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 micrograms/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]), 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% O2) for 10 d, after which pulmonary artery pressure (PAP; mm Hg) and cardiac index (CI; 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 +/- 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Thompson
B T
BT
Pulmonary/Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, Boston 02114.
Spence
C R
CR
Janssens
S P
SP
Joseph
P M
PM
Hales
C A
CA
D000704:Analysis of Variance; D000818:Animals; D002417:Cattle; D002455:Cell Division; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004848:Epithelium / Q000187:drug effects / Q000254:growth & development; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology / Q000600:supply & distribution / Q000627:therapeutic use*; D006965:Hyperplasia; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D006984:Hypertrophy; D000860:Hypoxia / Q000150:complications*; D066298:In Vitro Techniques; D007263:Infusions, Parenteral; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000473:pathology*; D011651:Pulmonary Artery; D011652:Pulmonary Circulation / Q000187:drug effects
D006493:Heparin