We studied the effects of manidipine, a newly synthesized dihydropyridine Ca2+ channel antagonist, on endothelin-1 (ET-1)-induced [Ca2+]i signaling and immediate-early gene induction in vascular smooth muscle A7r5 cells and glomerular mesangial cells (MCs). ET-1-induced a dose-dependent, biphasic increase in [Ca2+]i in both A7r5 cells and MCs. Manidipine inhibited the ET-1-induced [Ca2+]i increase by reducing both the transient and sustained Ca2+ increments in A7r5 cells and MCs. At concentrations of 10(-10) to 10(-6) mol/L, inhibition was dose dependent with a median effective dose (ED50) of 10(-9) mol/L. A 20-minute preincubation period was required to observe the maximal inhibitory effect of manidipine. In contrast, manidipine (10(-5) mol/L) potentiated ET-1-induced c-fos and c-jun expression in A7r5 cells. This potentiating effect appeared 30 minutes after manidipine was added to the media and lasted for 15 hours. Manidipine alone had no detectable effect on c-fos steady-state messenger ribonucleic acid level. Manidipine induced c-jun expression starting at 60 minutes but with much lower potency. These data demonstrate that manidipine is a potent inhibitor for ET-1-induced [Ca2+]i signaling and that manidipine has multiple effects on ET-1-induced signaling, including potentiating the immediate-early gene response.