Catecholamine-induced cardiac hypertrophy uncouples beta-adrenoceptors from slow calcium channels.
Changes in the parameters of Ca(2+)-dependent slow action potentials (APs) and in their sensitivity to noradrenaline, forskolin, dibutyryl-cAMP and extracellular Ca2+ concentration were studied and compared in left ventricular trabeculae from normal control rats and rats with cardiac hypertrophy. 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 (Vmax) increased by 76% and the AP duration at 50% repolarization (APD50) prolonged by 56%. The Vmax, an indicator of the slow inward Ca2+ current, increased, in a dose-dependent manner, in response to the beta-adrenoceptor agonist noradrenaline, the adenylate cyclase activator forskolin, the protein kinase activator cAMP and elevated Ca2+ concentration in normal control preparations, whereas in hypertrophied myocardium, the beta-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 beta-adrenoceptors from slow Ca2+ channels in the transmembrane signalling process.
Mészáros
J
J
Department of Anatomy, Medical University of Debrecen, Hungary.
Lévai
G
G
D000200:Action Potentials / Q000187:drug effects; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D006332:Cardiomegaly / Q000139:chemically induced / Q000503:physiopathology*; D005576:Colforsin / Q000494:pharmacology; D004558:Electric Stimulation; D006321:Heart / Q000502:physiology*; D007545:Isoproterenol / Q000633:toxicity; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D015220:Calcium Channels; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D009638:Norepinephrine