Inhibitory Effects of Protein Kinase C on Inwardly Rectifying K+- and ATP-Sensitive K+ Channel-Mediated Responses of the Basilar Artery

Abstract

Background and Purpose— The structurally related, inwardly rectifying K+ (KIR) channel and the ATP-sensitive K+ (KATP) channel are important modulators of cerebral artery tone. Although protein kinase C (PKC) activators have been shown to inhibit these channels with the use of patch-clamp electrophysiology, effects of PKC on K+ channel function in intact cerebral blood vessels are unknown. We therefore tested whether pharmacological alteration of PKC activity affects cerebral vasodilator responses to KIR and/or KATP channel activators in vivo. Methods— We measured changes in basilar artery diameter using a cranial window preparation in anesthetized rats. In addition, intracellular recordings of smooth muscle membrane potential were made in isolated basilar arteries. Results— K+ (5 to 15 mmol/L) and aprikalim (1 to 10 &mgr;mol/L) each elicited reproducible vasodilatation. The PKC activator phorbol-12,13-dibutyrate (PdBu) (50 nmol/L) inhibited responses to K+ (by 40% to 55%) and aprikalim (by 40% to 70%), whereas responses to papaverine were unaffected. The PKC inhibitor calphostin C (0.1 &mgr;mol/L) augmented responses to K+ (by 2- to 3-fold) and aprikalim (2-fold) but not papaverine. In addition, K+ (5 mmol/L) and aprikalim (3 &mgr;mol/L) each hyperpolarized the basilar artery. PdBu inhibited these responses to aprikalim by 45% but had no effect on K+-induced hyperpolarization. Conclusions— These data suggest that both basal and stimulated PKC activity inhibit KIR and KATP channel–mediated cerebral vasodilatation in vivo. The inhibitory effect on KATP channel–mediated vasodilatation occurs at least partly by inhibition of hyperpolarization mediated by KATP channels. PKC inhibits K+-induced vasodilatation without affecting hyperpolarization, suggesting that the inhibitory effect of PKC on vasodilator responses to K+ does not involve altered KIR channel function.