Role of nitric oxide in heparin-induced attenuation of hypoxic pulmonary vascular remodeling

of nitric oxide in heparin-induced attenuation of hypoxic pulmonary vascular remodeling. J Appl Physiol 92: 2012–2018, 2002. First published February 1, 2002; 10.1152/ japplphysiol.00664.2001.—Heparin and nitric oxide (NO) at-tenuate changes to the pulmonary vasculature caused by prolonged hypoxia. Heparin may increase NO; therefore, we hypothesized that heparin may attenuate hypoxia-induced pulmonary vascular remodeling via a NO-mediated mecha-nism. In vivo, rats were exposed to normoxia (N) or hypoxia (H; 10 % O2) with or without heparin (1,200 U kg1 day1) and/or the NO synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME; 20 mg kg1 day1) for 3 days or 3 wk. Heparin attenuated increases in pulmonary arterial pressure, the percentage of muscular pulmonary vessels, and their medial thickness induced by 3 wk of H. Importantly, although L-NAME alone had no effect, it prevented these effects of heparin on vascular remodeling. In H lungs, hepa-rin increased NOS activity and cGMP levels at 3 days and 3 wk and endothelial NOS protein expression at 3 days but not at 3 wk. In vitro, heparin (10 and 100 U kg1 ml1) in-creased cGMP levels after 10 min and 24 h in N and anoxic (0 % O2) endothelial cell-smooth muscle cell (SMC) coculture. SMC proliferation, assessed by 5-bromo-2-deoxyuridine in-corporation during a 3-h incubation period, was decreased by heparin under N, but not anoxic, conditions. The antiprolif-erative effects of heparin were not altered by L-NAME. In conclusion, the in vivo results suggest that attenuation of hypoxia-induced pulmonary vascular remodeling by heparin is NO mediated. Heparin increases cGMP in vitro; however, the heparin-induced decrease in SMC proliferation in the coculture model appears to be NO independent. pulmonary hypertension; chronic hypoxia; nitric oxide syn-thase; cyclic 3,5-guanosine monophosphate; vascular smooth muscle; endotheliu