Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats

• Published in: Journal of applied physiology (1985) 1997-10, Vol.83 (4), p.1209-1215
• Main Authors: Hill, Nicholas S, Warburton, Rod R, Pietras, Linda, Klinger, James R
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive agents; Antihypertensive Agents - pharmacology; Antihypertensive Agents - therapeutic use; Biological and medical sciences; Cardiac Output - drug effects; Cardiovascular system; Endothelin Receptor Antagonists; Endothelin-1 - blood; Hemodynamics - drug effects; Hemodynamics - physiology; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - prevention & control; Hypertrophy, Right Ventricular - physiopathology; Hypertrophy, Right Ventricular - prevention & control; Lung - pathology; Male; Medical sciences; Monocrotaline - antagonists & inhibitors; Monocrotaline - pharmacology; Neovascularization, Pathologic - physiopathology; Neovascularization, Pathologic - prevention & control; Organ Size - drug effects; Organ Size - physiology; Pharmacology. Drug treatments; Pneumology; Poisons - pharmacology; Pulmonary Circulation - drug effects; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Rats; Rats, Sprague-Dawley; Sulfonamides - pharmacology; Sulfonamides - therapeutic use
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/jappl.1997.83.4.1209

Nicholas S. Hill, Rod R. Warburton, Linda Pietras, and James R. Klinger 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 0161-7567/97 $5.00 Copyright © 1997 the American Physiological Society