Functional Effects of Endothelin and Regulation of Endothelin Receptors in Isolated Human Nonfailing and Failing Myocardium

Abstract

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 ET A receptor antagonist BQ-123 shifted the concentration-response curves for ET-1 rightward. The ET B 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 Ca 2+ 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 ET A receptors without change in ET B 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 ET A receptor–mediated increases in myofibrillar Ca 2+ responsiveness. In DCM, functional effects of ET-1 are attenuated, but ET A receptor density and ET-1 peptide concentration are increased, indicating an activated local cardiac ET system and possibly a reduced postreceptor signaling efficiency.