Functional effects of endothelin and regulation of endothelin receptors in isolated human nonfailing and failing myocardium

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-I 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 degrees C). ET-I 0.0001 to 0.3 mu mol/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 mu mol/L and prazosin 0.1 mu mol/L did not affect the response to ET-I, but the mixed ET receptor antagonist bosentan and the ETA receptor antagonist BQ-123 shifted the concentration-response curves for ET-I rightward. The ETB receptor agonist sarafotoxin S6c 0.001 to 0.3 mu mol/L had no functional effects. The inotropic response to ET-I was not associated with increased intracellular Ca2+ transients, as assessed in aequorin-loaded muscle strips. ET receptor density (B-max; 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 B-max 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.