Bt. Thompson et al., INHIBITION OF HYPOXIC PULMONARY-HYPERTENSION BY HEPARINS OF DIFFERINGIN-VITRO ANTIPROLIFERATIVE POTENCY, American journal of respiratory and critical care medicine, 149(6), 1994, pp. 1512-1517
Citations number
22
Categorie Soggetti
Emergency Medicine & Critical Care","Respiratory System
Heparin inhibits smooth-muscle cell (SMC) growth in vitro and inhibits
the development of hypoxic pulmonary hypertension and Vascular remode
ling in vivo. We wondered whether preparations of heparin with differe
nt antiproliferative potency in vitro would differ in their ability to
inhibit the development of hypoxic pulmonary hypertension in vivo. Tw
o 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 +/- 1
2% [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 guine
a pigs exposed to hypoxia (10% O-2) for 10 d, after which pulmonary ar
tery pressure (PAP; mm Hg) and cardiac index (Cl; ml/min/kg) were meas
ured 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-treat
ed group (18 +/- 0.5; n - 7, p < 0.05 versus HC and NC). Total pulmona
ry 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 wa
s no difference in TPR between the HC and the E-S 300-treated group. H
owever, 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 di
ameter) of arteries landmarked to alveolar ducts (AD) and to terminal
bronchioles (TB) increased significantly with hypoxia. Medial thickeni
ng was not affected by E-S 300, but was significantly reduced by UJ 30
0. We conclude that heparins not only differ in their antiproliferativ
e activity in vitro, but also in their ability to inhibit the developm
ent of hypoxic pulmonary hypertension and remodeling in vivo. Heparin
may inhibit chronic hypoxic vascular remodeling by inhibiting SMC grow
th in vivo, and in vitro assessment of antiproliferative potency appea
rs to predict the in vivo response.