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Cardiovascular Research 1998 39(3):571-579; doi:10.1016/S0008-6363(98)00169-2
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

Beneficial effects of long-term selective endothelin type A receptor blockade in canine experimental heart failure

Gordon W Moea,*, Ana Albernaza, George O Naika, Michael Kirchengastb and Duncan J Stewarta

aTerrence Donnelly Heart Centre, St Michael's Hospital, University of Toronto, Toronto, Ontario M5B1W8, Canada
bKnoll AG, Ludwigshafen, Germany

* Corresponding author. Tel.: +1-416-8645319; Fax: +1-416-8645941; E-mail: moeg@smh.toronto.on.ca

Objectives: We examined the effects of chronic type A endothelin receptor (ETA) blockade in a dog model of pacing-induced cardiomyopathy. Methods: Eight dogs received an ETA antagonist, LU 135252 (50 mg/kg orally daily) and nine dogs received a matching placebo starting at day three of pacing and continued for the remainder of the three weeks of pacing. Results: In the placebo group, the mean pulmonary artery pressure and left ventricular end diastolic pressure increased from 16±3 and 8±2 mmHg, respectively, at baseline to 40±11 and 34±7 mmHg, respectively, at two weeks (both p<0.001 versus baseline). Cardiac output declined from 3.5±0.7 to 1.9±0.6 l/min (p<0.001). In the treatment group, LU 135252 attenuated the increase in mean pulmonary artery and left ventricular end diastolic pressure (16±3 and 9±1 mmHg at baseline to 29±3 and 27±3 mmHg, respectively, at two weeks (p<0.001), and the decline in cardiac output (3.2±0.3 to 2.6±0.8 l/min, p<0.01; p<0.05 versus placebo for the three parameters). Systemic and pulmonary vascular resistance increased only in the placebo group. Left ventricular end-diastolic volume increased to a similar degree. However, LU 135252 attenuated the increase in plasma norepinephrine level (placebo, 1.2±0.5 to 3.7±1.9 pmol/l; treatment, 0.8±0.3 to 2.4±0.6 pmol/l; both p<0.001 versus baseline; p<0.05 versus placebo). Conclusion: Our results suggest that endothelin-1 plays a role in the hemodynamic perturbations in canine pacing-induced cardiomyopathy. The favourable hemodynamic effects without concomitant aggravation of neurohormonal activation suggests that ETA receptor blockade may be beneficial in the treatment of heart failure.

KEYWORDS Endothelin; Heart failure; Hemodynamics; Remodeling; Natriuretic peptide


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