Response of sodium nitrite in the vascular bed of the rat mediated by xanthine oxidoreductase and aldehyde dehydrogenase 2
Description
The purpose of the research presented is to develop a better understanding of the mechanism by which nitrite is converted to nitric oxide. In the present study, the role xanthine oxidoreductase (XOR) and mitochondrial aldehyde dehydrogenase (mALDH2) plays in the mediation of vasodilator responses to sodium nitrite, the role nitrite plays in nitroglycerin induced vasodilation, the effect chronic treatment with sodium nitrite on monocrotaline induced pulmonary hypertension, and the response to peroxynitrite, a nitrite metabolite, was investigated using right heart catheterization techniques to measure pulmonary arterial pressure and the thermodilution technique to measure cardiac output In the first set of experiments, iv injections of sodium nitrite produced dose related decreases in systemic and pulmonary arterial pressures and increases in cardiac output. The decreases in pulmonary arterial pressure were enhanced when baseline tone was increased by U46619, hypoxia and treatment with L-NAME. Pulmonary and systemic vasodilator responses to sodium nitrite were attenuated by treatment with the XOR inhibitor allopurinol or the mALDH2 inhibitor cyanamide and these agents did not alter responses to the NO donors sodium nitroprusside or DEA/NO. The decreases in pulmonary arterial pressure under elevated tone conditions were similar when the rats breathed room air or a 10% O2 and 90% N2 gas mixture. In experiments in which systemic vasodilator responses were evaluated combination treatment with allopurinol and cyanamide did not produce a greater reduction in the response to sodium nitrite than did treatment with either agent alone In the experiments investigating the role nitrite plays in nitroglycerin induced vasodilation, intravenous injections of GTN and sodium nitrite decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressure under baseline and elevated tone conditions and decreases in systemic arterial pressure in response to GTN and sodium nitrite were attenuated by cyanamide, an ALDH2 inhibitor, whereas responses to the NO donor, sodium nitroprusside (SNP), were not altered. The decreases in pulmonary and systemic arterial pressure in response to GTN and SNP were not altered by allopurinol, an inhibitor of xanthine oxidoreductase (XOR), whereas responses to sodium nitrite were attenuated. GTN was approximately 1000 fold more potent than sodium nitrite in decreasing pulmonary and systemic arterial pressures. These results suggest that ALDH2 plays an important role in the bioactivation of GTN and nitrite in the pulmonary and systemic vascular beds but that the reduction of nitrite to vasoactive NO does not play an important role in mediating vasodilator responses to GTN in the intact chest rat In experiments in which the responses to peroxynitrite (PN) were investigated, the results show that injections of PN in doses of 10 -- 100 mmol/kg iv produced dose-related decreases in the pulmonary and systemic arterial pressure in the intact rat and that these responses were enhanced when tone was increased. The vasodilator responses were rapid in onset, short in duration, and reproducible. In addition, injections of 2 mmol/kg of L-PEN did not alter vasodilator responses of PN in the pulmonary and systemic vascular beds of the intact rat These data provide evidence in support of the hypothesis that XOR and mALDH2 can play a role in the bioactivation of nitrite in the rat, that pulmonary vasodilator responses to nitrite are not modulated by ventilatory hypoxia, and that monocrotaline induced pulmonary hypertension can be alleviated by chronic administration of sodium nitrite. These data also provide evidence that nitrite may not play a major role in NTG bioactivation and that peroxynitrite, a product of interaction of NO and superoxide, has potent vasodilator activity in the pulmonary and systemic vascular beds of the intact rat. These data suggest that multiple pathways are involved in the bioactivation of nitrite in the cardiovascular system of the rat and that sodium nitrite may be useful as a treatment for pulmonary hypertension. (Abstract shortened by UMI.)