Background: Heme oxygenase-1 (HO-1) is induced by hypoxia in vascular smooth muscle cells and leads to increased carbon monoxide (CO) production in vitro. The role of CO in the in vivo regulation of vascular tone is unknown. CO, like NO, activates guanylyl cyclase, increases cGMP production, and may lead to vasodilation. In this study, we examined the temporal expression of HO-1 in the lungs of rats exposed to hypoxia. We hypothesized that treament of rats with NiCl2, a known inducer of HO-1, would ameliorate the effects of hypoxia on the development of pulmonary hypertension. Methods: Right ventricular(RV) catheters were surgically placed in adult male Sprague Dawley rats which were then subjected to the following experimental conditions: normoxia (N)(n=5), hypoxia (10% O2) (H) (n=5), or hypoxia with NiCl2 treatment (HNiCl2) (n=4). Animals in the last group were treated with subcutaneous injections of NiCl2 (250 μmol/kg) every 48 hours. Systolic and mean RV pressures were measured at the end of 1 week and compared by ANOVA. Lung histologic studies were done to assess structural changes consistent with pulmonary hypertension and Northern analysis was performed for steady state HO-1 mRNA levels. Results: A sustained 3-fold elevation of HO-1 mRNA levels was observed only in the lungs of the HNiCl2-treated animals compared to N or H alone. Systolic and mean RV pressures in the HNiCl2 group were significantly lower than in H(p=0.0071 and p=0.008, respectively) but not significantly different from N. The hypoxic animals (H) developed structural remodeling of the pulmonary arterioles consistent with pulmonary hypertension whereas the animals in HNiCl2 did not. The histologic appearance of the lungs in HNiCl2 was comparable to that in the N controls. Conclusion: Treatment with NiCl2 led to increased HO-1 expression in hypoxic rat lungs and prevented the development of pulmonary hypertension.Table

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