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(Circulation Research. 1995;77:1114-1120.)
© 1995 American Heart Association, Inc.

Articles

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

Evidence of L-Type Ca²⁺ Channel–Dependent and –Independent Actions of Pinacidil

Martina Reslerova, Rodger Loutzenhiser

From the Smooth Muscle Research Group, Department of Pharmacology and Therapeutics, The University of Calgary (Canada).

Correspondence to Rodger D. Loutzenhiser, PhD, Department of Pharmacology and Therapeutics, The University of Calgary, Health Sciences Centre, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1, Canada.

Abstract K⁺ channel openers (PCOs), such as pinacidil, elicit vasodilation primarily by hyperpolarization-induced inhibition of L-type Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ channel activity. Overall, our findings do support the premise that L-type Ca²⁺ 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 Ca²⁺ channel modulation.

Key Words: ATP-sensitive K⁺ channels • pinacidil • angiotensin II • renal microcirculation • arterioles, afferent and efferent

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