Ns. Hill et al., NONSPECIFIC ENDOTHELIN-RECEPTOR ANTAGONIST BLUNTS MONOCROTALINE-INDUCED PULMONARY-HYPERTENSION IN RATS, Journal of applied physiology, 83(4), 1997, pp. 1209-1215
Endothelin-l (ET-I), a potent vasoactive and mitogenic peptide, has be
en implicated in the pathogenesis of several forms of pulmonary hypert
ension. We hypothesized that nonspecific blockade of ET receptors woul
d blunt the development of monocrotaline (MCT)-induced pulmonary hyper
tension in rats. A single dose of the nonspecific ET blocker bosentan
(100 mg/kg) given to intact rats by gavage completely blocked the pulm
onary vasoconstrictor actions of Big ET-1 and partially blunted hypoxi
c pulmonary vasoconstriction. After 3 wk, MCT-injected (105 mg/kg sc)
rats gavaged once daily with bosentan (200 mg/kg) had lower right vent
ricular (RV) systolic pressure (RVSP), RV-to-body weight (RV/BW) and R
V-to-left ventricular (LV) plus septal (S) weight [RV/(LV+S)] ratios a
nd less percent medial thickness of small pulmonary arteries than cont
rol MCT-injected rats. Lower dose bosentan (100 mg/kg) had no effect o
n these parameters after MCT or saline injection. Bosentan raised plas
ma ET-1 levels but had no effect on lung ET-1 levels. Bosentan (200 mg
/kg) also had no effect on wet-to-dry lung weight ratios 6 days after
MCT injection. When given during the last 10 days, but not the first 1
1 days of a 3-wk period after MCT injection, bosentan reduced RV/(LV+S
) compared with MCT-injected controls. We conclude that ET-1 contribut
es to the pathogenesis of MCT-induced pulmonary hypertension and acts
mainly during the later inflammatory rather than the acute injury phas
e after injection.