The antihypertensive effect of TC-81 ((+-)-3-(benzylmethylamino)-2,2-dimethylpropyl-methyl-4-(2-f luoro-5- nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate hydrochloride), a new calcium antagonist, was investigated in normotensive and hypertensive rats. By oral administration, the antihypertensive activity of TC-81 (ED20% in spontaneous hypertensive rats (SHR), DOCA-salt hypertensive rats and renal hypertensive rats were 0.37, 0.32, and 0.38 mg/kg p.o., respectively) was 7-14 times more potent in conscious hypertensive rats in comparison with nicardipine. Duration of the antihypertensive effect of TC-81 was about 2 times longer than that of nicardipine, and the response was elicited more slowly than that of nicardipine at an equipotent dose. Similar results were observed by intravenous injection, but the potency of TC-81 was only 3 times higher than that of nicardipine in anesthetized rats. Tolerance of the antihypertensive effect of TC-81 in long-term daily dosing and the rebound phenomenon after discontinuance of the treatment were not observed in hypertensive rats. TC-81, at a concentration of 10(-10)-3 x 10(-9) mol/l, inhibited the KCl-induced contraction of isolated rat vascular preparations. Moreover, TC-81 inhibited the norepinephrine-induced contraction of isolated SHR aorta preparation, but in isolated normotensive rat aorta, TC-81 inhibited the norepinephrine-induced contraction very little. From these observations, TC-81 can be characterized as having a strong, long-lasting, and slow-onset antihypertensive activity, especially by oral administration. Therefore, this new calcium antagonist may be useful for long-term antihypertensive therapy.