title: 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).
  
  
  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.
authors: Zentrum Innere Medizin, Abteilung Kardiologie und Pneumologie, Georg-August-Universität, Göttingen, Germany.
authors: B
authors: B
authors: Pieske
authors: B
authors: B
authors: Beyermann
authors: V
authors: V
authors: Breu
authors: B M
authors: BM
authors: Löffler
authors: K
authors: K
authors: Schlotthauer
authors: L S
authors: LS
authors: Maier
authors: S
authors: S
authors: Schmidt-Schweda
authors: H
authors: H
authors: Just
authors: G
authors: G
authors: Hasenfuss
mesh_terms: D000331:Aequorin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002303:Cardiac Output, Low / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D002311:Cardiomyopathy, Dilated / Q000150:complications; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008163:Luminescent Measurements; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000378:metabolism*; D012016:Reference Values
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D000331:Aequorin; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium