INHIBITION OF THE VOLTAGE-DEPENDENT CALCIUM CURRENT BY EXTRACELLULAR ATP IN HAMSTER VENTRICULAR CARDIOMYOCYTES

The modulation of the high-voltage-activated calcium current (I-Ca) by external ATP was examined in single ventricular cardiomyocytes of the hamster using the whole-cell configuration of the patch-clamp techniq ue. Extracellular application of ATP (0.1-100 mu M) was found to inhib it I-Ca reversibly. The inhibition followed a slow time course (half t ime similar to 25 s) and was accompanied by very small changes of the holding current and no shift in the current-voltage relationship. With 100 mu M ATP, peak I-Ca was reduced by similar to 30%. This response was not blocked by the P-1 inhibitor 8-cyclopentyl-1,3-dipropylxanthin e. The nonhydrolyzable ATP analogs adenosine 5'-O-(3-thiotriphosphate) and AMP-adenosine 5'-[beta,gamma-imido]triphosphate also reduced I-Ca . The ATP analog alpha,beta-methylene-ATP was about equipotent with AT P at 50 mu M. Internal guanosine 5'-O-(3-thiotriphosphate) (200 mu M) rendered the ATP-mediated inhibition of I-Ca poorly reversible, wherea s internal guanosine 5'-O-(2-thiodiphosphate) (200-500 mu M) had no ef fect. Holding the intracellular adenosine 3',5'-cyclic monophosphate c oncentration at a constant high level did not alter the ATP response. We conclude that external ATP inhibits I-Ca via a P-2 purinergic recep tor in hamster ventricular myocytes. Our results suggest the involveme nt of a G protein not coupled to adenylate cyclase. The inhibition of I-Ca by extracellular ATP might; have pathophysiological relevance und er conditions of myocardial injury.