INHIBITION OF HYPOXIC PULMONARY-HYPERTENSION BY HEPARINS OF DIFFERING IN-VITRO ANTIPROLIFERATIVE POTENCY

Heparin inhibits smooth-muscle cell (SMC) growth in vitro and inhibits the development of hypoxic pulmonary hypertension and Vascular remodeling in vivo. We wondered whether preparations of heparin with different antiproliferative potency in vitro would differ in their ability to inhibit the development of hypoxic pulmonary hypertension in vivo. Two such heparins, a weakly antiproliferative lot of Elkins-Sinn (E-S) (% inhibition of SMC growth at 10 mu g/ml = 13 +/- 9% [mean +/- SEM, n = 24]) and a more active lot from Upjohn (UJ) (% inhibition = 71 +/- 12% [n = 12, p < 0.05 versus E-S]I), were infused subcutaneously (300 U.S.P. units/day; E-S 300 versus UJ 300) via an osmotic pump into guinea pigs exposed to hypoxia (10% O-2) for 10 d, after which pulmonary artery pressure (PAP; mm Hg) and cardiac index (Cl; ml/min/kg) were measured in room air. Hypoxic controls (HC) received saline. PAP increased from 11 +/- 1 mm Hg in normoxic controls (NC) (n = 5) to 24 +/- 1 mm Hg in HC (n = 8, p < 0.05). The PAP was lower in the E-S 300 (21 +/- 1; n = 7, p < 0.05 versus HC and NC) and even lower in the UJ 300-treated group (18 +/- 0.5; n - 7, p < 0.05 versus HC and NC). Total pulmonary vascular resistance (TPR; mm Hg/ml/min/kg) increased significantly from 0.038 a 0.002 in NC to 0.076 +/- 0.003 (p < 0.05) in HC. There was no difference in TPR between the HC and the E-S 300-treated group. However, UJ 300 significantly reduced the TPR to 0.057 +/- 0.003 (p < 0.05 versus HC and NC). The medial thickness (as a percent of vessel diameter) of arteries landmarked to alveolar ducts (AD) and to terminal bronchioles (TB) increased significantly with hypoxia. Medial thickening was not affected by E-S 300, but was significantly reduced by UJ 300. We conclude that heparins not only differ in their antiproliferative activity in vitro, but also in their ability to inhibit the development of hypoxic pulmonary hypertension and remodeling in vivo. Heparin may inhibit chronic hypoxic vascular remodeling by inhibiting SMC growth in vivo, and in vitro assessment of antiproliferative potency appears to predict the in vivo response.