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1 Department of Physiology, New York Medical College, Valhalla, NY, USA
* To whom correspondence should be addressed. E-mail: mike_wolin{at}nymc.edu.
The mechanisms through which thiol oxidation and cellular redox influence the regulation of soluble guanylate cyclase (sGC) are poorly understood. This study investigated if promoting thiol oxidation via inhibiting NADPH generation by the pentose phosphate pathway (PPP) with 1 mM 6-aminonicotinamide (6-AN) or with the thiol oxidant diamide (1 mM) alters sGC activity and cGMP-associated relaxation to nitric oxide (NO) donors (SNAP and spermine-NONOate). Diamide and 6-AN inhibited NO-elicited relaxation of endothelium-removed bovine pulmonary arteries (BPA) and stimulation of sGC activity in BPA homogenates. Treatment of BPA with the thiol reductant dithiothreitol (1 mM) reversed inhibition of NO-mediated relaxation and sGC stimulation by 6-AN. The increase in cGMP protein kinase-associated phosphorylation of VASP on serine-239 elicited by 10 µM SNAP was also inhibited by diamide. Activation of sGC by SNAP was attenuated by low micromolar concentrations of oxidized GSH (GSSG) in concentrated, but not in dilute homogenates of BPA, suggesting that an enzymatic process contributes to the actions of GSSG. Relaxation to agents which function through cAMP (forskolin or isoproterenol) was not altered by PPP inhibition or diamide. Thus, a thiol oxidation mechanism controlled by the regulation of thiol redox by NADPH generated via the PPP appears to inhibit sGC activation and cGMP-mediated relaxation by NO in a manner consistent with it functioning as an important physiological redox-mediated regulator of vascular function.
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