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J Thorac Cardiovasc Surg 1996;112:890-897
© 1996 Mosby, Inc.

SURGERY FOR CONGENITAL HEART DISEASE

THE ENDOTHELIN ANTAGONIST BOSENTAN: HEMODYNAMIC EFFECTS DURING NORMOXIA AND HYPOXIC PULMONARY HYPERTENSION IN PIGS

Supported by grants from the Heart-Lung Foundation, the Swedish Medical Research Council, the Wallenberg foundation, the Thuring foundation, the Swedish Society of Medicine, the Salus Foundation, the Bergman Foundation, the Wiberg Foundation and funds from the Karolinska Institute.

Received for publication Dec. 11, 1995 Revisions requested Jan. 29, 1996; revisions received Feb. 26, 1996 Accepted for publication March 4, 1996. Address for reprints: Peter Holm, MD, Department of Thoracic Surgery, Karolinska Hospital, 171 76 Stockholm, Sweden.

Abstract

In this study, we investigated the hemodynamic effects and receptor-blocking properties of the nonselective endothelin antagonist bosentan in pigs during normoxia and acute hypoxia. Hypoxic pulmonary hypertension was induced by decreasing the fraction of inhaled oxygen to 0.1. In a control group of pigs, hemodynamic parameters proved to be stable through 2 hours of hypoxia. Infusions of endothelin-1, endothelin-3, and sarafotoxin 6c into the pulmonary artery resulted in pulmonary and systemic vasoconstriction during normoxia, whereas endothelin administration during hypoxic pulmonary hypertension resulted in pulmonary vasodilation. After administration of bosentan, the vasopressor effect of endothelin-1 during normoxia was significantly attenuated and the pulmonary vasodilatory effect of endothelin-1 during hypoxia was reduced. Furthermore, the development of hypoxic pulmonary hypertension was significantly reduced by bosentan. In contrast, bosentan did not influence the pulmonary vasopressor response to the thromboxane mimic U-46619. We therefore conclude that vasopressor endothelin receptors seem to be activated by endogenous endothelin released during hypoxia, leading to an increase in the pulmonary vascular tone. (J THORACCARDIOVASCSURG1996;112:890-7)

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