We examined the role of K+ channels in mediating the acute vascular actions of hydrochlorothiazide, indapamide, cicletanine, and cromakalim, studying the effect of K+ channel blockers on drug-induced relaxation and drug-induced 86Rb efflux in guinea pig mesenteric arteries. Cromakalim-induced relaxation was unaffected by charybdotoxin, apamin, or phencyclidine (PCP) but was reduced by 75% (with 30 microM cromakalim) by glibenclamide (p < 0.001). Cromakalim increased 86Rb efflux from guinea pig vessels, an effect that was abolished by glibenclamide. Hydrochlorothiazide and cicletanine-induced relaxations have been shown to be inhibited by charybdotoxin by unaffected by glibenclamide, apamin, or PCP. Hydrochlorothiazide and cicletanine increased 86Rb efflux from guinea pig mesenteric arteries. These increases were abolished by charybdotoxin. Indapamide-induced relaxation was not affected by incubation with any of the K+ channel blockers. Indapamide did not alter basal 86Rb efflux. The results suggest that in guinea pig mesenteric arteries indapamide-induced relaxation is not mediated by an action on K+ channels. Cromakalim-induced effects are mediated by KATP. Large conductance KCa mediates the hydrochlorothiazide and cicletanine-induced vascular effects in part.