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J Thorac Cardiovasc Surg 2001;122:365-370
© 2001 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CPS)

Endothelin receptor subtype A blockade selectively reduces pulmonary pressure after cardiopulmonary bypass

From the Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC.

This work is supported by National Institutes of Health grants R01HL56603 and R01HL57952 and by an unrestricted grant from the Texas Biotechnology Corporation (San Diego, Calif).

Received for publication June 6, 2000. Revisions requested Sept 8, 2000; revisions received Feb 2, 2001. Accepted for publication Feb 5, 2001. Address for reprints: Francis G. Spinale, MD, PhD, Division of Cardiothoracic Surgery, 114 Doughty St, Suite 625, Charleston, SC 29425.

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.
Objectives: 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.

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