Palonidipine

Inhibitions by palonidipine hydrochloride (TC-81), a new Ca entry blocker, of the contractile responses to norepinephrine (NE), serotonin (5-HT), prostaglandin F2 alpha (PGF2 alpha) 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, PGF2 alpha, and U-46619 in a concentration-dependent manner, but their relative inhibitions were less than 50% at 10(-8) M. In a Ca(2+)-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(-7) M 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, PGF2 alpha 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.

The antianginal effects of palonidipine, a novel 1,4-dihydropyridine derivative, and nifedipine on various myocardial ischemic models were compared. (1) Palonidipine at 0.5 mg/kg, p.o. significantly inhibited vasopressin-induced ST depression of ECG in Donryu rats. This activity was about 5 times more potent than that of nifedipine and was long-lasting. (2) Palonidipine at 1 mg/kg, i.d. significantly inhibited ST depression induced by isoproterenol in Wistar rats. This activity of TC-81 was more potent than that of nifedipine. (3) Palonidipine at 3 micrograms/kg, i.v. produced an increase in regional myocardial tissue blood flow in the ischemic region of chronic coronary artery occluded dogs. (4) In isolated dog coronary artery, palonidipine at a concentration of 10(-10) M or greater inhibited the amplitude of 3,4-DAP-induced cyclic contractions in a concentration-dependent manner. This activity was 10-30 times more potent than that of nifedipine. (5) An intracoronary injection of endothelin (30 pmol/kg) reduced the coronary blood flow, subepicardial tissue blood flow, and subepicardial pH in anesthetized dogs. The ST elevation of ECG over 0.1 mV also occurred in 8 of 10 cases. In all the cases, ventricular extrasystoles were noted, and 9 out of 10 animals died. Pretreatment with palonidipine (3 micrograms/kg, i.v.) inhibited endothelin-induced ischemic changes, with a potency greater than that of nifedipine. These results suggest that palonidipine may be useful for the therapy of angina-pectoris.