EFFECTS OF A NOVEL, POTENT BENZOTHIAZEPINE CA2-PIG VENTRICULAR MYOCYTES( CHANNEL ANTAGONIST, DTZ323, ON GUINEA)

The effects of a 1,5-benzothiazepine derivative, -(acetyloxy)-5-[2-[[2 -(3,4-dimethoxyphenyl)ethyl]- methylamino]ethyl]-2,3- 2-(4-methyoxyphe nyl)-1,5-benzothiazepine-4(5H)-one (DTZ323), on membrane currents were investigated in guinea-pig ventricular myocytes using the whole-cell patch-clamp technique. DTZ323 suppressed the L-type Ca2+ channel curre nts (I-Ca(L)) more selectively than the T-type Ca2+ channel and the Na + channel currents. DTZ323 inhibited I-Ca(L) in a use- and a voltage-d ependent manner with 24 times higher potency than that of diltiazem. R ate of recovery of I-Ca(L) from the conditioned block by DTZ323 was fa ster compared with diltiazem and verapamil, and was steeply dependent on the holding potential at resting membrane potential range in ventri cular myocytes (-90 to -60 mV). Our results suggest that DTZ323 is a s elective Ca2+ channel antagonist, the most potent among the 1,5-benzot hiazepine Ca2+ channel antagonists, and that the voltage- and use-depe ndent effect of DTZ323 on I-Ca(L) is due to the steep voltage dependen ce of the rate of dissociation from the cardiac L-type Ca2+ channels.