In order to investigate renin- and angiotensin-independent mechanisms of the angiotensin converting enzyme (ACE) inhibitor ramipril we examined the effects of ramiprilat on calcium mobilization in cultured vascular smooth muscle cells. Ramiprilat (10(-7) M) induced a slow increase of basal [Ca2+]i from 52 +/- 7 nM to 162 +/- 12 nM (p less than .001). This increase of basal [Ca2+]i was associated with contraction of vascular smooth muscle cells as assessed by microscopy in vitro. While ramiprilat itself induced an increase of basal [Ca2+]i, the Ca(2+)-mobilizing effect of angiotensin II (AII) was blunted in the presence of the ACE inhibitor (659 +/- 38 nM vs 360 +/- 45 nM, p less than .001). The calcium channel blocker verapamil did not affect the stimulatory effect of ramiprilat on basal [Ca2+]i. The intracellular Ca2+ antagonist TMB 8 attenuated the ramiprilat-induced increase of basal [Ca2+]i (162 +/- 12 nM vs 101 +/- 14 nM, p less than .05). In the present study, the effect of ramiprilat on [Ca2+]i was not blocked by inhibition of prostaglandin synthesis by meclofenamate (10(-5) M); however, this finding does not rule out in vivo effects of ramiprilat-stimulated prostaglandins. These results suggest that ramipril affects Ca2+ kinetics in vascular smooth muscle cells. Ramiprilat-induced contraction of cultured smooth muscle cells may not be relevant in vivo, but the increase of basal [Ca2+]i by ramiprilat may reflect a "reset" of the cellular Ca(2+)-mobilizing mechanism or a depletion of cellular Ca2+ stores and may thus explain the attenuation of the Ca(2+)-mobilizing effect of AII. This mechanism may result in a decrease of vasopressor-dependent vascular tone in vivo and may contribute to the vasodilatory effect of ramipril.