(Hypertension. 2000;36:376.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
ß-Adrenoceptor Dysfunction After Inhibition of NO Synthesis
From the Departments of Pharmacology (E.J.W., A.K.J., S.J.L.) and Psychology (A.K.J.) and The Cardiovascular Center (E.J.W., A.K.J.), University of Iowa, Iowa City.
Correspondence to Stephen J. Lewis, PhD, Department of Pharmacology, University of Iowa, Iowa City, IA 52242. E-mail stephen-lewis{at}uiowa.edu
Abstract—Gs protein–coupled ß-adrenoceptors rapidly desensitize on exposure to agonists in reconstituted membrane preparations, whereas rapid tachyphylaxis to ß-adrenoceptor–mediated vasodilation does not readily occur in vivo. This study examined the possibility that endothelium-derived nitrosyl factors prevent the rapid desensitization of ß-adrenoceptors in the vascular smooth muscle of resistance arteries in pentobarbital-anesthetized rats. The fall in mean arterial blood pressure and in hindquarter vascular resistance produced by the ß-adrenoceptor agonist isoproterenol (ISO, 0.1 to 10 µg/kg IV) was slightly but significantly smaller in rats treated with the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 100 µmol/kg IV) than in saline-treated rats. The ISO-induced fall in mesenteric resistance was similar in L-NAME–treated and in saline-treated rats. The fall in hindquarter vascular resistance and in mesenteric resistance produced by ISO (8x10 µg/kg IV) was subject to tachyphylaxis on repeated injection in rats treated with L-NAME (100 µmol/kg IV) but not in rats treated with saline. Injections of L-S-nitrosocysteine (1200 nmol/kg IV), a lipophobic S-nitrosothiol, before each injection of ISO (10 µg/kg IV) prevented tachyphylaxis to ISO in L-NAME–treated rats. The vasodilator effects of ISO (0.1 to 10 µg/kg IV) in L-NAME–treated rats that received 8 injections of ISO (10 µg/kg IV) were markedly smaller than in L-NAME–treated rats that received 8 injections of saline. These results indicate that (1) the vasodilator actions of ISO in pentobarbital-anesthetized rats only minimally involve the release of endothelium-derived nitrosyl factors, (2) the effects of ISO are subject to development of tachyphylaxis in L-NAME–treated rats, and (3) tachyphylaxis to ISO is prevented by L-S-nitrosocysteine. These findings suggest that endothelium-derived nitrosyl factors may prevent desensitization of ß-adrenoceptors in vivo.
Key Words: adrenergic receptor agonists • hemodynamics • nitric oxide • rats
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