Journal of Applied Physiology, Vol 81, Issue 3 1264-1272, Copyright © 1996 by American Physiological Society

ARTICLES

Regulation of Ca(2+)-activated K+ channels in pulmonary vascular smooth muscle cells: role of nitric oxide

W. Peng, J. R. Hoidal and I. S. Farrukh
Department of Internal Medicine, Veterans Affairs Medical Center, Salt Lake City, Utah, USA.

Nitric oxide (NO.) is believed to mediate nitrovasodilators and acetylcholine-induced vasodilatation via increasing intracellular guanosine 3',5'-cyclic monophosphate (cGMP) levels. The cellular mechanisms involved in No.-mediated pulmonary vasodilatation are complex and include membrane hyperpolarization. Using the patch-clamp technique in cell-attached and inside-out configurations, we examined the effect of NO. gas, 3-morpholinosydnomimine hydrochloride (SIN-1), and perfusate from ACh-stimulated human pulmonary arterial endothelial cells, or endothelium-derived relaxing factors (EDRF), on the Ca(2+)-dependent K+ (KCa) channels in isolated cultured human pulmonary arterial smooth muscle cells (HPSMC). NO., SIN-1, and EDRF caused similar increases in KCa channel activity. Inhibiting cGMP generation with methylene blue or inhibiting the effect(s) of cGMP with the cGMP antagonist 8-bromoguanosine 3',5'-cyclic monophosphorothioate Rp isomer Rp-cGMPS prevented the NO.- and SIN-1-mediated activation of KCa channels, respectively. Treating the human pulmonary arterial endothelial cells with methylene blue blocked the EDRF-mediated activation of KCa channels in HPSMC. The cGMP analogue 8-bromo-cGMP increased KCa channel activity in intact cells and in excised inside-out HPSMC membrane patches. In the presence of cGMP and ATP, the alpha-isozyme of the cGMP-dependent protein kinase (I alpha-cGMP-PK) significantly increased KCa channel activity, and the channel activation was further increased on addition of the protein phosphatase inhibitors okadaic acid and calyculin A. Furthermore, the cGMP-mediated KCa channel activation was reduced by the cyclic nucleotide-dependent protein kinase inhibitor N-[2-methylamino)ethyl]-5-isoquinlinesulfonamide (H-8). Thus, in HPSMC, the mechanism of NO.- and native EDRF-induced KCa channel activation appears to be mediated via cGMP-I alpha-cGMP-PK phosphorylation of KCa channels.

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