Biomedical subjects

B B Hoffman

Publications and source records attributed to B B Hoffman.

At least 163 records · Page 9Linked to original sources

PubMed1986

Age-related change in adrenergic regulation of glycogen phosphorylase in rat hepatocytes.

The effects of development on adrenergic regulation of glycogenolysis were studied in rat liver. In isolated hepatocytes, the activation of glycogen phosphorylase by alpha-adrenergic stimulation decreased moderately with advancing age. However, activation by beta-adrenergic receptors more markedly declined and almost disappeared in isolated hepatocytes from 6-month-old rats. Furthermore, the ability to glucagon to stimulate phosphorylase activity and cAMP generation was found to decrease with increasing age. The age-related changes in the pattern of stimulation of glycogen phosphorylase by catecholamines in isolated hepatocytes were accompanied by parallels changes in the numbers of alpha 1- and beta-adrenoceptors in membranes prepared from the isolated hepatocytes. A progressive decrease in the total number of alpha 1-receptors measured with [3H]-prazosin and beta-receptors measured with [125I]cyanopindolol (CYP) was found with increasing age. The loss of beta-adrenergic receptors was much more dramatic. Our results suggest that age-related alterations of hepatic glycogen phosphorylase activation by catecholamines may in part be explained by the changes in the expression adrenergic receptors.

Aging↗

PubMed1986

Desensitization of adenosine receptor-mediated inhibition of lipolysis. The mechanism involves the development of enhanced cyclic adenosine monophosphate accumulation in tolerant adipocytes.

Adipocytes contain adenosine receptors, termed A1 receptors, which inhibit lipolysis by decreasing adenylate cyclase activity. The inhibition of lipolysis by adenosine agonists in vivo acutely suppresses the plasma concentrations of free fatty acids (FFA) and triglycerides. We have found that infusions of the adenosine receptor agonist phenylisopropyladenosine (PIA) initially decreases plasma FFA concentrations; however, with prolonged exposure (6 d), rats become very tolerant to the effects of the drug. Adipocytes isolated from epididymal fat pads from PIA-infused rats have altered lipolytic responses. When lipolysis is stimulated with a relatively high concentration of isoproterenol (10(-7) M), PIA does not inhibit lipolysis in adipocytes from the infused animals. However, PIA inhibits isoproterenol-stimulated cyclic AMP (cAMP) accumulation in adipocytes from the infused rats although with decreased sensitivity compared with controls. The explanation for the impaired antilipolytic effect appears to be due to the fact that isoproterenol-stimulated cAMP accumulation is markedly increased in cells from infused rats. Indeed, basal lipolysis and lipolysis stimulated with lower concentrations of isoproterenol (10(-9), 10(-8) M) are effectively inhibited by PIA. cAMP accumulation is greatly increased in adipocytes from infused rats when stimulated by isoproterenol, ACTH, and forskolin. The results have some striking analogies to changes induced in nerve cells by prolonged exposure to narcotics. These data suggest that tolerance to PIA develops in adipocytes as a consequence of enhanced cAMP accumulation.

Adenosine Deaminase↗

PubMed1986

Agonist-induced down-regulation of muscarinic cholinergic and alpha 2-adrenergic receptors after inactivation of Ni by pertussis toxin.

