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1 Physiology, New York Medical College, Valhalla, NY, USA
* To whom correspondence should be addressed. E-mail: mike_wolin{at}nymc.edu.
Hypoxia relaxes endothelium-removed bovine coronary arteries (BCA) through mechanisms that do not appear to involve reactive O2 species, prostaglandins or NO. Due to similarities in the relaxation of BCA to hypoxia (PO2 = 8-10 torr) and inhibitors of the pentose phosphate pathway (PPP) including 6-aminonicotinamide and epiandrosterone, we measured the NADPH and NADP and found that hypoxia caused NADPH oxidation (decreased (NADPH/NADP). The relaxation to hypoxia was similar to previously reported properties of relaxation to PPP inhibitors in that both responses were associated with glutathione oxidation, and depressed intracellular calcium release and calcium influx mediated contractile responses. Inhibitors of potassium channels had minimal effects on these relaxation responses. Relaxation to hypoxia and PPP inhibitors were attenuated by a thiol reductant (3 mM dithiothreitol) and by eliciting contraction with an activator of protein kinase C (phorbol-12,13-dibutyrate). In the presence of contraction to U46619, the relaxation to hypoxia and PPP inhibitors were attenuated by the SERCA pump inhibitor 200 µM cyclopiazoic acid and by 10 mM pyruvate. Hypoxia decreased BCA levels of glucose-6-phosphate, but not ATP. Pyruvate prevented the hypoxia-elicited decrease in glucose-6-phosphate and glutathione oxidation, and it increased NADPH levels under hypoxia to levels observed under normoxia. Thus, hypoxia causes a metabolic stress on the PPP which promotes BCA relaxation through processes controlled by lowering the levels of cytosolic NADPH.
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