Divergent Mechanisms of ATP-Sensitive K + Channel–Induced Vasodilation in Renal Afferent and Efferent Arterioles

Abstract

Abstract K + channel openers (PCOs), such as pinacidil, elicit vasodilation primarily by hyperpolarization-induced inhibition of L-type Ca 2+ channel activation. The physiological role of other mechanisms suggested to contribute to PCO-induced vasodilation is not well established. In the renal microcirculation, L-type Ca 2+ channels play a prominent role in vasoconstriction of the afferent arteriole (AA) but are absent or physiologically silent in the efferent arteriole (EA). Thus, L-type Ca 2+ channel–dependent and –independent mechanisms can readily be distinguished in this model. In the present study, we found that pinacidil potently inhibited Bay K 8644–induced AA vasoconstriction. Pinacidil also preferentially inhibited angiotensin II–induced AA vasoconstriction (approximately ninefold greater potency than EA). These results are consistent with an AA effect of pinacidil on L-type Ca 2+ channel activation. Unexpectedly, 10 μmol/L pinacidil inhibited AA and EA responses to similar extents (84±10% and 71±9%, respectively). In both AAs and EAs, glibenclamide restored normal reactivity, indicating an involvement of the ATP-sensitive K + channels. In the EA, however, pretreatment with diltiazem did not alter the effects of pinacidil. Nevertheless, 45 mmol/L KCl reversed the EA actions of pinacidil, indicating an essential requirement for a normal K + gradient. These findings suggest that the EA actions of pinacidil involve alterations in membrane potential but not changes in L-type Ca 2+ channel activity. Overall, our findings do support the premise that L-type Ca 2+ channel modulation is involved in PCO-induced vasodilation in the renal microcirculation. The EA actions of pinacidil, however, suggest important additional vasodilatory mechanisms that also involve ATP-sensitive K + channel–induced hyperpolarization but are independent of L-type Ca 2+ channel modulation.