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(Circulation. 2000;102:491.)
© 2000 American Heart Association, Inc.

Brief Rapid Communication

Selective Endothelin-A Versus Combined Endothelin-A/Endothelin-B Receptor Blockade in Rat Chronic Heart Failure

Paul Mulder, PhD; Houssaine Boujedaini, BS; Vincent Richard, PhD; Genevieve Derumeaux, MD, PhD; Jean Paul Henry; Sylvanie Renet; Jerry Wessale, PhD; Terry Opgenorth, PhD; Christian Thuillez, MD, PhD

From INSERM E9920, (IFRMP n°23) Rouen University Medical School, Rouen, France (P.M., H.B., V.R., G.D., J.P.H., S.R., C.T.) and Abbott Laboratories, Abbott Park, Ill (J.W., T.O.).

Correspondence to Prof C. Thuillez, INSERM E9920, Faculté de Médecine et Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, France. E-mail Christian.Thuillez{at}chu-rouen.fr

Background—The relative efficacy of endothelin-A (ET_A) receptor blockade versus combined ET_A-ET_B receptor blockade in chronic heart failure (CHF) is still largely unknown.

Methods and Results—We compared, in a rat model of CHF (coronary ligation), the hemodynamic and structural effects of 1 month of treatment with the ET_A antagonist ABT-627 (5 mg · kg^-1 · d^-1), the ET_B antagonist A-192621 (30 mg · kg^-1 · d^-1) or a combination of the 2 drugs. Doses were chosen for their capacity to block the pressor response to ET-1 (for ET_A blockade) or the depressor responses to sarafotoxin S6c or ET-1 (for ET_B blockade). ET_A and combined ET_A-ET_B blockade reduced systolic blood pressure to the same extent, whereas ET_B blockade had no effect. In contrast, only combined ET_A-ET_B blockade significantly reduced heart rate. Both ET_A and combined ET_A-ET_B blockade, but not ET_B blockade alone, increased left ventricular (LV) fractional shortening and wall thickening and reduced LV end-diastolic pressure, as well as LV end-diastolic and end-systolic volumes. However, all treatments (including ET_B blockade) decreased LV collagen accumulation.

Conclusions—The chronic blockade of both ET_A and ET_B receptors improved systemic hemodynamics, as well as LV function and remodeling, to the same extent as ET_A receptor blockade alone. However, only combined ET_A-ET_B receptor blockade decreased heart rate. Whether this differential effect on heart rate affects the long-term outcome after treatment with ET_A or mixed ET_A-ET_B antagonists in CHF remains to be determined.

Key Words: endothelin • heart failure • heart rate • remodeling

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