Inhibitory effects of protein kinase C on inwardly rectifying K+- and ATP-sensitive K+ channel-mediated responses of the basilar artery.
OBJECTIVE
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 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 micromol/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 micromol/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 micromol/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.
Chrissobolis
Sophocles
S
Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
Sobey
Christopher G
CG
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001464:Barium / Q000494:pharmacology; D001488:Basilar Artery / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology; D010847:Picolines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011714:Pyrans / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014654:Vascular Patency / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D010847:Picolines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011714:Pyrans; D014665:Vasodilator Agents; D001464:Barium; C061043:aprikalim; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; C058819:calphostin C; D011188:Potassium; D005905:Glyburide