Thromboxane Synthase Inhibition Blunts the Development of Pulmonary Hypertension and Vascular Remodeling in Hypoxic Neonatal Piglets

Abstract

The development of chronic hypoxia (CH)‐induced neonatal pulmonary hypertension (PH) is associated with increased production of thromboxane (TxA2) and an upregulation of L‐type calcium (CaL) channels. Thus, we hypothesized that TxA2 synthase inhibition may blunt the development of PH by mitigating the upregulation of CaL channels. Newborn piglets were exposed to 21 days of normoxia (N), CH or CH plus the TxA2 synthase inhibitor, furegrelate (oral 3 mg/kg, 3x daily). In vivo pulmonary vascular resistance index (PVRI) was 3.15 ‐fold higher in CH (104±1 WU) compared to N (33±1 WU) piglets. Furegrelate partially blunted the elevated PVRI in CH piglets (64±0.5 WU). Furegrelate also reversed the elevated transpulmonary pressure in isolated lungs of CH piglets by 66%, and blunted the overexpression of CaL channels and anomalous Ca2+‐dependent tone. Pulmonary arterial distensibility was decreased in lungs of CH compared to N piglets, indicative of vascular remodeling. Furegrelate partially restored distensibility to normal levels. Our findings suggest that pharmacological inhibition of TxA2 synthase blunts the development of hypoxia‐induced neonatal PH by preserving vascular function and structural integrity. Funded by NIH R01 HL83013