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

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.