Chronic Direct Stimulation of Adenylyl Cyclase Induces Cardiac Desensitization to Catecholamine and Beta-Adrenergic Receptor Downregulation in Rabbits

Abstract

Chronic stimulation of beta-adrenergic receptors (betaARs) induces betaAR downregulation. However, it is not known whether continuous activation of adenylyl cyclase without direct stimulation of betaARs leads to receptor downregulation. This study investigated the effects of chronic stimulation of adenylyl cyclase with colforsin, on hemodynamic variables, and on myocardial betaAR density. In all, 55 rabbits received intravenous colforsin (1.6 microg/kg/min, n = 20), isoproterenol (ISO; 0.4 microg/kg/min, n = 16), or saline (n = 19) for two weeks. After chronic drug administration, responses of systolic (Delta% peak LV +dP/dt) and diastolic function (Delta% peak LV -dP/dt), and heart rate (Delta% heart rate), to acute administration of ISO (0.05 to 0.2 microg/kg/min) or colforsin (5 to 20 nmol/kg/min) were decreased compared to those before chronic administration. betaAR density in the colforsin group (69.8 +/- 13.8 fmol/ml protein) was less than that in the saline group (79.8 +/- 15.0 fmol/ml protein, P < 0.05), but was greater than that in the ISO group (56.3 +/- 8.4 fmol/ml protein, P < 0.05). Thus, chronic direct stimulation of adenylyl cyclase elicited systolic and diastolic functional desensitization to betaAR stimulation or adenylyl cyclase stimulation, and myocardial betaAR downregulation.