20-Hydroxyeicosatetraenoic acid-induced vasoconstriction and inhibition of potassium current in cerebral vascular smooth muscle is dependent on activation of protein kinase C.
20-Hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450 metabolite of arachidonic acid, is a potent vasoconstrictor, and has been implicated in the myogenic activation of renal and cerebral arteries. We examined the role of protein kinase C (PKC) in the signal transduction pathway by which 20-HETE induces vasoconstriction and inhibition of whole-cell K+ current in cat cerebral vascular smooth muscle. 20-HETE induced a concentration-dependent constriction in isolated pressurized cat middle cerebral arteries (-29 +/- 8% at 1 microM). However, in the presence of an N-myristoylated PKC pseudosubstrate inhibitor peptide (MyrPsiPKC-I(19-27)), 20-HETE induced a concentration-dependent vasodilation (26 +/- 4% at 1 microM). In whole-cell voltage clamp studies, application of 20-HETE inhibited whole-cell K+ current recorded in cat cerebral vascular smooth muscle cells, an effect that was attenuated by MyrPsiPKC-I(19-27). Further evidence for the role of PKC activation in response to 20-HETE is the finding that 20-HETE increased the phosphorylation of myristoylated, alanine-rich PKC substrate in cultured cat cerebral vascular smooth muscle cells in a concentration- and PKC-dependent manner. These data provide evidence that PKC is an integral part of the signal transduction pathway by which 20-HETE elicits vasoconstriction of cerebral arteries and inhibition of whole-cell K+ current in cat cerebral vascular smooth muscle.
Lange
A
A
Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Gebremedhin
D
D
Narayanan
J
J
Harder
D
D
D000818:Animals; D002415:Cats; D002536:Cerebral Arteries / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D019814:Myristic Acid; D010446:Peptide Fragments / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents
D006893:Hydroxyeicosatetraenoic Acids; D010446:Peptide Fragments; D015221:Potassium Channels; D014662:Vasoconstrictor Agents; D019814:Myristic Acid; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate