title: Endothelin receptor subtype A blockade selectively reduces pulmonary pressure after cardiopulmonary bypass.
abstract: BACKGROUND
  The bioactive peptide endothelin-1 is elevated during and after cardiopulmonary bypass and exerts cardiovascular effects through its 2 receptor subtypes, endothelin-1A and endothelin-1B. Increased endothelin-1A receptor stimulation after cardiopulmonary bypass can cause increased pulmonary vascular resistance and modulate myocardial contractility. However, whether and to what degree selective endothelin-1A blockade influences these parameters in the postbypass setting is not completely understood.
  
  
  OBJECTIVE
  Our objective was to measure left ventricular function and hemodynamics in a porcine model of cardiopulmonary bypass after selective blockade of endothelin-1A.
  
  
  METHODS
  Adult pigs (n = 23) underwent 90 minutes of cardiopulmonary bypass and were randomized 30 minutes after bypass to receive a selective endothelin-1A antagonist (TBC 11251, 10 mg/kg; n = 13) or saline vehicle (n = 10).
  
  
  RESULTS
  After bypass and before randomization, pulmonary vascular resistance rose nearly 4-fold, and left ventricular preload recruitable stroke work fell to one third of baseline values (both P <.05). In the vehicle group pulmonary vascular resistance continued to rise, and preload recruitable stroke work remained reduced. However, after endothelin-1A blockade, the rise in pulmonary vascular resistance was significantly blunted compared with that in the vehicle group. Moreover, the reduction in pulmonary vascular resistance with endothelin-1A blockade was achieved without a significant change in systemic perfusion pressures.
  
  
  CONCLUSIONS
  The present study demonstrated that increased activity of the endothelin-1A receptor likely contributes to alterations in pulmonary vascular resistance in the postbypass setting. Selective endothelin-1A blockade may provide a means to selectively decrease pulmonary vascular resistance without significant effects on systemic hemodynamics.
authors.affiliation: Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: C
authors.initials: C
authors.lastname: Joffs
authors.forename: C A
authors.initials: CA
authors.lastname: Walker
authors.forename: J W
authors.initials: JW
authors.lastname: Hendrick
authors.forename: D J
authors.initials: DJ
authors.lastname: Fary
authors.forename: D K
authors.initials: DK
authors.lastname: Almany
authors.forename: J N
authors.initials: JN
authors.lastname: Davis
authors.forename: A T
authors.initials: AT
authors.lastname: Goldberg
authors.forename: F A
authors.initials: FA
authors.lastname: Crawford
authors.forename: F G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002315:Cardiopulmonary Bypass; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000097:blood / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000097:blood / Q000503:physiopathology; D007555:Isoxazoles / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology; D013552:Swine; D013876:Thiophenes / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*
chemical_list: D019332:Endothelin-1; D007555:Isoxazoles; D017466:Receptors, Endothelin; D013876:Thiophenes; C106276:sitaxsentan