Inhibitory effects of palonidipine hydrochloride (TC-81) on contractions induced by various vasoconstrictors in rat aorta

Inhibitions by palonidipine hydrochloride (TC-81), a new Ca entry blocker, of the contractile responses to norepinephrine (NE), serotonin (5-HT), prostaglandin F2α (PGF2α) and U-46619, a thromboxane A2 analog, were investigated in isolated rat aorta strips and compared with the inhibition of the high K+ response. TC-81 and nicardipine inhibited the contractile responses to NE, 5-HT, PGF2α, and U-46619 in a concentration-dependent manner, but their relative inhibitions were less than 50% at 10-8 M. In a Ca2+-free medium, 2-hr pretreatment with TC-81 or nicardipine did not inhibit the contractile responses to various vasoconstrictors, but it inhibited the responses to the addition of Ca. Their inhibitory potencies were less than the inhibition with high K+. Also, the treatment with TC-81 or nicardipine at 10-7M did not affect the tissue level of cyclic AMP. These results suggest that in isolated rat aorta, the inhibition by TC-81 of the contractile responses to NE, 5-HT, PGF2α and U-46619 is not due to inhibition of intracellular Ca2+ release or an increase in cyclic AMP; rather, it is due to inhibition of the Ca2+ influx. This inhibitory effect was less than that seen on the high K+ response.