Desensitization of the responsiveness to hormones or drugs is often mediated by down-regulation of receptors. The stimulatory coupling protein (Ns) of adenylate cyclase has been shown to be involved in the down-regulation of stimulatory beta-adrenergic receptors. Whether the inhibitory coupling protein (Ni) is involved in the down-regulation of receptors that inhibit adenylate cyclase is not known. We wished to determine whether down-regulation of inhibitory muscarinic cholinergic and alpha 2-adrenergic receptors occurs in neuroblastoma X glioma hybrid cells after the ability of Ni to inhibit adenylate cyclase is inactivated by pertussis toxin. After treatment of cells with pertussis toxin, the ability of carbachol or epinephrine to inhibit prostaglandin E1-stimulated cAMP accumulation in intact cells was either completely prevented or markedly attenuated, respectively, indicating functional inactivation of Ni. Furthermore, pertussis toxin treatment of membrane fragments from these cells did not result in labeling of the 41,000-dalton alpha-subunit of Ni with ADP ribose from [32P] NAD, indicating maximal ADP ribosylation of Ni by prior treatment of cells with pertussis toxin. Carbachol treatment of cells resulted in down-regulation of muscarinic cholinergic receptors to 45.7 +/- 12.5% and 52.5 +/- 13.5% of control values for toxin-untreated and toxin-treated cells, respectively. Epinephrine treatment of cells caused homologous desensitization of alpha 2-receptor-mediated inhibition of cAMP accumulation and down-regulation of alpha 2-adrenergic receptors to 42.9 +/- 11.4% and 53.2 +/- 5.3% of control values for toxin-untreated and toxin-treated cells, respectively. Down-regulation of muscarinic cholinergic receptors by carbachol and of alpha 2-adrenergic receptors by epinephrine was not due to the effect of retained agonist and was agonist specific, since it could be prevented by the antagonists atropine and yohimbine, respectively. We conclude that agonist-mediated down-regulation of both the muscarinic cholinergic receptor and the alpha 2-adrenergic receptor does not require functional inhibitory coupling.

1-Methyl-3-isobutylxanthine↗

PubMed1986

Age-related decrease in beta adrenergic receptor-mediated vascular smooth muscle relaxation.

Beta adrenergic receptor-mediated vascular smooth muscle relaxation decreases with increasing age. We have examined the mechanism responsible for this phenomenon using rat mesenteric arteries from young (5-6 weeks) and older (10-12 months) rats. The beta adrenergic agonist isoproterenol produced a dose-dependent relaxation of serotonin-constricted mesenteric artery rings from young rats, whereas the maximal ability of isoproterenol to relax arterial rings from the older rats was found to be reduced markedly (92.7 vs. 27.6%, P less than .0001). The relaxation responses caused by acetylcholine and nitroglycerin, which appear to act independently of cyclic AMP (cAMP), are similar in the two groups. The loss in responsiveness of the mesenteric artery to isoproterenol was not explained by a change in beta receptor number in the vessels (29 +/- 4 in young rats vs. 31 +/- 7 fmol/mg of protein in the older rats). The maximal stimulation of cAMP accumulation by isoproterenol was lower in the older vessels; forskolin activated cAMP accumulation equally in the two groups. However, the vessels from the older rats were less sensitive to forskolin-induced vascular relaxation. Also, the ability of dibutyryl cAMP to promote vascular relaxation was diminished in the older vessels. These data suggest that the diminished cAMP accumulation in older vessels in response to isoproterenol might not necessarily in itself explain completely the reduced physiological response and that an additional defect in the beta adrenergic-mediated relaxation in the vascular smooth muscle of older rats may lie at the level of cAMP-dependent protein kinase activation or more distally.

1-Methyl-3-isobutylxanthine↗

PubMed1986

Alpha adrenergic receptors in the rabbit bladder base smooth muscle: alpha-1 adrenergic receptors mediate contractile responses.

