Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats.
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.
Hill
N S
NS
Division of Pulmonary, Sleep Disorders, and Critical Care Medicine, Rhode Island Hospital, Brown University School of Medicine, Providence, Rhode Island 02903, USA.
Warburton
R R
RR
Pietras
L
L
Klinger
J R
JR
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000077300:Bosentan; D002302:Cardiac Output / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology / Q000517:prevention & control; D008168:Lung / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000503:physiopathology / Q000517:prevention & control; D009929:Organ Size / Q000187:drug effects / Q000502:physiology; D011042:Poisons / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011042:Poisons; D013449:Sulfonamides; D016686:Monocrotaline; D000077300:Bosentan