INHIBITION OF MAXI-K CURRENTS IN FERRET PORTAL-VEIN SMOOTH-MUSCLE CELLS BY THE ANTIFUNGAL CLOTRIMAZOLE

The antifungal agent clotrimazole (CLT) is a potent small-molecule inh ibitor of Ca-activated K (K-Ca) currents of intermediate conductance i n murine erythroleukemia cells. This study demonstrates that CLT also inhibits large-conductance K-Ca currents (maxi-K currents) in acutely dissociated vascular smooth muscle (VSM) cells of ferret portal vein. The magnitude of block of a component of the whole cell K current by C LT was sensitive to test potential. CLT inhibited unitary maxi-K curre nts in outside-out patches, apparently by decreasing the mean open tim e. A metabolite of CLT lacking an imidazole ring also inhibited K curr ents. In contrast, the antifungal drug ketoconazole increased these sa me currents. Thus the inhibitory action of CLT appears to be due to a direct interaction with the channel protein rather than to imidazole b lock of cytochrome P-450 activity. Consistent with inhibition of maxi- K currents by CLT, superfusion of strips of portal vein VSM with CLT e nhanced isometric tension and spontaneous rate of contraction, suggest ing that CLT modulation of maxi-K currents may alter vasomotor functio ning.