Desensitization of the beta-2 adrenoceptor-mediated vasodilation in rat aorta after prolonged treatment with the beta-2 adrenoceptor agonist clenbuterol.
Administration to rats of the selective beta-2 adrenoceptor agonist (+/-)-clenbuterol (CLEN) (0.3 mg.kg-1 s.c., twice daily for 14 days) decreased the relaxant responses to the beta adrenoceptor agonist (-)-isoproterenol (IS) and to CLEN in KCl-contracted aortic rings. The treatment did not modify the vasodilation induced by forskolin (a direct activator of the catalytic subunit of the adenylate cyclase), 3-isobutyl-1-methylxanthine (a phosphodiesterase inhibitor), adenosine or acetylcholine. IS increased (cAMP) cyclic AMP levels dose-dependently in rat aorta, and this effect was reduced markedly in arteries from CLEN-treated rats. By contrast, the treatment did not modify the forskolin-induced cAMP production. The contractile response to (-)-norepinephrine (NE) was inhibited in the presence of IS or CLEN in control aortic rings. However, this modulatory effect was not seen in arteries from CLEN-treated rats. Preincubation of the arteries with either cholera toxin (an activator of the stimulatory guanine nucleotide binding protein, Gs) or forskolin reduced NE-induced vasoconstriction to the same extent in aortic rings from both control and CLEN-treated rats. The chronotropic response to NE in rat atria (beta-1-mediated) was not affected by the treatment. These results suggest that prolonged administration of CLEN to rats induced desensitization of beta-2 adrenoceptor-mediated vascular relaxation by alterations at the level of the beta-2 adrenergic receptor, but not in the mechanisms related to Gs, adenylate cyclase or in those distal to cAMP production.
Kazanietz
M G
MG
Cátedra de Farmacologia, Facultad de Farmacia y Bioquímica, UBA, Argentina.
Enero
M A
MA
D000818:Animals; D001011:Aorta / Q000187:drug effects; D002772:Cholera Toxin / Q000494:pharmacology; D002976:Clenbuterol / Q000494:pharmacology*; D000242:Cyclic AMP / Q000096:biosynthesis; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*
D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; D002772:Cholera Toxin; D000242:Cyclic AMP; D009638:Norepinephrine; D002976:Clenbuterol