Nitrite directly vasodilates hypoxic vasculature via nitric oxide-dependent and -independent pathways
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Background and purpose: It is postulated that nitrite requires reduction to nitric oxide in order to exert its relaxant effect upon isolated hypoxic vessels. Herein, we evaluate the relative contribution of nitric oxide and characterize the downstream mechanisms of nitrite-induced vasorelaxation. Experimental approach: Aortic rings were treated with pharmacological agents and exposed to hypoxia (<1% O2). Following pre-constriction, nitrite (10 µM final) was added to appropriate baths; isometric tension was recorded throughout. Key results: Nitrite (under hypoxic conditions at physiological pH) is capable of exerting physiological effects that cannot be completely inhibited by the inhibitor of soluble guanylate cyclase (sGC), 1H [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one or a nitric oxide scavenger (carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide). Simultaneous blockade of both sGC and cyclooxygenase (COX) completely inhibited the response to nitrite. With regard to the nitric oxide-dependent component, we confirm that aldehyde oxidase, but not xanthine oxidase or endothelial nitric oxide synthase, was important for the actions of nitrite in our model. Conclusions and implications: Nitric oxide generated from nitrite is not exclusively responsible for the physiological actions observed in isolated hypoxic vessels. Nitrite operates via different pathways dependent on the presence or absence of endothelium to produce vasorelaxation. In intact vessels, both sGC and COX enzymes appear to be important. Irrespective of this difference in relaxation mechanism, nitrite is capable of producing the same maximum relaxation, regardless of the presence of endothelium. Having investigated possible nitrite reduction sites, we confirm that aldehyde oxidase is important for the actions of nitrite
British Journal of Pharmacology
Pinder, A.G., Pittaway, E., Morris, K. and James, P.E. (2009) 'Nitrite directly vasodilates hypoxic vasculature via nitric oxide‐dependent and‐independent pathways', British Journal of Pharmacology, 157(8), pp.1523-1530.
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