5′-Guanylimidodiphosphate stimulation of slow Ca 2+ current in myocardial cells

Abstract

Positive inotropic agents which elevate cyclic AMP, such as catecholamines, histamine, and methylxanthines, increase the number of membrane slow cationic channels available for voltage activation. 5′-Guanylimidodiphosphate (GPP(NH)P), an agent known to directly activate adenylate cyclase in a variety of broken cell preparations, was tested for its ability to induce slow Ca 2+ channels in embryonic chick ventricular myocardial cells. The preparations used were reaggregated cell culture and intact noncultured ventricular myocardium. When the myocardial cells were rendered inexcitable by tetrodotoxin (which blocks the fast Na + channels), addition of any of the positive inotropic agents stated above gives rise to slowly-rising overshooting electrical responses (the “slow response”) accompanied by contractions within 1 to 3 min. The addition of GPP(NH)P (10 −5 to 10 −3 m) also induced the slow response within 5 to 30 min. The slow responses induced by GPP(NH)P were blocked by agents known to block slow channels and Ca 2+ current, such as Mn 2+ (1 m m) and verapamil (10 −6 m). GTP did not induce the slow response. These results support the hypothesis that the intracellular level of cyclic AMP controls the availability of the slow Ca 2+ channels in the myocardial sarcolemma.