| OBJECTIVE Increasing evidence indicates that nitrite may be useful for the treatment of pulmonary arterial hypertension, but the mechanism by which nitrite exerts its beneficial effect remains uncertain. The purpose of this study was to investigate the effects and mechanism of action of chronic sodium nitrite treatment in a rat PAH model.METHODS Seventy healthy male Sprague-Dawley rats were randomly assigned to 7 groups (n= 10 each):the sham group (group S), the PAH group (group P), the sodium nitrite 3 mg/kg group (group N1), the sodium nitrite 6 mg/kg group (group N2), the sodium nitrite 3 mg/kg+XOR inhibitor group (group NIX), the sodium nitrite 6 mg/kg+XOR inhibitor group (group N2X) and the XOR inhibitor group(group X). A left-to-right shunt pulmonary artery hypertension model was established via an arterial-venous shunt surgery that created a shunt between the abdominal aorta and the inferior vena cava in all groups except group S. After eleven weeks, sodium nitrite was administered (3 mg·kg-1 and 6 mg·kg-1) once per day for 21 days in groups N1 and NIX and groups N2 and N2X.Allopurinol (30 mg/kg), which is a XOR inhibitor, was administered in group X and in group N1X, group N2X 1 h before sodium nitrite administration.RESULTS①Shunting of the abdominal aorta and inferior vena cava resulted in a significant increase in pulmonary arterial pressures. The intragastric administration of sodium nitrite(6 mg/kg) and XOR inhibitor resulted in a significant reduction of the mPAP, but treatment with a 3 mg/kg dose of sodium nitrite did not significantly reduce the mPAP in PAH models. Compared with animals that received no inhibitors, the use of inhibitors caused no significant changes in the mPAP. MAP had no significant difference in the seven groups.② Rats with high pulmonary blood flow pulmonary artery hypertension had significantly higher RV/LV+IS weights than the sham operation rats. The rats with high pulmonary blood flow pulmonary artery hypertension that were treated with intragastrically administered sodium nitrite (6 mg/kg for 21 days) had significantly lower RV/LV+S weights than untreated rats with high pulmonary blood flow pulmonary artery hypertension. Compared with animals that received no inhibitors, the use of inhibitors caused no significant changes in RV/LV+IS weights.③ Compared with group S, the serum NO level decreased in group P, group N1, group NIX and group N2X (P< 0.05). Compared with group P, the serum NO level increased in group N2 (P< 0.05). When the different dosage groups were compared, the level of serum NO was increased in the group treated with 6 mg/kg of sodium nitrite (P< 0.05). No statistically significant differences in NO content were observed when rat lung homogenates from the four groups were compared (P> 0.05). NO levels in the lung tissue decreased in groups NIX and N2X(P< 0.05)④ The histological analysis of sections from the left lower lung lobe revealed the development of medial hypertrophy in the small pulmonary arteries from animals with high pulmonary blood flow pulmonary artery hypertension. Treatment with 6 mg/kg of intragastrically administered sodium nitrite daily for 21 days resulted in a reduction in the extent of medial hypertrophy in the small pulmonary arteries in comparison to the vessels from untreated animals with high pulmonary blood flow pulmonary artery hypertension.⑤ Western blotting revealed that eNOS//GAPDH and XOR/GAPDH ratios of group P were significantly lower than those of group S (P＜0.05). However, the XOR/GAPDH ratios of the sodium nitrite-treated groups were significantly increased. The XOR/GAPDH ratio was significantly decreased in groups N1X and N2X.Conclusion These data suggest that long term administration of sodium nitrite improves the hemodynamics in rats with high pulmonary blood flow pulmonary artery hypertension and attenuates pulmonary vascular remodeling induced by pulmonary hypertension, but the mechanism of sodium nitrite that underlies this effect requires further study. |
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