title: Improved myocardial protection in the failing heart by selective endothelin-A receptor blockade.
abstract: OBJECTIVE
  Ischemia/reperfusion injury caused by cardioplegic arrest is still a major challenge in patients with reduced left ventricular function. We investigated the effect of chronic versus acute administration of the selective endothelin-A receptor antagonist (ERA) TBC-3214Na during ischemia/reperfusion in failing hearts.
  
  
  METHODS
  Male Sprague-Dawley rats underwent coronary ligation. Three days after myocardial infarction (MI), 19 randomly assigned animals (ERA chronic) were administered TBC-3214Na continuously with their drinking water, 29 MI rats received placebo, and 3 rats died during the observation period. Six weeks after infarction, hearts were evaluated in a blood-perfused working heart model during 60 minutes of ischemia and 30 minutes of reperfusion. In 14 MI rats, TBC-3214Na (ERA acute) was added to the cardioplegic solution during ischemia. Thirteen MI rats served as control.
  
  
  RESULTS
  At a similar infarct size, postischemic recovery of cardiac output (ERA chronic: 91% +/- 10%, ERA acute: 86% +/- 11% vs control: 52% +/- 15%; P < .05) and external heart work (ERA chronic: 90% +/- 10%, ERA acute: 85% +/- 13% vs control: 51% +/- 17%; P < .05) was significantly enhanced in both TBC-3214Na-treated groups whereas recovery of coronary flow was only improved in ERA acute rats (ERA acute: 121% +/- 23% vs ERA chronic: 75% +/- 13%; control: 64% +/- 15%; P < .05). Blood gas measurements showed enhanced myocardial oxygen delivery and consumption with acute TBC-3214Na therapy. Additionally, high-energy phosphates (phosphocreatine) were significantly higher and transmission electron microscopy revealed less ultrastructural damage under acute TBC-3214Na administration.
  
  
  CONCLUSIONS
  Acute endothelin-A receptor blockade is superior to chronic blockade in attenuating ischemia/reperfusion injury in failing hearts. Therefore, acute endothelin-A receptor blockade might be an interesting option for patients with heart failure undergoing cardiac surgery.
authors.affiliation: Department of Cardiac Surgery, LK St Poelten, Vienna Medical University, Vienna, Austria.
authors.forename: Karola
authors.initials: K
authors.lastname: Trescher
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dietl
authors.forename: Seth
authors.initials: S
authors.lastname: Hallström
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Wick
authors.forename: Margarita
authors.initials: M
authors.lastname: Wolfsberger
authors.forename: Robert
authors.initials: R
authors.lastname: Ullrich
authors.forename: Günther
authors.initials: G
authors.lastname: Jürgens
authors.forename: Ernst
authors.initials: E
authors.lastname: Wolner
authors.forename: Bruno K
authors.initials: BK
authors.lastname: Podesser