Alpha adrenergic receptors in rabbit bladder base smooth muscle were investigated by in vitro responses of smooth muscle strips to exogenous alpha agonist stimulation and in radioligand binding assays. Norepinephrine and phenylephrine caused significantly greater maximal contractile responses than did clonidine. Also, the contractile response was only inhibited weakly by the alpha-2 selective antagonist yohimbine but was potently inhibited by alpha-1 selective antagonists prazosin and BE2254, suggesting that the response is mediated predominantly by alpha-1 adrenergic receptors. The alpha-1 selective antagonist [125I]BE2254 was used to specifically label a single class of binding sites with a dissociation constant of 131.0 +/- 5.9 pM and a maximal binding capacity of 17.6 +/- 1.9 fmol/mg of protein. Catecholamines compete for [125I]BE2254 binding stereospecifically and with the characteristic alpha adrenergic potency series of (-)-epinephrine greater than (-)-norepinephrine much greater than (-)-isoproterenol. The alpha-1 selective antagonist prazosin (Kd = 2.4 nM) is much more potent in competing for [125I]BE2254 binding than is the alpha-2 selective antagonist yohimbine (Kd = 2900 nM). Also, this dissociation constant of prazosin of [125I]BE2254 binding for bladder base smooth muscle membranes was similar to prazosin's pA2 value of 8.23 to 8.58 in the contraction experiments. The results suggest that alpha-1 rather than alpha-2 receptors predominantly mediate catecholamine-induced contraction in the rabbit bladder base. Also, these receptor sites can be measured directly with the specific antagonist radioligand, [125I]BE2254.

Adrenergic alpha-Agonists↗

PubMed1986

Desensitization of aortic smooth muscle contraction in rats harboring pheochromocytoma.

Desensitization of smooth muscle contraction was studied in aortic ring segments obtained from New England Deaconness Hospital rats harboring pheochromocytomas, a norepinephrine-secreting tumor. Rats were studied 5 to 6 weeks after implantation of the pheochromocytoma, by which time severe hypertension had developed. Aortic ring segments from the pheochromocytoma rats were significantly less sensitive to the alpha-1 adrenergic agonist phenylephrine [log10 (ED50) = -7.21 +/- 0.09 vs. -7.63 +/- 0.11 in controls). In addition, the maximal force of contraction induced by phenylephrine was decreased in the aortas from pheochromocytoma rats (1.31 +/- 0.15 g) compared to controls (2.17 +/- 0.23 g). The potency of the thromboxane A2 receptor agonist U-46,619 was decreased in the aortic ring segments from pheochromocytoma rats compared to controls, although it elicited a similar maximal force of contraction. Desensitization of alpha receptor-mediated contraction was prevented by treating the pheochromocytoma-bearing rats with the reversible alpha adrenergic antagonist phentolamine (200 micrograms/kg/hr) via osmotic minipumps for 2 weeks. However, phentolamine did not decrease the hypertension in these rats. Also, large doses of the irreversible alpha adrenergic antagonist phenoxybenzamine (4 mg/kg/day i.p.) did not decrease blood pressure in rats harboring pheochromocytoma or did the drug completely block aortic alpha receptors in these rats as it did in controls. The results indicate that pheochromocytoma induces heterologous desensitization of smooth muscle contraction in rat aorta. The desensitization is due to direct effects of catecholamines unrelated to hypertension. The New England Deaconess Hospital rat harboring pheochromocytoma is an interesting model to study the effects of high concentrations of plasma catecholamines on smooth muscle contraction.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1986

Muscarinic cholinergic receptor-induced enhancement of PGE1-stimulated cAMP accumulation in neuroblastoma X glioma cells: prevention by pertussis toxin.

Chronic treatment of neuroblastoma X glioma hybrid cells (NG 108-15) with the muscarinic cholinergic agonist carbachol, which acutely inhibits adenylate cyclase, resulted in a 104 +/- 10% increase in PGE1-stimulated cAMP accumulation. Pretreatment of intact cells with pertussis toxin can structurally modify the inhibitory regulatory protein, Gi, by ADP-ribosylation and thus abolish the acute inhibition by carbachol. Pretreatment of the cells with pertussis toxin also resulted in a 27 +/- 8% increase in PGE1-stimulated cAMP accumulation. In the pertussis toxin-treated cells, chronic treatment with carbachol did not further enhance the PGE1 stimulation. These results suggest that functional Gi is required for the development of muscarinic cholinergic-induced enhancement of PGE1-stimulated cAMP accumulation.

Adenosine Diphosphate Ribose↗

PubMed1986

Decline in beta adrenergic receptor-mediated vascular relaxation with aging in man.

