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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.
Pentose phosphate pathway (PPP) inhibitors, 6-aminonicotinamide (6-AN) and epiandrosterone (EPI), were employed to examine if changes in NADP(H) redox regulates contractile force in endothelium-removed bovine coronary arteries (BCA). 6-AN (0.01-5 mM) or EPI (1-500 µM) elicited dose-dependent relaxation in BCA contracted with 30 mM KCl, 0.1 µM U44619, and endothelin-1, but not with phorbol-12,13-dibutyrate, a protein kinase C activator, that causes Ca2+-independent contraction. Relaxation to PPP inhibition was associated with oxidation of NADPH and glutathione (GSH). Relaxation to 6-AN was not mediated by H2O2, because it was not altered by hypoxia or the peroxide scavenger ebselen (100 µM). The thiol reductant DTT (3 mM) attenuated relaxation to 6-AN and EPI by 30-40%. Inhibition of glycolysis or mitochondrial electron transport did not elicit relaxation in BCA contracted with 30 mM KCl, suggesting these pathways may not be involved in relaxation elicited by PPP inhibition. High doses of K+-channel blockers (e.g. TEA (10 mM) and 4-aminopyridine (10 mM)) only partially inhibited relaxation to 6-AN. Based on changes in Fura-2 fluorescence ratio, 6-AN and EPI appeared to markedly reduce intracellular Ca2+. Thus, PPP inhibition oxidizes NADPH and GSH, and appears to activate a novel coordination of redox-controlled relaxing mechanisms in BCA mediated primarily through decreasing intracellular Ca2+.
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