(Circulation. 1998;98:2323-2330.)
© 1998 American Heart Association, Inc.
Basic Science Reports |
Endothelin A Receptor Blockade Causes Adverse Left Ventricular Remodeling but Improves Pulmonary Artery Pressure After Infarction in the Rat
From the Department of Medicine, Montreal Heart Institute (Q.T.N., M.W., J.L.R.), the Department of Biochemistry, Royal Victoria Hospital, McGill University (P.C.), the Department of Physiology, University of Montreal, Quebec (A.C.); the Terrance Donnelly Heart Center, St Michael's Hospital, University of Toronto (D.J.S., P.P.), Ontario; and the Department of Pharmacology, University of Sherbrooke (P.S.), Sherbrooke, Quebec, Canada.
Correspondence to Jean L. Rouleau, MD, Department of Medicine, Montreal Heart Institute, 5000 Bélanger St E, Montreal, Quebec H1T 1C8, Canada. E-mail rouleau{at}icm.umontreal.ca.
Background—Endothelin A (ETA) receptor antagonists have been shown to improve ventricular remodeling and survival in rats when started 10 days after infarction. Whether starting them earlier would have a more or less beneficial effect is uncertain.
Methods and Results—Rats surviving an acute myocardial infarction (MI) for 24 hours (n=403) were assigned to saline or the ETA receptor antagonist LU 127043 or its active enantiomer LU 135252 for 4 weeks. Chronic LU treatment had no effect on survival, with 46% of LU rats and 47% of saline-treated rats with large MI surviving to the end of the study. LU treatment led to scar thinning, further left ventricular (LV) dilatation, an increase in LV end-diastolic pressure, and an increase in wet lung weight (P<0.05). Despite this detrimental effect on LV function, LU led to a significant decrease in RV systolic (50±2 to 44±2 mm Hg, P<0.05 vs saline) and right atrial pressures. LU treatment also prevented the increase in pulmonary ET-1 found in saline-treated rats with large MI but did not modify the increase in cardiac ET-1 in hearts with large MI.
Conclusions—The early use of the ETA receptor antagonists LU 127043 or its active enantiomer LU 135252 after infarction in the rat leads to impaired scar healing and LV dilatation and dysfunction. This is accompanied by a decrease in RV systolic and right atrial pressures and a decrease in pulmonary but not cardiac ET-1 levels. It would thus appear that the early use of ETA receptor antagonists after infarction may be detrimental.
Key Words: infarction • remodeling • hemodynamics • endothelin
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