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(Circulation. 2001;104:2075.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Long-Term Effects of Nonselective Endothelin A and B Receptor Antagonism in Postinfarction Rat

Importance of Timing

Quang Trinh Nguyen, MSc; Peter Cernacek, MD PhD; Martin G. Sirois, PhD; Angelino Calderone, PhD; Nathalie Lapointe, MSc; Duncan J. Stewart, MD; Jean L. Rouleau, MD

From the Department of Medicine, Montreal Heart Institute, Montreal, Quebec (Q.T.N., P.C., M.G.S., A.C.), and the Division of Cardiology (N.L., J.L.R.) and the Terrance Donnelly Heart Center, St Michael’s Hospital (D.J.S.), University of Toronto, Toronto, Ontario, Canada.

Correspondence to Dr Jean L. Rouleau, Division of Cardiology, Toronto General Hospital, Eaton North 13-212, 200 Elizabeth St, Toronto, ON, Canada, M5G 2C4. E-mail jean.rouleau{at}uhn.on.ca

Background— Some controversy exists as to the effects of endothelin (ET) receptor antagonism on long-term post–myocardial infarction (MI) evolution, particularly as it relates to the timing of the intervention after MI (<24 hours 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 ET_A and ET_B 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 36% (P=0.012 versus untreated and P<0.001 versus early initiation). Early initiation of LU led to scar thinning, further left ventricular (LV) dilatation, LV dysfunction, and an excessive rise in right ventricular systolic pressure. Later initiation of LU did not modify scar formation but resulted in LV dilatation and dysfunction compared with the untreated group. Cardiac fibrosis tended to increase in the LU-treated MI groups. LU in the sham group reduced cardiac endothelial constitutive nitric oxide synthase but did not modify the changes that occurred with a large MI.

Conclusions— The use of the nonselective ET_A and ET_B receptor antagonist LU results in reduced survival, ventricular dilatation, and dysfunction whether started early or late after MI. Early initiation of LU resulted in scar expansion and a particularly unfavorable outcome.

Key Words: myocardial infarction • survival • endothelium-derived factors • remodeling

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