Peroxynitrite does not impair pulmonary and systemic vascular responses

Abstract

The effects of peroxynitrite (ONOO-) on vascular responses were investigated in the systemic and hindquarters vascular bed and in the isolated perfused rat lung. Intravenous injections of ONOO- decreased systemic arterial pressure, and injections of ONOO- into the hindquarters decreased perfusion pressure in a dose-related manner. Injections of ONOO- into the lung perfusion circuit increased pulmonary arterial perfusion pressure. Responses to ONOO- were rapid in onset, short in duration, and repeatable without exhibiting tachyphylaxis. Repeated injections of ONOO- did not alter systemic, hindquarters, or pulmonary responses to endothelium-dependent vasodilators or other vasoactive agonists and did not alter the hypoxic pulmonary vasoconstrictor response. Injections of sodium nitrate or nitrite or decomposed ONOO- had little effect on vascular pressures. Pulmonary and hindquarters responses to ONOO- were not altered by a cyclooxygenase inhibitor in a dose that attenuated responses to arachidonic acid. These results demonstrate that ONOO- has significant pulmonary vasoconstrictor, systemic vasodepressor, and vasodilator activity; that short-term repeated exposure does impair vascular responsiveness; and that responses to ONOO- are not dependent on cyclooxygenase product release.

Potential Benefits of Peroxynitrite

“…These data suggest that PN does not impair endothelial function in the hindlimb vascular bed. The results showing that vasodilator responses to acetylcholine are not inhibited are consistent with results in the hindquarters vascular bed or in aortic rings of the rat, in isolated cat coronary arteries, and in isolated rat pulmonary arteries where responses to acetylcholine were enhanced by the highest dose of PN studied [25,105,125,202]. These data are in contrast to studies showing that responses to vasodilator agents, including acetylcholine, are reduced after the development of tachyphylaxis to PN [59,154].…”

“…The hindlimb vasodilator responses to PN were rapid in onset, short in duration, and the vasodilator responses to PN could be repeated without causing tachyphylaxis [210]. The absence of the development of tachyphylaxis to the vasodilator response to PN is in agreement with studies in the systemic and hindlimb vascular bed of the rat, and in isolated coronary arteries from the dog and cat [23,25,202]. Although PN has been reported to produce vascular dysfunction, the results of these studies observed that vascular responses of PN to could be repeated as subsequent injections, in doses up to 4000 nmol, had no significant effect on baseline perfusion pressure or on responses to vasoactive agonists [210].…”

“…In these series of experiments responses to PN were not altered by the presence of meclofenamate, a nonselective cyclooxygenase inhibitor. These studies show that PN has significant pulmonary vasoconstrictor and hindquarters and systemic vasodepressor and vasodilator activities, and that repeated short-term exposure did not impair vascular responsiveness in these vascular beds, and finally that responses to PN are not dependent upon cyclooxygenase product release [202].…”

“…Although PN causes vasodilation in a number of isolated arterial preparations [21,23], the responses in the systemic and perfused hindquarters vascular beds and in the isolated perfused lung of the rat were not documented. We investigated the role of PN on vascular responses in these beds and observed that iv injections of PN produced dose-dependent decreases in hindquarters and systemic arterial pressure, whereas injections of PN into the lung perfusion circuit produced increases in pulmonary arterial pressure [202]. Moreover, responses to PN were rapid in onset, short in duration, and repeatable without exhibiting tachyphylaxis.…”

“…However, responses in other vascular beds of the cat are not well described, that led this laboratory to investigate responses of PN in the hindlimb vascular bed of the cat [202,210]. Injections of PN into the perfusion circuit caused dose-dependent decreases in perfusion pressure.…”