Pulmonary vasodilator responses to sodium nitrite are mediated by an allopurinol-sensitive mechanism in the rat

Abstract

PJ. Pulmonary vasodilator responses to sodium nitrite are mediated by an allopurinol-sensitive mechanism in the rat. Am J Physiol Heart Circ Physiol 296: H524 -H533, 2009. First published December 12, 2008 doi:10.1152/ajpheart.00543.2008.-Recent studies show that pulmonary vasodilator responses to nitrite are enhanced by hypoxia. However, the mechanism by which nitrite is converted to vasoactive nitric oxide (NO) is uncertain. In the present study, intravenous injections of sodium nitrite decreased pulmonary and systemic arterial pressures and increased cardiac output. The decreases in pulmonary arterial pressure were enhanced when tone in the pulmonary vascular bed was increased with U-46619. Under elevated tone conditions, decreases in pulmonary and systemic arterial pressures in response to nitrite were attenuated by allopurinol in a dose that did not alter responses to the NO donors, sodium nitroprusside and diethylamine/NO, suggesting that xanthine oxidoreductase is the major enzyme-reducing nitrite to NO. Ventilation with a 10% O 2 gas mixture increased pulmonary arterial pressure, and the response to hypoxia was enhanced by N G -nitro-L-arginine methyl ester and not altered by allopurinol. This suggests that NO formed by the endothelium and not from the reduction of plasma nitrite modulates the hypoxic pulmonary vasoconstrictor response. Although intravenous injections of sodium nitrite reversed pulmonary hypertensive responses to U-46619, hypoxia, and N G -nitro-L-arginine methyl ester, the pulmonary vasodilator response to nitrite was not altered by ventilation with 10% O2 when baseline pulmonary arterial pressure was increased to similar values in animals breathing room air or the hypoxic gas. These data provide evidence that xanthine oxidoreductase is the major enzyme-reducing nitrite to vasoactive NO, and that this mechanism is not modified by hypoxia. nitric oxide; xanthine oxidoreductase; pulmonary hypertension; nitric oxide synthase ENDOTHELIAL NITRIC OXIDE (NO) formation plays an important role in the regulation of the pulmonary and systemic vascular beds (15, 28). The importance of NO has been demonstrated in experimental animals and in human subjects by the use of NO synthase (NOS) inhibitors (2,15,28). Although NO synthesis is important in the regulation of baseline tone in most vascular beds, the role of NO in the regulation of tone in the pulmonary vascular bed of the rat has been questioned (15). NO once released from the endothelium into the blood reacts rapidly with red cell hemoglobin (14, 21a, 26). Furthermore, NO that escapes hemoglobin scavenging can be oxidized to nitrite (21a). NO formed from nitrite that escapes inactivation relaxes vascular smooth muscle by a cGMP-dependent mechanism (7, 26). It has been reported that plasma nitrite concentrations reflect constitutive NOS activity and correlate with endothelial function (21a). In addition, recent research speculates that nitrite anion represents a storage form of NO that can have important pharmacological actions (13,22). This is...

Mitochondrial aldehyde dehydrogenase mediates vasodilator responses of glyceryl trinitrate and sodium nitrite in the pulmonary vascular bed of the rat

“…The results of the present study show that vasodilator responses to sodium nitrite are inhibited by cyanamide. These data suggest that both XOR and ALDH2 can act to reduce nitrite to vasoactive NO in the rat (7,20,40).…”

“…The mechanism by which nitrite is reduced to NO in the rat is uncertain, but the reduction of inorganic nitrite to NO can be mediated by enzymatic mechanisms and by nonenzymatic disproportionation at low pH (12,13,16,19,22,27,35). Moreover, it has also been reported that vasodilator responses to sodium nitrite can be attenuated by allopurinol, suggesting that XOR can play a role in bioactivation of nitrite (7,20,40). The results of the present study show that vasodilator responses to sodium nitrite are inhibited by cyanamide.…”

“…These data are in agreement with previous studies in the L-NAME-treated rat in which decreases in systemic arterial pressure in response to sodium nitrite are attenuated by cyanamide and provide support for the hypothesis that ALDH2 plays an important role in the bioactivation of nitrite (40). It has been reported that pulmonary and systemic vasodilator responses to sodium nitrite can be attenuated by allopurinol, an inhibitor of XOR (7). The hypothesis that XOR contributes to the bioactivation of GTN by reducing nitrite derived from the activity of ALDH2 on GTN was investigated in experiments with allopurinol.…”

“…The administration of L-NAME produced significant increases in pulmonary and systemic arterial pressures and a decrease in cardiac output (7). In animals treated with L-NAME (25-50 mg/kg iv), pulmonary arterial pressure was significantly increased, and decreases in pulmonary and systemic arterial pressures in response to intravenous injections of GTN and sodium nitrite were attenuated by cyanamide treatment.…”

“…The left jugular and femoral veins were catheterized with PE-50 tubing for intravenous injections and infusions of agents. For pulmonary arterial pressure measurements, a specifically designed 3-Fr single-lumen catheter with a curved tip and with radio-opaque markers was passed from the right jugular vein to the main pulmonary artery under fluoroscopic guidance (Picker-Surveyor Fluoroscope), as previously described (7). Pulmonary and systemic arterial pressures were measured with Namic Perceptor DT transducers (Boston Scientific), digitized by a Biopac MP100 data acquisition system (Biopac Systems), and stored on a Dell personal computer (PC).…”