Long-term effects of nonselective endothelin A and B receptor antagonism in postinfarction rat - Importance of timing

Background-Some controversy exists as to the effects of endothelin (ET) rec eptor antagonism on long-term post-myocardial infarction (MI) evolution, pa rticularly as it relates to the timing of the intervention after MI (< 24 h ours versus 10 days). Methods and Results-Sham rats and rats surviving an acute MI for > 20 hours (n = 301) were assigned to treatment with saline or the nonselective ETA a nd ETB receptor antagonist LU 420627 (LU) started < 24 hours (early) or 10 days (late) after MI and continued for 100 days. Long-term LU treatment led to increased mortality of rats with large MI, regardless of the timing of initiation of therapy. Early initiation of LU reduced survival from 61% to 16% (P <0.001 versus untreated), and later initiation reduced survival to 3 6% (P=0.012 versus untreated and P <0.001 versus early initiation). Early i nitiation of LU led to scar thinning, further left ventricular (LV) dilatat ion, LV dysfunction, and an excessive rise in right ventricular systolic pr essure. Later initiation of LU did not modify scar formation but resulted i n LV dilatation and dysfunction compared with the untreated group. Cardiac fibrosis tended to increase in the LU-treated MI groups. LU in the sham gro up reduced cardiac endothelial constitutive nitric oxide synthase but did n ot modify the changes that occurred with a large MI. Conclusions-The use of the nonselective ETA and ETB receptor antagonist LU results in reduced survival, ventricular dilatation, and dysfunction whethe r started early or late after MI. Early initiation of LU resulted in scar e xpansion and a particularly unfavorable outcome.