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Selected Publication:
Pieske, B; Beyermann, B; Breu, V; Löffler, BM; Schlotthauer, K; Maier, LS; Schmidt-Schweda, S; Just, H; Hasenfuss, G.
Functional effects of endothelin and regulation of endothelin receptors in isolated human nonfailing and failing myocardium.
Circulation. 1999; 99(14):1802-1809
Doi: 10.1161/01.CIR.99.14.1802
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- Leading authors Med Uni Graz
- Pieske Burkert Mathias
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- 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 degrees C). ET-1 0.0001 to 0.3 micromol/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 micromol/L and prazosin 0.1 micromol/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 micromol/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.
- Find related publications in this database (using NLM MeSH Indexing)
- Aequorin - pharmacology
- Calcium - metabolism
- Cardiac Output, Low - etiology
- Cardiomyopathy, Dilated - complications
- Endothelin-1 - metabolism
- Humans - metabolism
- Luminescent Measurements - metabolism
- Myocardial Contraction - drug effects
- Myocardium - metabolism
- Peptides, Cyclic - pharmacology
- Receptors, Endothelin - antagonists and inhibitors
- Reference Values - antagonists and inhibitors
- Find related publications in this database (Keywords)
- endothelin
- cardiomyopathy
- contractility
- receptors
- Ca2+ handling