Vasodilator action of KB-944, a new calcium antagonist

Vasodilator action of diethyl 4-(benzothiazol-2-yl)benzylphosphonate (KB-944) was mainly examined in comparison with papaverine in isolated perfused heart and anesthetized or conscious dogs. In isolated perfused heart, KB-944 (1-30 micrograms/heart i.a.) and diltiazem (1-30 micrograms/heart i.a.) produced a dose-dependent increase in coronary flow, and dose-dependent decrease in the heart rate and the myocardial contractile force. On the other hand, papaverine (3-100 micrograms/heart i.a.) produced a dose-dependent increase in coronary flow and heart rate, and did not practically affect the myocardial contractile force. KB-944 was about 3 times as active as papaverine and diltiazem on the percent increase of coronary flow. In anesthetized dogs, KB-944 (0.03-0.3 mg/kg i.v. or 10 mg/kg i.d.), diltiazem (0.03-0.3 mg/kg i.v. or 10 mg/kg i.d.) and papaverine (0.1-1 mg/kg i.v.) significantly increased the coronary blood flow with hypotension. Simultaneously, KB-944 and diltiazem decreased the heart rate, whereas papaverine increased it. Furthermore, KB-944 and diltiazem selectively increased the coronary blood flow more than the carotid blood flow, though papaverine increased the carotid blood flow more than the coronary blood flow. In case of i.v. route, KB-944 and diltiazem were about 5 times as active as papaverine on the percent increase of coronary blood flow. In case of i.d. route, the effect on coronary blood flow and heart rate induced by KB-944 was quantitatively similar to that induced by diltiazem, although the decrease in blood pressure induced by diltiazem was lesser than that produced by KB-944. In conscious dogs, KB-944 (0.03-0.3 mg/kg i.v. or 10-100 mg/kg p.o.) produced a dose-dependent increase in coronary blood flow and heart rate. In case of i.v. route, this vasodilator activity of KB-944 was 10 times as potent as that of papaverine. Thus, KB-944 is a more potent coronary vasodilator. Furthermore, KB-944 is well absorbed from the intestinal tract, and produces a long-acting increase in the coronary blood flow.