Vasoconstrictors inhibit ATP-sensitive K+ channels in arterial smooth muscle through protein kinase C.
The effects of vasoconstrictor-receptor (neuropeptide Y, alpha-adrenergic, serotonergic, histaminergic) stimulation on currents through ATP-sensitive potassium (KATP) channels in arterial smooth muscle cells were examined. Whole-cell KATP currents, activated by the synthetic KATP channel opener pinacidil or by the endogenous vasodilator, calcitonin gene-related peptide, which acts through protein kinase A, were measured in smooth muscle cells isolated from mesenteric arteries of rabbit. Stimulation of NPY-, alpha 1-, serotonin (5-HT2)-, and histamine (H1)-receptors inhibited KATP currents by 40-56%. The signal transduction pathway that links these receptors to KATP channels was investigated. An inhibitor of phospholipase C (D609) and of protein kinase C (GF 109203X) reduced the inhibitory effect of these vasoconstrictors on KATP currents from 40-56% to 11-23%. Activators of protein kinase C, a diacylglycerol analogue and phorbol 12-myristate 13-acetate (PMA), inhibited KATP currents by 87.3 and 84.2%, respectively. KATP currents, activated by calcitonin gene-related peptide, were also inhibited (47-87%) by serotonin, phenylephrine, and PMA. We propose that KATP channels in these arterial myocytes are subject to dual modulation by protein kinase C (inhibition) and protein kinase A (activation).
Department of Pharmacology, University of Vermont, Colchester 05446-2500, USA.
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Bonev
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Nelson
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D004553:Electric Conductivity; D004789:Enzyme Activation; D008638:Mesenteric Arteries / Q000166:cytology / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism*; D011817:Rabbits; D012702:Serotonin Antagonists / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012702:Serotonin Antagonists; D014662:Vasoconstrictor Agents; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D015740:Calcitonin Gene-Related Peptide