Effects of methyclothiazide on contractile responses and Ca2+ entry into vascular smooth muscle cells

The possible involvement of calcium and potassium channels in mediating the vascular actions of methyclothiazide (MCTZ), a thiazide diuretic, was inve stigated in isolated aortic rings from 12 week-old hypertensive rats. MCTZ (10(-4) M) inhibits the contractile response induced by addition of Ca2+ to a depolarizing solution, the maximal contracture is reduced by 87.16+/-6.4 %. Furthermore this inhibitory effect was unaffected by charybdotoxine a se lective blocker of calcium-activated K+ channels (Kca). This suggesting tha t MCTZ inhibits voltage-gated Ca2+ channels and blunts the Ca2+ entry into vascular smooth muscle cells. This inhibition was partially attenuated by e ither mechanical removal of the endothelium or No-nitro-L-arginine (NOLA) t reatment, suggesting that MCTZ effects are also mediated by an endothelium- dependent mechanism involving endothelium-dependent relaxing factor (EDRF)/ nitric oxide (NO) release. Taken together, these observations could point to a role of voltage-gated C a2+ channels and endothelial release of EDRF/NO in the antihypertensive act ion of MCTZ.