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 (K-ATP) channels in arterial smooth muscle cells were examined. Whole-cell K-ATP currents, activated by the synthetic K-ATP 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 (H-1)-receptors inhibited K-ATP currents by 40-56%. The signal transduction pathway that links these receptors to K-ATP channels was investigated. An inhibitor of phospholipase C (D609) and of protein kinase C (GF 109203X) reduced the inhibitory effect of these vasoconstrictors on K-ATP currents from 40-56% to 11-23%. Activators of protein kinase C, a diacylglycerol analogue and phorbol 12-myristate 13-acetate (PMA), inhibited K-ATP currents by 87.3 and 54.2%, respectively. K-ATP currents, activated by calcitonin gene-related peptide, were also inhibited (47-87%) by serotonin, phenylephrine, and PMA. We propose that K-ATP channels in these arterial myocytes are subject to dual modulation by protein kinase C (inhibition) and protein kinase A (activation).