Modulation of myocardial relaxation by basal release of endothelin from endocardial endothelium

Abstract

Objective: The aim was to study the potential role of basal endothelin-1 release from endocardial endothelium in isolated ferret papillary muscle preparations. Methods: The following interventions were studied: (1) no treatment (time control): (2) endothelin-1 (5 nM); (3) endothelin-1 (5 nM) in the presence of the specific ET_A receptor antagonist, BQ123 (10 μM); (3) BQ123 (10 μM) in endocardium-intact muscles; and (5) BQ123 (10 μM) in endocardium-denuded muscles (n = 6 in each group). Results: Untreated muscles remained stable throughout the experiment. SQ123 fully inhibited the positive inotropic effect of exogenous endothelin-1. In endocardium-intact preparations (n = 6), exposure to BQ123 induced a progressively earlier onset and time course of isometric twitch relaxation [time to peak tension −12.3(SEM 1.8)%, relaxation half time −13.3(1.1)%; both p < 0.01], but had no effect on peak tension or on rate of tension development. Selective denudation of endocardial endothelium induced similar relaxant effects, but also significantly reduced peak tension. In endocardial endothelium-denuded preparations (n = 6), addition of BQ123 did not result in further contractile changes. Conclusions: Endocardial endothelium in situ on papillary muscle preparations tonically releases endothelin, resulting in a significantly delayed onset of isometric twitch relaxation. There is no evidence for basal endothelin-1 release from microvascular endothelial cells in this superfused preparation. A similar release of endothelin-1 from endocardial endothelium in the intact heart could influence myocardial contractile behaviour independently of changes in coronary perfusion. Endothelin-1 may have a physiological role in modulating myocardial relaxation. Cardiovascular Research 1994;28: 1694-1699