Functional Effects of Endothelin and Regulation of Endothelin Receptors in Isolated Human Nonfailing and Failing Myocardium
2012 | journal article
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Functional Effects of Endothelin and Regulation of Endothelin Receptors in Isolated Human Nonfailing and Failing Myocardium
Pieske, B. ; Beyermann, B.; Breu, V.; Löffler, B. M.; Schlotthauer, K.; Maier, L. S. & Schmidt-Schweda, S. et al. (2012)
Circulation, 99(14) pp. 1802-1809. DOI: https://doi.org/10.1161/01.cir.99.14.1802
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- Authors
- Pieske, Burkert ; Beyermann, Beate; Breu, Volker; Löffler, Bernd M.; Schlotthauer, Klaus; Maier, Lars S. ; Schmidt-Schweda, Stephan; Just, Hanjörg ; Hasenfuss, Gerd
- Abstract
- ackground—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.
- Issue Date
- 2012
- Journal
- Circulation
- ISSN
- 0009-7322
- Language
- English