Beta adrenergic relaxation of vascular smooth muscle, mediated by cyclic AMP, is blunted with age in a variety of experimental animals. The applicability of these observations to man is uncertain. The dorsal hand vein technique provides an excellent method to examine the direct effects of aging on vascular responsiveness. Thirty-nine healthy male volunteers over the age range of 19 to 79 were studied. No differences in vascular responsiveness to phenylephrine, an alpha adrenergic agonist, were found for either the ED50 (dose producing 50% vasoconstriction) or Emax (maximum vasoconstriction attained). In marked contrast, vascular relaxation induced by isoproterenol, a beta adrenergic agonist, was significantly different in both the ED50 (dose producing 50% of maximum relaxation from a preconstricted state) and Emax (maximum relaxation attained). ED50 +/- S.E.M. for the youngest and oldest deciles were 8.9 +/- 2.3 and 60 +/- 17.0 ng/min, respectively (P less than .05); Emax +/- S.E.M. were 96.7 +/- 3.3 and 37.7 +/- 8.7%, respectively (P less than .001). Nitroglycerin, a smooth muscle relaxant whose effects are not mediated through the cyclic AMP system, was also used to examine the specificity of this blunted response to isoproterenol. Almost complete relaxation was achieved with the infusion of nitroglycerin in the older group. These results suggest that aging is associated with a specific decrease in beta adrenoreceptor-mediated vascular relaxation.

Adult↗

PubMed1986

Suppression of free fatty acids and triglycerides in normal and hypertriglyceridemic rats by the adenosine receptor agonist phenylisopropyladenosine.

Activation of adenosine receptors leads to the inhibition of lipolysis in the fat cells of several species including humans. We have examined the effects of the adenosine analog phenylisopropyladenosine (PIA) on lipolysis in vivo in intact rats. PIA suppresses markedly serum-free fatty acid (FFA) concentrations when injected s.c. (-)-PIA is more potent than (+)-PIA in suppressing FFA concentrations; also, this effect of (-)-PIA is blocked by the adenosine receptor antagonist 8-(p-sulfophenyl)theophylline. (-)-PIA also suppressed plasma triglyceride (TG) concentrations by approximately 50% in these rats. Utilizing Triton WR1339 injections, we found that the decrease in serum TG concentrations was associated with a marked fall in very low density lipoprotein secretion rate. We also examined the effects of (-)-PIA on FFA and TG concentrations in two models of hypertriglyceridemia in rats: stretozotocin-induced diabetes and sucrose feeding. Both groups had elevated FFA and TG concentrations compared with controls. An injection of (-)-PIA suppressed markedly FFA concentrations and essentially normalized the serum concentration of TG in these rats. We conclude that (-)-PIA suppresses markedly lipolysis and triglyceride secretion in control and hypertriglyceridemic rats suggesting that the activation of adenosine receptors may have major metabolic effects in vivo.

Adenosine↗

PubMed1985

Epinephrine infusion induces hyporesponsiveness of vascular smooth muscle.

Exposure to vasoactive drugs may lead to desensitization of vascular smooth muscle responsiveness. We have explored this phenomenon by infusing epinephrine into awake rabbits for 2h and then assessing smooth muscle contraction, both in vivo and ex vivo. Epinephrine was infused at a rate of 1 microgram X min-1 which resulted in a 15-fold increase in the plasma epinephrine concentration. The dose of phenylephrine required to cause a 25 mmHg increase in mean arterial pressure significantly increased from 109 +/- 56 micrograms prior to the infusion to 261 +/- 143 at the end of the 2h infusion (p less than 0.01). The sensitivity to phenylephrine remained decreased when reassessed 2h later. Untreated rabbits displayed no change in alpha-adrenergic responsiveness when assessed at 2 hourly intervals over the time-course of the experiment. Contraction of aortic rings removed from both epinephrine-treated and control rabbits was determined in vitro in tissue baths. The EC50 of norepinephrine-induced contraction increased from 31 +/- 6 to 210 +/- 20 nM while there was also a 30% decrease in the maximal force of contraction (EMax) in treated vessels. The EC50 only partially recovered after 4h of incubation ex vivo, while the EMax was restored to the control value. The EC50 for histamine in the aortic rings from epinephrine-treated rabbits was not different from controls although there was a 25% reduction in the EMax at 2h. We conclude that desensitization of alpha-adrenergic mediated vascular contractility develops rapidly in vivo and is only slowly reversible after removal of the agonist.

