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(Circulation. 1999;99:1802-1809.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Functional Effects of Endothelin and Regulation of Endothelin Receptors in Isolated Human Nonfailing and Failing Myocardium
Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10–13, 1996, and published in abstract form (Circulation. 1996;94[suppl I]:I-406).
From the Zentrum Innere Medizin, Abteilung Kardiologie und Pneumologie, Georg-August-Universität, Göttingen, Germany (B.P., B.B., K.S., L.S.M., G.H.); Preclinical Research, Hoffmann–La Roche, Basel, Switzerland (V.B., B.M.L.); and Medizinische Klinik III, Abteilung Kardiologie und Angiologie, Albert-Ludwigs-Universität, Freiburg, Germany (S.S., H.J.).
Correspondence to Priv-Doz Dr Burkert Pieske, MD, Zentrum Innere Medizin, Abteilung Kardiologie und Pneumologie, Georg-August-Universität, Robert-Koch-Str 40, 37075 Göttingen, Germany.
Background—An activated endothelin (ET) system may be of pathophysiological relevance in human heart failure. We characterized the functional effects of ET-1, ET receptors, and ET-1 peptide concentration in left ventricular myocardium from 10 nonfailing hearts (NF) and 27 hearts in end-stage failure due to idiopathic dilative cardiomyopathy (DCM).
Methods and Results—Inotropic effects were characterized in isolated muscle strips (1 Hz; 37°C). ET-1 0.0001 to 0.3 µmol/L significantly (P<0.05) increased twitch force by maximally 59±10% in NF and by 36±11% in DCM (P<0.05 versus NF). Preincubation with propranolol 1 µmol/L and prazosin 0.1 µmol/L did not affect the response to ET-1, but the mixed ET receptor antagonist bosentan and the ETA receptor antagonist BQ-123 shifted the concentration-response curves for ET-1 rightward. The ETB receptor agonist sarafotoxin S6c 0.001 to 0.3 µmol/L had no functional effects. The inotropic response to ET-1 was not associated with increased intracellular Ca2+ transients, as assessed in aequorin-loaded muscle strips. ET receptor density (Bmax; radioligand binding) was 62.5±12.5 fmol/mg protein in NF and 122.4±24.3 fmol/mg protein in DCM (P<0.05 versus NF). The increase in Bmax in DCM resulted from an increase in ETA receptors without change in ETB receptors. ET-1 peptide concentration (radioimmunoassay) was higher in DCM than in NF (14 447±2232 versus 4541±1340 pg/mg protein, P<0.05).
Conclusions—ET-1 exerts inotropic effects in human myocardium through ETA receptor–mediated increases in myofibrillar Ca2+ responsiveness. In DCM, functional effects of ET-1 are attenuated, but ETA receptor density and ET-1 peptide concentration are increased, indicating an activated local cardiac ET system and possibly a reduced postreceptor signaling efficiency.
Key Words: endothelin • cardiomyopathy • contractility • receptors • Ca2+ handling
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