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CLINICAL STUDIES

Endothelin_B receptors are functionally important in mediating vasoconstriction in the systemic circulation in patients with left ventricular systolic dysfunction

Peter J. Cowburn, MBBS, MRCP^* , John G. F. Cleland, MD, FRCP, FESC, FACC, John D. McArthur, MB, ChB, FRCP, Margaret R. MacLean, PhD^* , John J. V. McMurray, BSc, MD, FRCP, FESC^* , Henry J. Dargie, MB, ChB, FRCP, FESC^* and James J. Morton, PhD^*

^* Medical Research Council Clinical Research Initiative in Heart Failure, University of Glasgow, Glasgow, Scotland, United Kingdom
Department of Cardiology, Western Infirmary, Glasgow, Scotland, United Kingdom
The Academic Unit, Department of Cardiology, Kingston-upon-Hull, United Kingdom

Manuscript received February 12, 1998; revised manuscript received August 25, 1998, accepted December 4, 1998.

Reprint requests and correspondence: Dr. John G. F. Cleland, Castle Hill Hospital, Castle Road, Cottingham Hull, HU16 5JQ, United Kingdom
J.Cleland{at}bio.gla.ac.uk

OBJECTIVES

This study was designed to assess the functional importance of endothelin (ET)_B receptors in patients with left ventricular systolic dysfunction (LVSD) by comparing the hemodynamic effects of ET-1, a nonselective ET_A and ET_B agonist, with ET-3, a selective ET_B receptor agonist.

BACKGROUND

Knowledge of the functional importance of ET_B receptors in mediating vasoconstriction in chronic heart failure will help determine whether antagonists at both ET_A and ET_B receptors are required to fully prevent vasoconstriction to endogenously produced ET-1.

METHODS

We infused ET-1 (5 and 15 pmol/min) and ET-3 (5 and 15 pmol/min) into two separate groups of eight patients with LVSD with similar baseline hemodynamic indices. Hemodynamics were measured using a pulmonary thermodilution catheter and an arterial line.

RESULTS

Endothelin-1 infusion led to systemic vasoconstriction, with a rise in mean arterial pressure (mean ± SEM 100 ± 3 to 105 ± 3 mm Hg, p < 0.02) and systemic vascular resistance (1,727 ± 142 to 2,055 ± 164 dyn/s/cm^–5, p < 0.001) and a fall in cardiac index (2.44 ± 0.21 to 2.22 ± 0.20 liters/min/m², p < 0.01). Endothelin-3 infusion also led to systemic vasoconstriction, with a rise in mean arterial pressure (99 ± 6 to 105 ± 6 mm Hg, p < 0.01) and systemic vascular resistance (1,639 ± 210 to 1,918 ± 245 dyn/s/cm^–5, p < 0.01) and a fall in cardiac index (2.66 ± 0.28 to 2.42 ± 0.24 liters/min/m², p < 0.05). Pulmonary hemodynamic measurements did not change significantly in either group.

CONCLUSIONS

Both ET-1 and ET-3 infusions led to systemic vasoconstriction; the hemodynamic changes observed were of a similar magnitude at the same molar concentration. This suggests that ET_B receptors are functionally important in mediating vasoconstriction, at least in the systemic circulation, in patients with LVSD.

Abbreviations and Acronyms   CHF = chronic heart failure   CI = cardiac index   CO = cardiac output   DCM = dilated cardiomyopathy   ET = endothelin   LVSD = left ventricular systolic dysfunction   MPAP = mean pulmonary artery pressure   PCWP = pulmonary capillary wedge pressure   PVR = pulmonary vascular resistance   RAP = right atrial pressure   SNP = sodium nitroprusside   SVR = systemic vascular resistance

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