LAUSR

Abstract It is now well recognized that endothelial KCa2.3 and KCa3.1 channel activities contribute to dilation of resistance arteries via endothelium‐mediated hyperpolarization and vascular smooth muscle relaxation. In this study, we have investigated the functional effect of the KCa channel activator SKA‐31 in third order rat mesenteric arteries using arterial pressure myography. Isolated arteries were cannulated, pressurized intraluminally to 70 mmHg at 36 °C and then constricted with 1 &mgr;M phenylephrine. Acute bath exposure to SKA‐31 evoked a robust and reversible inhibition of developed tone (IC50 = 0.22 &mgr;M). The vasodilatory effects of SKA‐31 and acetylcholine were blunted in the presence of KCa2.3 and KCa3.1 channel antagonists, and were largely prevented following endothelial denudation. Western blot and q‐PCR analyses of isolated mesenteric arteries revealed KCa2.3 and KCa3.1 channel expression at the protein and mRNA levels, respectively. Penitrem‐A, an inhibitor of KCa1.1 channels, decreased vasodilatory responses to acetylcholine, sodium nitroprusside and NS‐1619, but had little effect on SKA‐31. Similarly, bath exposure to the eNOS inhibitor L‐NAME did not alter SKA‐31 and acetylcholine‐mediated vasodilation. Collectively, these data highlight the major cellular mechanisms by which the endothelial KCa channel activator SKA‐31 inhibits agonist‐evoked vasoconstriction in rat small mesenteric arteries.