Effect of heparin and warfarin on chronic hypoxic pulmonary hypertension and vascular remodeling in the guinea pig

Chronic hypoxia produces pulmonary hypertension and pulmonary vascular remodeling. Heparin partially prevents the rise in right ventricular pressure and vascular remodeling in chronically hypoxic mice. To determine if this is due to the anticoagulant property of heparin or another property, we compared the effect of oral warfarin given at an anticoagulating dose (0.5 mg/kg/day) to heparin given by continuous infusion at dose that does not prolong the partial thromboplastin time (PTT) (20 units/kg/h) on hypoxic pulmonary hypertension and vascular remodeling in the guinea pig. Normoxic control animals either untreated or treated with heparin or Coumadin were all alike in blood gases, pulmonary vascular resistance, right heart weights, and pulmonary histology. Hypoxia (10% O₂ for 10 days) induced similar and significant increases in mean pulmonary artery (PA) pressure in both the hypoxic control and warfarin groups (19 ± 1 mm Hg (mean ± SEM) in both groups versus 11 ± 0.1 mm Hg in the normoxic control group; p < 0.05). Total pulmonary vascular resistance (TPR) was also increased from 0.041 ± 0.002 in the normoxic control group to 0.087 ± 0.007 and 0.071 ± 0.003 mm Hg/ml/min/kg in the hypoxic control and warfarin groups, respectively (p < 0.05). Whereas anticoagulation with warfarin did not protect the guinea pig from developing pulmonary hypertension, heparin markedly reduced PA and TPR (15 ± 1 mm Hg and 0.052 ± 0.002 mm Hg/ml/min/kg, respectively; p < 0.05 versus hypoxic control or warfarin). There was also less medial thickening in distal pulmonary arteries in the heparin group (7.4 ± 0.4% in the heparin group versus 9.1 ± 0.5% and 9.0 ± 0.6% in the hypoxic control and warfarin groups, respectively; p < 0.05). We conclude that the beneficial effect of heparin on chronic hypoxic pulmonary hypertension and vascular remodeling may not be related to anticoagulation, as the PTT was not elevated in the heparin group, whereas both PTT and the prothrombin time were elevated in the warfarin group.