Animals↗

PubMed1985

Differential effects of adrenergic agonists and phorbol esters on the alpha 1-adrenoceptors of hepatocytes and aorta.

Epinephrine, norepinephrine and phenylephrine stimulate phosphatidylinositol labeling with [32P]Pi in both rat hepatocytes and rabbit aorta. Methoxamine was a full agonist for this effect in rabbit aorta whereas cirazoline and oxymetazoline were partial agonists. In contrast, these three agents (methoxamine, cirazoline and oxymetazoline) were unable to stimulate phosphatidylinositol labeling in rat hepatocytes. Furthermore, cirazoline and oxymetazoline were able to displace the dose-response curve to epinephrine in rat hepatocytes, i.e., they behaved as antagonists. Binding competition curves of these agents with labeled adrenergic ligands indicate that the affinity of alpha 1-adrenergic receptors in these two tissues (aorta and liver) for the different agents tested was very similar. In addition it was observed that phorbol myristate-acetate inhibited in a dose-dependent fashion the epinephrine-mediated stimulation of phosphatidylinositol labeling in hepatocytes but was without effect on the action of the amine in aorta. Our data suggest that stereochemical differences for alpha 1-adrenergic activation in liver and aorta may exist and indicate that the ability of phorbol esters to inhibit alpha 1-adrenergic effects is not universal.

Adrenergic alpha-Agonists↗

PubMed1985

Effects of pheochromocytoma on cardiovascular alpha adrenergic receptor system.

We have examined the in vivo consequences of prolonged stimulation of the cardiovascular alpha-adrenergic receptor system in a rat model harboring pheochromocytoma. New England Deaconess Hospital rats with transplanted pheochromocytomas developed systolic hypertension and their plasma norepinephrine concentrations were approximately 60-fold greater than controls. Alpha 1-adrenergic receptors were quantitated in hearts from controls and rats with transplanted pheochromocytoma using the alpha 1-receptor selective antagonist [3H]prazosin. Down-regulation of alpha 1-receptors was found in the hearts of pheochromocytoma rats (33.0 vs. 23.0 fmol/mg protein) without any significant change in the affinities of these receptors for the circulating catecholamine, norepinephrine. Furthermore, the responsiveness of the blood vessel to the alpha-adrenergic stimulation was assessed using in vitro contractile experiments. Aortic rings from pheochromocytoma animals showed an eight fold decrease in sensitivity (EC50) and a 74% decrease in maximal contractility (Emax) to norepinephrine as compared with controls. Similarly, mesenteric artery rings prepared from the same animals showed a five fold loss of EC50 but no decrease in Emax to phenylephrine as compared with controls. In addition, serotonin EC50 and Emax of these mesentery preparations remained unaltered. Coupled with our previous findings [9], the present study suggests that rats with pheochromocytoma secreting large amounts of norepinephrine provide a valuable model system for studying in vivo desensitization of the cardiovascular alpha-receptor systems as well as the beta-adrenergic receptor system.

Animals↗

PubMed1985

Conjugates of catecholamines. 5. Synthesis and beta-adrenergic activity of N-(aminoalkyl)norepinephrine derivatives.

A novel series of N-aminoalkyl congeners and model derivatives of norepinephrine has been synthesized. Compounds that were structurally related to epinephrine were prepared from fully protected intermediates. Alternatively, isoproterenol-related compounds were synthesized via reductive amination of preformed methyl ketone derivatives with norepinephrine. The beta-adrenergic activities of these new compounds were assessed through measurement of intracellular cyclic AMP accumulation in S49 mouse lymphoma cells and displacement of iodocyanopindolol (ICYP) from membrane preparations. Congeners that contained an underivatized primary amine function exhibited virtually no activity in these assays. However, when this amine function was acylated (e.g., to an amide, carbamate, urea, sulfonamide, etc.), the products exhibited generally increased beta-adrenergic activity, which was, however, strongly dependent on the nature of the acylating group and also the length of the spacer. In particular, a benzyl carbamate derivative containing a branched, seven-carbon spacer group was 40 times more potent than isoproterenol in the in vitro S49 assay.

Adrenergic beta-Agonists↗

PubMed1985

Conjugates of catecholamines. 6. Synthesis and beta-adrenergic activity of N-(hydroxyalkyl)catecholamine derivatives.

A new series of catecholamines has been prepared in which the N-alkyl substituent of dl-epinephrine or dl-isoproterenol has been extended by a methylene chain terminated by a hydroxyl group or derived functionality (e.g., carbamate or ester). These functionalized catecholamines (congeners) and model compounds were prepared with the goal of eventual attachment to polymeric carrier molecules. The beta-adrenergic agonist activity of the derivatives was evaluated in vitro by measuring the intracellular accumulation of cyclic AMP in S49 mouse lymphoma cells and by the displacement of iodocyanopindolol (ICYP). A n-butylcarbamate derivative (compound 15) was the most active compound in this series with a potency 190 times greater than dl-isoproterenol in the S49 assay. The biological results indicate that minor modifications in structure in the N-alkyl substituent of the catecholamine can influence the pharmacologic activity.

Adrenergic beta-Agonists↗

PubMed1985

Direct measurement of vascular alpha 1-adrenoceptors.

alpha-Adrenoceptors play an important role in regulating vascular tone. [125I]BE2254, a high affinity antagonist, has been utilized to label alpha 1-receptors in membrane preparations from rabbit aorta. [125I]BE2254 specifically labels a single class of binding sites with the characteristics of alpha 1-receptors. Catecholamines compete for [125I]BE2254 binding stereospecifically and with the characteristic alpha-adrenergic potency series (-)-adrenaline greater than or equal to (-)-noradrenaline much greater than (-)-isoprenaline. The alpha 1-adrenoceptor selective antagonist prazosin is much more potent than yohimbine in competing for the [125I]BE2254 binding sites, which suggests that the alpha-adrenoceptor identified is predominantly of the alpha 1 subtype. The extension of radioligand binding techniques to individual rabbit aortas should simplify the study of vascular alpha-adrenoceptor regulation.

Adrenergic alpha-Antagonists↗

PubMed1985

Decreased membrane fluidity and beta-adrenergic responsiveness in atherosclerotic quail.

The effects of increased cholesterol on erythrocyte membrane fluidity and beta-adrenergic function were studied in a quail model of atherosclerosis. Birds fed a cholesterol-supplemented diet developed severe atherosclerosis and hypercholesterolemia after 6 wk. This cholesterol-enriched diet led to a markedly elevated serum cholesterol and a 26% increase in the cholesterol-to-phospholipid ratio in erythrocyte membranes. Electron paramagnetic resonance spectra measured with 5- and 12-doxyl-stearic acid spin-label probes were used to estimate the order of quail erythrocyte membranes. Membrane preparations from cholesterol-fed birds were more highly ordered near the membrane leaflet surface, as well as deeper in the membrane interior, compared with controls. beta-Adrenergic receptor stimulation of adenosine 3',5'-cyclic monophosphate accumulation was blunted in erythrocytes from the hypercholesterolemic quail. There was no change in beta-receptor density or affinity in the cholesterol-enriched membranes. These studies demonstrate that cholesterol incorporation into erythrocyte membranes in vivo is associated with decreased membrane fluidity and decreased beta-adrenergic responsiveness. The atherosclerotic quail may serve as a useful model to further probe the sequelae of hypercholesterolemia on the function of integral membrane proteins.

