ENDOTHELIN-A RECEPTOR BLOCKADE CAUSES ADVERSE LEFT-VENTRICULAR REMODELING BUT IMPROVES PULMONARY-ARTERY PRESSURE AFTER INFARCTION IN THE RAT

Background-Endothelin A (ET,) receptor antagonists have been shown to improve ventricular remodeling and survival in rats when started 10 da ys after infarction. Whether starting them earlier would have a more o r less beneficial effect is uncertain. Methods and Results-Rats surviv ing an acute myocardial infarction (MI) for 24 hours (n=403) were assi gned to saline or the ET, receptor antagonist LU 127043 or its active enantiomer LU 135252 for 4 weeks. Chronic LU treatment had no effect o n survival, with 46% of LU rats and 47% of saline-treated rats with la rge MI surviving to the end of the study. LU treatment led to scar thi nning, further left ventricular (LV) dilatation, an increase in LV end -diastolic pressure, and an increase in wet lung weight (P<0.05). Desp ite this detrimental effect on LV function, LU led to a significant de crease in RV systolic (50+/-2 to 44+/-2 mm Hg, P<0.05 vs saline) and r ight atrial pressures. LU treatment also prevented the increase in pul monary ET-1 found in saline-treated rats with large MT but did not mod ify the increase in cardiac ET-I in hearts with large MI.Conclusions-T he early use of the ETA receptor antagonists LU 127043 or its active e nantiomer LU 135252 after infarction in the rat leads to impaired scar healing and LV dilatation and dysfunction. This is accompanied by a d ecrease in RV systolic and right atrial pressures and a decrease in pu lmonary but not cardiac ET-I levels. It would thus appear that the ear ly use of ETA receptor antagonists after infarction may be detrimental .