EFFECTS OF KT-362, A SARCOLEMMAL AND INTRACELLULAR CALCIUM-ANTAGONIST, ON CALCIUM TRANSIENTS OF CULTURED NEONATAL RAT VENTRICULAR CELLS - ACOMPARISON WITH GALLOPAMIL AND RYANODINE

We evaluated the effects of oxopropyl]-2,3,4,5,-tetrahydro-1,5-benzoth iazepine fumarate), a putative intracellular calcium antagonist, on th e intracellular free calcium concentration ([Ca2+](i)) of cultured neo natal rat ventricular cells using microfluorometry of fura-2. The effe cts were compared with those. of gallopamil (D-600), a sarcolemmal cal cium channel antagonist, and ryanodine, a modulator of sarcoplasmic re ticulum (SR) function. KT-362 decreased both systolic [Ca2+](i) (sCa) and diastolic [Ca2+](i) (dCa) in cell aggregates, in a concentration ( 1, 3, 10, and 30 mu M) and stimulation frequency (0.2, 0.5, and 1.0 Hz ) dependent manner. The time to peak of the Ca2+ transient was signifi cantly prolonged by KT-362 at a concentration of 30 mu M, while the ha lf-life of the Ca2+ transient was prolonged at concentrations of great er than or equal to 10 mu M. Gallopamil (1 mu M) decreased both sCa an d dCa in a frequency (0.2, 0.5, and 1.0 Hz) dependent fashion, as was the case for KT-362, but did not change the time course of Ca2+ transi ents. Ryanodine (10 mu M) prolonged the time to peak and half-life of the Ca2+ transient, as was also the case for KT-362, while the effect of ryanodine on dCa differed from that of KT-362. Finally, the effect of KT-362 on Ca2+ transients could be mimicked by simultaneous applica tion of gallopamil and ryanodine. These results suggest that KT-362 is a novel compound that exerts depressant effects on both sarcolemmal C a2+ channels, and perhaps Ca2+ release channels of the sarcoplasmic re ticulum, in cultured neonatal rat ventricular cells.