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Cardiovascular Research 1997 33(1):131-138; doi:10.1016/S0008-6363(96)00174-5
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

Regulation of left ventricular relaxation in the isolated guinea-pig heart by endogenous endothelin

Bernard D Prendergasta, Peter B Anningb, Malcolm J Lewisb and Ajay M Shaha,*

aCardiovascular Sciences Research Group, Department of Cardiology, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK
bCardiovascular Sciences Research Group, Department of Pharmacology, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK

Objective: To examine the effects of endogenous endothelin-1 on cardiac contraction in the isolated heart using endothelin receptor antagonists. Methods: Isolated ejecting guinea-pig hearts were perfused with Krebs buffer (1 µM indomethacin) at 37°C, constant loading and heart rate, and high-fidelity left ventricular pressure was monitored by an apical 2F Millar catheter. The effects of the following interventions on left ventricular performance and coronary flow were determined: (a) no treatment (i.e., time controls) (n = 8); (b) the specific ETA receptor antagonist, BQ123 (1 µM, n = 8); (c) the specific ETB receptor antagonist, IRL1038 (0.1 µM, n = 4; 1 µM, n = 6); (d) exogenous endothelin-1 (0.01 nM, n = 6; 0.1 nM, n = 6); (e) the specific ETB receptor agonist, BQ3020 (5 nM, n = 8). Results: All parameters were stable in control (untreated) hearts. BQ123 induced progressive acceleration of early left ventricular pressure decline and a fall in left ventricular end-diastolic pressure with no effect on peak left ventricular pressure, dP/dtmax, stroke volume or coronary flow. IRL1038 had no effect on any of these parameters. In contrast, exogenous endothelin-1 exerted potent vasoconstrictor effects associated with a fall in peak left ventricular pressure, dP/dtmax and stroke volume. Similar changes were observed with BQ3020. Concentrations of endothelin-1 < 0.1 nM, which had no vasoconstrictor effect, produced no change in LV function. Conclusions: These data indicate that basal intracardiac release of endothelin-1 significantly delays LV relaxation in the isolated guinea-pig heart, but has no effect on coronary flow. The contrasting effects of endogenous endothelin-1 (elicited by BQ123) and exogenous endothelin-1 are likely to reflect differences in their site of action and in their effective concentrations at these sites.

KEYWORDS Endothelin-1; Endothelium; Contractile function; Relaxation; Guinea pig; heart

* Corresponding author. Tel.+44 1222 742338; Fax +44 1222 761442; E-mail: shaham2@cf.ac.uk


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