Animals↗

PubMed1985

Desensitization of beta-adrenergic receptor-mediated vascular smooth muscle relaxation.

Responsiveness to catecholamines may be blunted after prolonged exposure to an agonist; this phenomenon, termed desensitization, is often mediated by receptor down-regulation. beta-Adrenergic receptors mediate relaxation of vascular smooth muscle. We have examined the possibility that this response may be desensitized after prolonged exposure to increased concentrations of epinephrine. Rats were treated with epinephrine infusions (300 micrograms/kg/hr from a minipump) for 7 days and had levels of plasma epinephrine 70-fold greater than those of controls. The mesenteric artery rings from the epinephrine-treated rats contracted normally when exposed to serotonin; however, the extent of relaxation promoted by the beta-adrenergic agonist isoproterenol was blunted (86 +/- 4 vs. 43 +/- 9%; p less than 0.05). Acetylcholine and nitroglycerine, which may act through a cyclic GMP mechanism, caused virtually identical relaxation responses in both control and epinephrine-treated groups. To determine the mechanism for the loss in responsiveness to isoproterenol, we measured adrenergic receptors in individual mesenteric arteries using [125I]cyanopindolol. Specific binding of [125I]cyanopindolol was found to have the expected characteristics of interaction with beta receptors. There was no difference in the number of beta-adrenergic receptors between control and epinephrine-treated animals (24 +/- 5 vs. 26 +/- 6 fmol/mg of protein), although there was significantly marked down-regulation of beta-adrenergic receptors in hearts (23 +/- 2 vs. 10 +/- 1 fmol/mg of protein; p less than 0.001) and lungs (172 +/- 29 vs. 76 +/- 7 fmol/mg of protein; p less than 0.01) in the same rats. The ability of isoproterenol to stimulate cyclic AMP production in the mesenteric arteries from the two groups was not significantly different (20.3 +/- 3.5 vs. 23.8 +/- 4.7 pmol of cAMP/mg of protein/2 min). Furthermore, mesenteric artery relaxation was found to be decreased in response to the cyclic AMP analogue dibutyryl cyclic AMP (45 +/- 2.0 vs. 28 +/- 2.0%; p less than 0.001) in the epinephrine-infused rats. These data suggest that the desensitization of beta-adrenergic receptor-mediated smooth muscle relaxation may be caused by a mechanism distal to cyclic AMP production.

1-Methyl-3-isobutylxanthine↗

PubMed1985

Prolonged hyporesponsiveness of vascular smooth muscle contraction after halothane anesthesia in rabbits.

Halothane diminishes smooth muscle contractility in vascular tissue. In order to further characterize this phenomenon we undertook a series of in vivo and ex vivo experiments. Pressor dose-response curves to the selective alpha 1-adrenergic agonist, phenylephrine, were constructed in groups of rabbits before, during and 2 hr after halothane anesthesia and the dose of phenylephrine that induced a 25 torr increase in mean arterial pressure (ED25) was derived by polynomial regression analysis. ED25 torr increased significantly during halothane anesthesia, and rabbits remained in this insensitive state when the ED25 was assessed 2 hr after anesthesia. The halothane-induced loss of responsiveness was corroborated by ex vivo experiments utilizing aortic rings from halothane-anesthetized rabbits. The maximal contraction to norepinephrine (NE) was significantly lower in halothane-treated aortic rings and only slowly returned to normal by 4 hr. The EC50 (the dose causing a 50% maximal contraction) for NE was significantly greater in aortic rings from halothane-anesthetized rabbits. This loss of sensitivity, reflected by the higher EC50 was not restored by 4 hr of ex vivo incubation in a halothane-free medium. We conclude that halothane induces loss of sensitivity to adrenergic agonists that persists for several hours after termination of the halothane anesthetic.

Anesthesia↗