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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
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.
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Introduction |
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 Top Introduction References |
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Endothelin-1, generated by vascular endothelium, causes sustained vasoconstriction, mainly through an action on the ETA receptor subtype; in some tissues, vascular ETB 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 ETA and ETB 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 9%;
cardiac index was increased by 14%, and systemic and pulmonary
vascular resistances were reduced by 17% and 33%, respectively.
Interestingly, heart rate did not change, and plasma concentrations of
angiotensin II and norepinephrine were
unaltered.
That endothelin-1 contributes to basal vascular tone and blood pressure was already known, but Kiowski's group provided the first evidence that this mechanism operates in patients with heart failure. Since there was no control group without heart failure, their study does not tell us the extent to which bosentan acted against pathophysiologically raised tone, nor do we know yet whether the benefits add to those of angiotensin-converting enzyme inhibitors or are sustained. Finally, we did not learn from this study whether the increased vasoconstrictor tone is mediated primarily by ETA or ETB receptors.
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References |
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TopIntroductionReferences |
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1. Kiowski W, Sutch G, Hunziker P, Kim J, Oechslin E, Schmitt R, Jones R, Bertel O. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet. 1995;346:732-736.[Medline] [Order article via Infotrieve]
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