HETEROLOGOUS DESENSITIZATION OF BETA-ADRENOCEPTOR SIGNAL-TRANSDUCTIONIN-VIVO

The hemodynamic actions of pituitary adenylate cyclase-activating poly peptide (PACAP-27) rapidly diminish upon repeated i.v. injection in ra ts treated with the nitric oxide synthase inhibitor, N-G-nitro-L-argin ine methyl ester (L-NAME). We now report that the beta-adrenoceptor ag onist isoproterenol (0.5 mu g/kg, i.v.) produces pronounced hypotensiv e and vasodilator effects in anaesthetized rats pretreated with L-NAME (100 mu mol/kg, i.v.). However, the hypotensive and vasodilator actio ns of isoproterenol were markedly diminished in L-NAME-treated rats in which tachyphylaxis to PACAP was induced immediately prior to the inj ection of the beta-adrenoceptor agonist. This suggests that a reductio n in tissue concentrations of nitric oxide-containing factors allows t achyphylaxis to PACAP-27-mediated vasodilation to occur in vivo and th at this process leads to the heterologous desensitization of beta-adre noceptor-mediated responses.