P6377Cardiopulmonary effects of nitric oxide supplementation in a model of chronic hypoxia pulmonary hypertension

Abstract

Objective We previously demonstrated that the inhibition of phosphodiesterase type-5, an enzyme that degrades cGMP into inactive 5'-GMP, attenuates pulmonary remodeling and right ventricular (RV) hypertrophy (RVH) during exposure to chronic hypoxia (CH). The nitric oxide (NO) pathway is thought to play a major role in these changes. In this study, we investigate whether L-Arginine (L-ARG), a substrate of endothelial NO synthase (eNOS) and molsidomine (MOL), a NO donor, might alleviate the cardiovascular and pulmonary dysfunction led by CH. Methods Male rats (n=80; 10/group) were maintained in normoxic (21% O2) or hypoxic chambers (10% O2) for 14 days. Hypoxic rats were subdivided in four groups: untreated control, treated with L-ARG (45 mg/kg), eNOS inhibitor N-nitro-L-arginine methyl ester (L-NAME, 45 mg/kg) or MOL (15 mg/kg). Drugs were given daily in the drinking water. After sacrifice, we measured RV systolic pressure (RVSP), RV contractility (dP/dt), RVH, the lung/body weight ratio, the pulmonary vessels medial wall thickness, and the cardiac and pulmonary eNOS phosphorylation. Results Although CH increased RVSP, RV contractility and RVH, these increases were attenuated by L-ARG and MOL. Whereas L-ARG attenuated the RVH increase, MOL and L-NAME were ineffective. No treatment prevented the increase in lung/body weight ratio. Under all conditions, the lung tissue water content was unchanged, indicating no edema development. By contrast, CH rats developed a marked increase in medial wall thickness of small (0–100 mm) pulmonary arteries, while larger arteries were not affected. This increase was attenuated by L-ARG or MOL. Although CH decreased cardiac and pulmonary phosphorylated eNOS, L-ARG and MOL restored the normoxic level. Conclusions NO supplementation during CH attenuates RVSP, RVH and pulmonary remodeling, probably due to increased phosphorylation of eNOS. Despite normalizing RVSP, MOL does not influence RVH development.