Calcium antagonistic effects and the in vitro duration of actions of KW-3049, a new 1,4-dihydropyridine derivative, in isolated canine coronary arteries.

The newly-developed 1,4-dihydropyridine derivative KW-3049 was investigated for calcium antagonistic effects in isolated canine coronary arteries. KW-3049 relaxed the arteries contracted by KCI-depolarization with an IC50 of 7.4 x 10(-9) M, while the IC50 of nifedipine, verapamil and diltiazem were 9.1 x 10(-9) M, 1.7 x 10(-7) M and 3.1 x 10(-7) M, respectively. Comparison with negative inotropic activities examined in electrically-driven canine papillary muscles indicated that KW-3049 was more selective for vasorelaxing versus negative inotropic activities than nifedipine, verapamil and diltiazem. KW-3049 inhibited 45Ca-uptake induced by depolarization without affecting 45Ca-uptake in polarized arteries. Inhibitory effects of KW-3049 at 10(-9) and 10(-8) M on depolarization-induced contractions of arteries exhibited no recovery for up to 4 hr after washout of the tissues, whereas those of nifedipine, nitrendipine, verapamil and diltiazem at vasoinhibitory concentrations disappeared within 1 to 4 hr after washout. The uptake and efflux of [3H]compounds of KW-3049, nitrendipine, verapamil and diltiazem were examined. The uptake of compound after 2 hr of incubation was the highest for nitrendipine. The efflux rate of KW-3049 was 1/10 or less than those of the other compounds examined. In summary, the present results in isolated coronary arteries demonstrate that KW-3049 is a potent, vasculoselective calcium antagonist whose effects persist long even after washout of tissues presumably due to its slow dissociation rate from arteries.