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1 Biological Sciences & Pharmacology, University of Aarhus, Aarhus, Denmark
2 Pharmacology, University of Aarhus, Aarhus, Denmark
3 Biological Sciences, University of Aarhus, Aarhus, Denmark
* To whom correspondence should be addressed. E-mail: angela.fago{at}biology.au.dk.
The reduction of circulating nitrite to nitric oxide has emerged as an important physiological reaction aimed to increase vasodilation during tissue hypoxia. Although hemoglobin, xanthine oxidase, endothelial nitric oxide synthase and the bc1 complex of the mitochondria are known to reduce nitrite anaerobically in vitro, their relative contribution to the hypoxic vasodilatatory response has remained unsolved. Using a wire myograph, we have investigated how the nitrite-dependent vasodilation in rat aortic rings is controlled by oxygen tension, norepinephrine concentration, soluble guanylate cyclase (the target for vasoactive nitric oxide) and known nitrite-reductase activities under hypoxia. Vasodilation followed overall first-order dependency on nitrite concentration and, at low oxygenation and norepinephrine levels, was induced by low nitrite concentrations, comparable to those found in vivo. The vasoactive effect of nitrite during hypoxia was abolished upon inhibition of soluble guanylate cyclase and was unaffected by removal of the endothelium or by inhibition of xanthine oxidase and of the mitochondrial bc1 complex. In the presence of hemoglobin and inositol hexaphosphate (that increases the fraction of deoxygenated heme) the effect of nitrite was not different from that observed with inositol hexaphosphate alone, indicating that under the conditions here investigated deoxygenated hemoglobin did not contributed to nitrite vasoactivity. Taken together, our results indicate that the mechanism for nitrite vasorelaxation is intrinsic to the vessel and that under hypoxia physiological nitrite concentrations are sufficient to induce NO-mediated vasodilation independently of the nitrite reductase activities here investigated. Possible reaction mechanisms for nitrite vasoactivity, including formation of S-nitrosothiols within the arterial smooth muscle, are discussed.
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