Role of nitric oxide in heparin-induced attenuation of hypoxic pulmonary vascular remodeling.
Heparin and nitric oxide (NO) attenuate 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 mechanism. In vivo, rats were exposed to normoxia (N) or hypoxia (H; 10% O(2)) with or without heparin (1,200 U x kg-1 x day-1) and/or the NO synthase (NOS) inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME; 20 mg x kg-1 x day-1) 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, heparin 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 x kg-1 x ml-1) increased 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 incorporation during a 3-h incubation period, was decreased by heparin under N, but not anoxic, conditions. The antiproliferative 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.
Horstman
Damian J
DJ
Department of Biomedical Engineering, University of Virginia Health System, Charlottesville 22908, USA.
Fischer
Lars G
LG
Kouretas
Peter C
PC
Hannan
Robert L
RL
Rich
George F
GF
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology*; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D009929:Organ Size / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013995:Time
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D006493:Heparin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester