TBC3711, an ETA receptor antagonist, reduces neonatal hypoxia-induced pulmonary hypertension in piglets

The pulmonary vasculature of newborns with persistent pulmonary hypertensio n is characterized by active vasoconstriction and vascular remodeling. It h as been suggested that endothelin-1 (ET-1), a potent vasoconstrictor and gr owth promoter, may be involved in the pathogenesis of persistent pulmonary hypertension of the newborn. To determine whether treatment with an ETA rec eptor antagonist can reverse pulmonary hypertension in the neonate, 1-d-old piglets were exposed to hypoxia for 3 d to induce pulmonary hypertension a nd then treated for the remainder of the 14 d with an orally active, nonpep tidic ETA antagonist (TBC3711, 22 mg . kg(-1).d(-1)). At the end of the exp osure, Hb, pulmonary artery pressure, right ventricle to left ventricle plu s septum weight ratio, percentage wall thickness, ET-1 circulating levels, perfusion pressure, and dilator response to the nitric oxide (NO) donor, SI N-1 (3-morpholinosydnonimine-N-ethylcarbamide) in isolated perfused lungs w ere determined. Exhaled NO and hemodynamic variables were also examined in an intact anesthetized animal preparation that had undergone the same treat ment. By 3 d of exposure to hypoxia, piglets had already developed signific ant pulmonary hypertension as estimated by their pulmonary artery pressure (24.0 +/- 1.3 mm Hg versus 14.2 +/- 3.4 mm Hg) and percentage wall thicknes s (26.6 +/- 5.9% versus 18.7 +/- 2.4% for vessels 0-30 mum). Whereas furthe r exposure to hypoxia for 14 d did not enhance the increase in pulmonary ar tery pressure and percentage wall thickness, it did augment the right ventr icle to left ventricle plus septum weight ratio (0.71 +/- 0.09 versus 0.35 +/- 0.01). ET-1 circulating levels were increased only when exposure to hyp oxia was prolonged to 14 d (5.1 +/- 2.4 pg/mL versus 1.0 +/- 0.4 pg/mL). Tr eatment with TBC3711 from d 3 to d 14, once pulmonary hypertensive changes were established and while hypoxic exposure persisted, caused significant r eduction in the right ventricle to left ventricle plus septum weight ratio (0.60 +/- 0.06), pulmonary artery pressure (20.0 +/- 4.8 mm Hg), and percen tage wall thickness (18.5 +/- 3.3%) and restored the dilator response to th e NO donor SIN-1. Prolonged hypoxia. markedly reduced exhaled NO concentrat ions (0.3 +/- 0.6 ppb), although treatment of hypoxic animals with TBC3711 restored the concentration of exhaled NO (4.4 +/- 2.8 ppb) to the level of normoxic controls (4.9 +/- 3.0 ppb). Lastly, treatment with TBC3711 increas ed ET-I circulating levels in both die normoxic (5.4 +/- 2.8 pg/mL) and hyp oxic (13.0 +/- 63 pg/mL) groups. In conclusion, the specific ET, receptor a ntagonist, TBC3711, can significantly ameliorate the morphologic changes en countered in hypoxia-induced pulmonary hypertension in the newborn piglet a nd may improve the dilator response to NO.