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Division of Pulmonary, Sleep Disorders, and Critical Care Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island 02903
Received 29 December 1996; accepted in final form 4 June 1997.
Hill, Nicholas S., Rod R. Warburton, Linda Pietras, and
James R. Klinger. Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats.
J. Appl. Physiol. 83(4):
1209-1215, 1997.
Endothelin-1 (ET-1), a potent vasoactive and
mitogenic peptide, has been implicated in the pathogenesis of
several forms of pulmonary hypertension. We hypothesized that
nonspecific blockade of ET receptors would blunt the development of
monocrotaline (MCT)-induced pulmonary hypertension in rats. A
single dose of the nonspecific ET blocker bosentan (100 mg/kg) given to
intact rats by gavage completely blocked the pulmonary vasoconstrictor
actions of Big ET-1 and partially blunted hypoxic pulmonary
vasoconstriction. After 3 wk, MCT-injected (105 mg/kg sc) rats gavaged
once daily with bosentan (200 mg/kg) had lower right ventricular (RV)
systolic pressure (RVSP), RV-to-body weight (RV/BW) and
RV-to-left ventricular (LV) plus septal (S) weight [RV/(LV+S)] ratios
and less percent medial thickness of small pulmonary arteries than
control MCT-injected rats. Lower dose bosentan (100 mg/kg) had no
effect on these parameters after MCT or saline injection. Bosentan
raised plasma 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 11 days of a 3-wk period after MCT injection,
bosentan reduced RV/(LV+S) compared with MCT-injected controls. We
conclude that ET-1 contributes to the pathogenesis of MCT-induced
pulmonary hypertension and acts mainly during the later inflammatory
rather than the acute injury phase after injection.
natriuretic peptides
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