Cardioprotective and vasomotor effects of HO activity during acute and chronic hypoxia.

Prolonged hypoxia leads to the development of pulmonary hypertension. Recent reports have suggested enhancement of heme oxygenase (HO), the major source of intracellular carbon monoxide (CO), prevents hypoxia-induced pulmonary hypertension and vascular remodeling in rats. Therefore, we hypothesized that inhibition of HO activity by tin protoporphyrin (SnPP) would exacerbate the development of pulmonary hypertension. Rats were injected weekly with either saline or SnPP (50 micromol/kg) and exposed to hypobaric hypoxia or room air for 5 wk. Pulmonary and carotid arteries were catheterized, and animals were allowed to recover for 48 h. Pulmonary and systemic pressures, along with cardiac output, were recorded during room air and acute 10% O2 breathing in conscious rats. No difference was detected in pulmonary artery pressure between saline- and SnPP-treated animals in either normoxic or hypoxic groups. However, blockade of HO activity altered both systemic and pulmonary vasoreactivity to acute hypoxic challenge. Despite no change in baseline pulmonary artery pressure, all rats treated with SnPP had decreased ratio of right ventricular (RV) weight to left ventricular (LV) plus septal (S) weight (RV/LV + S) compared with saline-treated animals. Echocardiograms suggested dilatation of the RV and decreased RV function in hypoxic SnPP-treated rats. Together these data suggest that inhibition of HO activity and CO production does not exacerbate pulmonary hypertension, but rather that HO and CO may be involved in mediating pulmonary and systemic vasoreactivity to acute hypoxia and hypoxia-induced RV function.