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(Circulation. 1995;92:3372.)
© 1995 American Heart Association, Inc.

Articles

Evidence for Endothelin-1–Mediated Vasoconstriction in Severe Chronic Heart Failure

Endothelin Antagonism in Heart Failure

David J. Webb, MD, FRCP, FRCPE, FFPM

From the University of Edinburgh, Scotland.

Correspondence to David J. Webb, MD, FRCP, FRCPE, FFPM, Clinical Pharmacology Unit and Research Centre, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, Scotland. E-mail d.j.webb@ed.ac.uk.

	Introduction

 
Endothelin-1, generated by vascular endothelium, causes sustained vasoconstriction, mainly through an action on the ET_A receptor subtype; in some tissues, vascular ET_B receptors contribute. As well as affecting tone in resistance and capacitance vessels, endothelin augments the activity of the renin-angiotensin and sympathetic nervous systems, stimulates mitogenesis, and can cause renal vasoconstriction and sodium retention. Since these are features of heart failure, the endothelin system is an attractive target for therapeutic intervention. Plasma endothelin concentrations in heart failure are two to four times normal and correlates with symptomatic and hemodynamic indexes of severity. A crucial question is whether endothelin contributes to the pathophysiology of heart failure or simply acts as a marker of its severity.

Kiowski et al¹ now report evidence that endothelin-1 contributes to vasoconstriction in severe chronic heart failure. Twenty-four patients with New York Heart Association class III chronic heart failure and ejection fractions 30% received either the combined ET_A and ET_B receptor antagonist bosentan (100 mg, then 200 mg, each over a period of 15 minutes and separated by 1 hour) or vehicle, both given intravenously, randomly, and double-blind. Angiotensin-converting enzyme inhibitors were discontinued for four half-lives before each study. Baseline endothelin-1 and big endothelin-1 concentrations were increased and correlated directly with the extent of pulmonary hypertension, with right and left heart filling pressures, and with pulmonary vascular resistance as well as inversely with cardiac output. Compared with placebo, bosentan reduced mean arterial pressures by 8%, pulmonary artery pressures by 14%, and pulmonary artery wedge pressures by . . . [Full Text of this Article]

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