Inhibitory effect of cicletanine on vascular smooth muscle cell proliferation

We investigated the effect of cicletanine on vascular smooth muscle cell proliferation. In cultured vascular smooth muscle cells from rat mesenteric artery, cicletanine (10^-5 to 10^-4 M) increased prostacyclin synthesis (measured as 6-keto-PGF(1α) by radioimmunoassay) dose-dependently. When added to cells in which mitogenesis was activated by 10% fetal bovine serum, cicletanine (3.3 x 10^-5 to 10^-4 M) inhibited [³H] thymidine incorporation up to 31% of the control level. Inhibitory effect of cicletanine on mitogenesis was also confirmed at 48 h by cell counts (control: 18965 ± 629, cicletanine 10^-4 M: 14840 ± 430, n = 6). The effect of cicletanine on platelet-derived growth factor (PDGF)-stimulated [³H] thymidine incorporation was not abolished by prostaglandin synthesis inhibition with aspirin, but the prostacyclin analogue OP-41483 (125-1000 ng/ml) inhibited it dose-dependently. Calcium entry blockers, nifedipine (3.3 x 10^-6 M) and diltiazem (10^-4 M), inhibited both [³H] thymidine incorporation and cell proliferation, while furosemide did not affect it. Cicletanine also inhibited PDGF-stimulated [³H] thymidine incorporation in cultured glomerular mesangial cells. We conclude that cicletanine stimulates prostacyclin synthesis and inhibits cell proliferation in cultured vascular smooth muscle cells, which may possibly be related to the intracellular calcium mobilization. Such a property might be contributory to the antihypertensive activity of cicletanine.