Yoshiaki Okamiya

Differences in Responses to TC-81 Among Various Arteries in Dogs

Summary: The vasodilation induced by TC-81 was investigated in vitro and in vivo. In helical strips of dog arteries precontracted with 65.4 mM KCl, TC-81, nicardipine, nifedipine, diltiazem, and papaverine produced concentration-dependent relaxation. The potencies of TC-81 were in the following order: basilar > coronary > femoral > renal > mesenteric arteries. The other drugs also showed a similar property of greater response in basilar and coronary arteries than in renal and mesenteric arteries. However, the difference in reactivity to TC-81 was greater. On the other hand, TC-81, nicardipine, and papaverine dose-dependently increased the blood flow in vertebral, coronary, and femoral arteries in anesthetized dogs. However, the blood flow in renal and mesenteric arteries was not changed or decreased. The decreases in vessel resistance induced by TC-81 were in the following order: vertebral > coronary > femoral > renal = mesenteric arteries, agreeing with the experimental results in vitro. These results suggest that Ca2+ antagonists have the pharmacological property of vasodilating cerebral and heart blood vessels more selectively than other arteries, and this property of TC-81 might be an advantage compared with other drugs.

Relationship between tissue content of TC-81 and relaxation of rat aorta

This study dealt with the relationship between the relaxant action of TC-81, a new Ca2+ antagonist, and its distribution in rat aorta depolarized by high K+ (65.4 mM). The inhibitory effect by TC-81 on K(+)-induced contraction and 45Ca2+ uptake was strongly time-dependent. TC-81 and nicardipine, each 10(-9) M, produced gradual relaxation of high-K(+)-induced contraction. The tissue contents of TC-81 and nicardipine increased with time courses that reflected decreasing tension. Both the maximum tissue content of TC-81 and the maximum relaxation were significantly greater than those for nicardipine. Also, the relaxations produced by TC-81 and nicardipine were correlated with the logarithm of the content of each drug in muscle tissues. However, the dissociation of TC-81 from the tissues was slower than that of nicardipine. The data suggest that the action of TC-81 is closely related to a gradual distribution of drug into muscle tissue, resulting in a slow onset of action. Also, the saturation time of TC-81 was longer than that of nicardipine, thereby accounting for the greater relaxation with TC-81.