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Ann Thorac Surg 2000;70:1522-1530
© 2000 The Society of Thoracic Surgeons

Original articles: cardiovascular

Characterization of the pulmonary arterial response to endothelin-1 and bosentan in neonatal pigs

Patrick W. Domkowski, MD, PhDa, John T. Cockerham, MDa, Peter A. Kot, MDa, Jeff L. Myers, MD, PhDa, Richard A. Hopkins, MDa

a Department of Surgery, Brown University School of Medicine, Providence, Rhode Island, USA

Address reprint requests to Dr Hopkins, Cardiothoracic Surgery, 164 Summit Ave, Providence, RI 02906
e-mail: rahopkins{at}lifespan.org

Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000.

Background. This study determined the pulmonary vascular responses to intravenous (IV) administration of endothelin-1 (ET-1) before and after an IV bolus of bosentan (Ro 47-0203), an endothelin receptor antagonist, in anesthetized open-chest 48-hour-old and 2-week-old Yorkshire pigs.

Methods. Eighteen 48-hour-old and 25 2-week-old pigs were randomly allocated to receive either (1) 400 ng · kg-1 · min-1 of ET-1 or (2) 5 mg/kg or 10 mg/kg of Ro 47-0203 followed by 400 ng · kg-1 · min-1 of ET-1 over a 10-minute interval. Pulmonary vascular resistance (PVR, dyne sec/cm-5), elastic modulus (EYo, dyne/cm2), and characteristic impedance (Zo) were determined (± SEM).

Results. In 48-hour-old pigs, ET-1 decreased pulmonary artery pressure (PAP, dyne/cm2; 21,317 ± 1833 versus 17,757 ± 1823; p = 0.003). In 2-week-old pigs, ET-1 elevated PAP (19,009 ± 1834 versus 21,935 ± 2104; p = 0.003) and PVR (1624 ± 254 versus 2302 ± 416; p = 0.001), whereas bosentan abolished the ET-1 induced pulmonary and systemic vasoconstriction. Neither agent altered EY or Zo.

Conclusions. ET-1 caused a pulmonary depressor response in 48-hour-old pigs and a constrictor response in 2-week-old pigs, whereas bosentan inhibited the ET-1 induced pulmonary arteriolar vasoconstriction in 2-week-old pigs. The response to ET-1 changes from dilation in 48-hour-old pigs (neonates) to constriction in 2-week-old pigs (infants) suggests a maturational dependent alteration in ET receptors during the first 2 weeks of life. These data suggest that bosentan may have potential clinical application in the treatment of newborn pulmonary hypertensive episodes as it ablated ET-1 induced pulmonary vasoconstriction, while maintaining systemic pressure.


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Discussion
Ann. Thorac. Surg. 2000 70: 1530. [Extract] [Full Text] [PDF]





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