Inhibition of maxi-K currents in ferret portal vein smooth muscle cells by the antifungal clotrimazole

Abstract

The antifungal agent clotrimazole (CLT) is a potent small-molecule inhibitor of Ca-activated K (KCa) currents of intermediate conductance in murine erythroleukemia cells. This study demonstrates that CLT also inhibits large-conductance KCa 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 CLT was sensitive to test potential. CLT inhibited unitary maxi-K currents in outside-out patches, apparently by decreasing the mean open time. A metabolite of CLT lacking an imidazole ring also inhibited K currents. In contrast, the antifungal drug ketoconazole increased these same currents. Thus the inhibitory action of CLT appears to be due to a direct interaction with the channel protein rather than to imidazole block of cytochrome P-450 activity. Consistent with inhibition of maxi-K currents by CLT, superfusion of strips of portal vein VSM with CLT enhanced isometric tension and spontaneous rate of contraction, suggesting that CLT modulation of maxi-K currents may alter vasomotor functioning.