptor antagonists on cardiac morphological and functional alterations in rats harboring pheochromocytoma.

New England Deaconness Hospital rats harboring a transplantable pheochromocytoma exhibit plasma norepinephrine concentrations 20-fold higher than controls. A cardiomyopathy (CM) characterized by multifocal areas of interstitial and replacement fibrosis, mixed inflammatory infiltrates and contraction band necrosis is evident 35 to 45 days after tumor implantation. Using a morphological scoring system of 0 (no cardiac damage) to 3 (involvement of almost the complete ventricular cross-section sampled), a CM score of 1.8 +/- 0.1 was found in rats harboring pheochromocytoma, a significant increase over that in age- and sex-matched controls (0.4 +/- 0.1, P less than .001). The pheochromocytoma rats also had hypertension (systolic blood pressure = 182 +/- 4 vs. 131 +/- 2 mm Hg in controls, P less than .001). In an effort to prevent the CM, rats harboring pheochromocytoma were treated with either the beta receptor antagonist timolol, the alpha receptor antagonists phentolamine or phenoxybenzamine or the nonspecific vasodilator hydralazine. Hydralazine normalized systolic blood pressure (135 +/- 6 mm Hg), whereas timolol (144 +/- 5 mm Hg), phenoxybenzamine (166 +/- 5 mm Hg) or phentolamine (154 +/- 10 mm Hg) only moderately decreased blood pressure in rats harboring pheochromocytoma. Hydralazine had no effect on CM score (1.8 +/- 0.1). Timolol markedly attenuated the CM score (0.6 +/- 0.1), whereas the alpha adrenergic antagonists were not as effective (phenoxybenzamine CM score = 1.3 +/- 0.2; phentolamine CM score = 1.7 +/- 0.2). Furthermore, timolol prevented desensitization of beta adrenergic receptor-mediated contraction in the hearts of rats harboring pheochromocytoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗
PubMed1987

Characterization of vasopressor response to sympathetic stimulation in the pithed rat: differential regulation of neuronally stimulated and blood-borne catecholamine-stimulated pressor responses in rats harboring pheochromocytoma.

The vasopressor response to sympathetic stimulation in the pithed rat was characterized both by analyzing the effects of chemical sympathectomy, adrenalectomy and selective antagonists on the vasopressor response and by measurement of changes in plasma concentrations of catecholamines. Stimulation of the spinal sympathetic outflow evoked a biphasic pressor response: an initial transient component was caused mainly by postganglionic sympathetic nerve stimulation (the direct response); a slowly developing secondary component was mediated predominantly by circulating catecholamines released from the adrenal medulla (the adrenal response). Parallel analysis of plasma catecholamines showed that the rise in epinephrine appeared to be closely related to this adrenal component. The pressor response in adrenalectomized rats was selectively blocked by prazosin but not by yohimbine; however, in sympathectomized rats, the pressor response was abolished by prazosin and yohimbine together but not by either drug given alone. These results suggest that the direct, neurogenic component is mediated mainly by alpha-1 adrenoceptors whereas the secondary, adrenally mediated response occurs by activation of both alpha-1 and alpha-2 adrenoceptors. Furthermore, the in vivo regulation of each component of the pressor response was studied in rats harboring pheochromocytoma (PHEO), a tumor causing marked elevations in endogenous catecholamine concentrations. In PHEO rats, the direct pressor response was found to be relatively intact but the adrenal response was blunted. Inasmuch as there was normal rise in plasma epinephrine to electrical stimulation in PHEO rats, the results suggest a differential regulation of neuronally stimulated and blood-borne catecholamine-mediated pressor responses in PHEO rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗
PubMed1987

Role of the sympathetic nervous system in the maintenance of hypertension in rats harboring pheochromocytoma.

Hypertension due to pheochromocytoma is generally considered to be a straightforward, direct consequence of the elevated concentrations of circulating catecholamines. However, clonidine, a centrally acting antihypertensive drug, has been reported to lower blood pressure in patients with pheochromocytoma, suggesting the possibility that the sympathetic nervous system is involved in the maintenance of hypertension in this disease. We have investigated this possibility in New England Deaconess Hospital rats harboring a transplantable pheochromocytoma that secretes norepinephrine and dopamine. Both clonidine and chlorisondamine, a ganglionic blocker, markedly decreased blood pressure in tumor-bearing rats. However, in other rats made acutely hypertensive with a norepinephrine infusion, neither clonidine nor chlorisondamine decreased blood pressure. This result indicates that in an acute model of hypertension, where baroreflex mechanisms have likely withdrawn sympathetic tone, neither clonidine nor chlorisondamine had nonspecific antihypertensive effects. A central nervous system site of action for the antihypertensive effect of clonidine in the rats harboring pheochromocytoma was suggested by the observation that the opiate antagonist naloxone both reversed and prevented clonidine's effect on blood pressure. Prazosin and yohimbine were utilized to determine the respective contributions of alpha-1 and alpha-2 adrenergic receptors in the maintenance of hypertension in rats harboring pheochromocytoma. Both drugs markedly lowered blood pressure in these rats. Our data suggest that both the sympathetic nervous system and circulating catecholamines are involved in the maintenance of hypertension due to pheochromocytoma.

Adrenal Gland Neoplasms↗