THE JOURNALOF PHARMACOLOGYANDEXPERIMENTALTHERAPEUTICS

Administration to rats of the selective beta-2 adrenoceptor ago fist (±)-clenbuterol(CLEN) (0.3 mg.kg1 s.c., twice dailyfor 14 days)decreased the relaxant responses to the beta adrenoceptor agonist (—)-isoproterenol(IS) and to CLEN in KCI-contracted aortic rings. The treatment did not modify the vasodilation in duced by forskolin (a direct activator of the catalytic subunit of the adenylate cyclase), 3-isobutyl-1-methyixanthine (a phospho diesteraseinhibitor),adenosineor 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 CAMPproduction.The contractileresponseto (—)-norepineph rifle (NE) was inhibited in the presence of IS or CLEN in control aortic rings. However,this modulatoryeffect was not seen in artedes from CLEN-treated rats. Prancubation of the arteries with either cholera toxin (an activator of the stimulatory guanine nucleotide binding proteIn, 6,,) or forskolin reduced NE-IndUCed vasoconstriction to the same extent in aortic nngs from both control and CLEN-treated rats. The chronotropic response to NEin rat atna(beta-i-mediated)was not affectedby the treat ment. These results suggest that prolonged administration of CLEN to rats Induced desensitization of beta-2 adrenoceptor mediated vascula