Endothelin receptor subtype A blockade selectively reduces pulmonary pressure after cardiopulmonary bypass.
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.
Joffs
C
C
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Walker
C A
CA
Hendrick
J W
JW
Fary
D J
DJ
Almany
D K
DK
Davis
J N
JN
Goldberg
A T
AT
Crawford
F A
FA
Spinale
F G
FG
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*
D019332:Endothelin-1; D007555:Isoxazoles; D017466:Receptors, Endothelin; D013876:Thiophenes; C106276:sitaxsentan