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Thiol oxidation causes pulmonary vasodilation by activating K⁺ channels and inhibiting store-operated Ca²⁺ channels

Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, La Jolla, California

Submitted 21 July 2006 ; accepted in final form 8 November 2006

Cellular redox change regulates pulmonary vascular tone by affecting function of membrane and cytoplasmic proteins, enzymes, and second messengers. This study was designed to test the hypothesis that functional modulation of ion channels by thiol oxidation contributes to regulation of excitation-contraction coupling in isolated pulmonary artery (PA) rings. Acute treatment with the thiol oxidant diamide produced a dose-dependent relaxation in PA rings; the IC₅₀ was 335 and 58 µM for 40 mM K⁺- and 2 µM phenylephrine-induced PA contraction, respectively. The diamide-mediated pulmonary vasodilation was affected by neither functional removal of endothelium nor 8-bromoguanosine-3'-5'-cyclic monophosphate (50 µM) and HA-1004 (30 µM). A rise in extracellular K⁺ concentration (from 20 to 80 mM) attenuated the thiol oxidant-induced PA relaxation. Passive store depletion by cyclopiazonic acid (50 µM) and active store depletion by phenylephrine (in the absence of external Ca²⁺) both induced PA contraction due to capacitative Ca²⁺ entry. Thiol oxidation by diamide significantly attenuated capacitative Ca²⁺ entry-induced PA contraction due to active and passive store depletion. The PA rings isolated from left and right PA branches appeared to respond differently to store depletion. Although the active tension induced by passive store depletion was comparable, the active tension induced by active store depletion was 3.5-fold greater in right branches than in left branches. These data indicate that thiol oxidation causes pulmonary vasodilation by activating K⁺ channels and inhibiting store-operated Ca²⁺ channels, which subsequently attenuate Ca²⁺ influx and decrease cytosolic free Ca²⁺ concentration in pulmonary artery smooth muscle cells. The mechanisms involved in thiol oxidation-mediated pulmonary vasodilation or activation of K⁺ channels and inhibition of store-operated Ca²⁺ channels appear to be independent of functional endothelium and of the cGMP-dependent protein kinase pathway.

diamide; pulmonary artery; smooth muscle contractility; pulmonary hypertension; capacitative calcium entry; redox status

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