Inhibitory effects of protein kinase C on inwardly rectifying K+- and ATP-sensitive K+ channel-mediated responses of the basilar artery

Background and Purpose-The structurally related, inwardly rectifying K+ (K-IR) channel and the ATP-sensitive K+(K-ATP) 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 K-IR and/or K-ATP channel activators in vivo. Methods-We measured chances 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 mumol/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 mumol/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 mumol/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 K-IR and K-ATP channel-mediated cerebral vasodilatation in vivo. The inhibitory effect on K-ATP channel-mediated vasodilatation occurs at least partly by inhibition of hyperpolarization mediated by K-ATP 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 K-IR channel function.