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J Thorac Cardiovasc Surg 1999;117:314-323
© 1999 Mosby, Inc.

SURGERY FOR CONGENITAL HEART DISEASE

ENDOTHELIN RECEPTOR BLOCKADE PREVENTS THE RISE IN PULMONARY VASCULAR RESISTANCE AFTER CARDIOPULMONARY BYPASS IN LAMBS WITH INCREASED PULMONARY BLOOD FLOW

From the Departments of Cardiothoracic Surgery^a and Pediatrics,^d University of California San Francisco; the Department of Pediatrics,^b New York University, New York; and the Department of Pharmokinetics and Metabolism,^c Parke-Davis Pharmaceutical Research, Ann Arbor, Mich.

Supported by grant 94-212 from the American Heart Association, California Affiliate, by Research Award 6-FY98-0615 from the March of Dimes, and by a grant from Parke-Davis Pharmaceutical Research.

Read at the Twenty-fourth Annual Meeting of The Western Thoracic Surgical Association, Whistler, British Columbia, June 24-27, 1998.

Received for publication July 7, 1998. revisions requested Aug 27, 1998. revisions received Sept 28, 1998. Accepted for publication Oct 1, 1998. Address for reprints: Jeffrey R. Fineman, MD, University of California, San Francisco, 505 Parnassus Ave, Box 0106, M-680, San Francisco, CA 94143-0106.

Background: Children with increased pulmonary blood flow may experience morbidity as the result of increased pulmonary vascular resistance after operations in which cardiopulmonary bypass is used. Plasma levels of endothelin-1, a potent vasoactive substance implicated in pulmonary hypertension, are increased after cardiopulmonary bypass.
Objectives: In a lamb model of increased pulmonary blood flow after in utero placement of an aortopulmonary shunt, we characterized the changes in pulmonary vascular resistance induced by hypothermic cardiopulmonary bypass and investigated the role of endothelin-1 and endothelin-A receptor activation in postbypass pulmonary hypertension.
Methods: In eleven 1-month-old lambs, the shunt was closed, and vascular pressures and blood flows were monitored. An infusion of a selective endothelin-A receptor blocker (PD 156707; 1.0 mg/kg/h) or drug vehicle (saline solution) was then begun 30 minutes before cardiopulmonary bypass and continued for 4 hours after bypass. The hemodynamic variables were monitored, and plasma endothelin-1 concentrations were determined before, during, and for 6 hours after cardiopulmonary bypass.
Results: After 90 minutes of hypothermic cardiopulmonary bypass, both pulmonary arterial pressure and pulmonary vascular resistance increased significantly in saline-treated lambs during the 6-hour study period (P < .05). In lambs pretreated with PD 156707, pulmonary arterial pressure and pulmonary vascular resistance decreased (P < .05). After bypass, plasma endothelin-1 concentrations increased in all lambs; there was a positive correlation between postbypass pulmonary vascular resistance and plasma endothelin-1 concentrations (P < .05).
Conclusions: This study suggests that endothelin-A receptor–induced pulmonary vasoconstriction mediates, in part, the rise in pulmonary vascular resistance after cardiopulmonary bypass. Endothelin-A receptor antagonists may decrease morbidity in children at risk for postbypass pulmonary hypertension. This potential therapy warrants further investigation.

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