Catecholamine-induced cardiac hypertrophy uncouples β-adrenoceptors from slow calcium channels

Abstract

Changes in the parameters of Ca 2+-dependent slow action potentials (APs) and in their sensitivity to noradrenaline, forskolin, dibutryl-cAMP and extracellular Ca 2+ concentration were studied and compared in left ventricular trageculae from normal control rats and rats with cardiac hypertophy. Cytochemical studies were also carried out to determine changes in the activity of membrane-bound adenylate cyclase. Hypertrophy was induced by administration of 5 mg/kg isoproterenol once daily for 7 days. In hypertrophied cardiac muscle, the overshoot of the slow APs was increased by 75%, the maximum rate of rise (V̇ max) increased by 76% and the AP duration at 50% repolarization (APD 50) prolonged by 56%. The V̇ max, an indicator of the slow inward Ca 2+ current, increased, in a dose-dependent manner, in response to the β-adrenoceptor agonist noradrenaline, the adenylate cyclase activator forskolin, the protein kinase aktivator cAMP and elevated Ca 2+ concentration in normal control preparations, whereas in hypertrophied myocardium, the β-agonist noradrenaline and the adenylate cyclase activator forskolin had no effect. In cytochemical studies with ATP as substrate, adenylate cyclase activity was localized in the sarcolemma, and significantly fewer reaction products appeared on the outer side of the cell membrane in hypertrophied myocytes than in control myocytes. The results suggest that catecholamine-induced cardiac hypertrophy damages the catalytic subunit of membrane-bound adenylate cyclase, thus uncoupling β-adrenoceptors from slow Ca 2+ channels in the transmembrane signalling process.