Furegrelate, a Thromboxane Synthase Inhibitor, Blunts the Development of Pulmonary Arterial Hypertension in Neonatal Piglets

Abstract

The development of pulmonary arterial hypertension (PAH) in pediatric patients has been linked to the production of the arachidonic acid metabolite, thromboxane A2 (TxA2). The present study evaluated the therapeutic effect of furegrelate sodium, a thromboxane synthase inhibitor, on the development of PAH in a neonatal piglet model. Three-day-old piglets were exposed to 21 days of normoxia (N; 21% FIO2) or chronic hypoxia (CH; 10% FIO2). A third group of piglets received the oral TxA2 synthase inhibitor, furegrelate (3 mg/kg, 2 or 3 times daily) at the induction of CH. In vivo hemodynamics confirmed a 2.55-fold increase of the pulmonary vascular resistance index (PVRI) in CH piglets (104±7 WU) compared to N piglets (40±2 WU). The CH piglets treated twice daily with furegrelate failed to show improved PVRI, but furegrelate three times daily lowered the elevated PVRI in CH piglets by 34% to 69±5 WU and ameliorated the development of right ventricular hypertrophy. Microfocal X-ray computed tomography (CT) scanning was used to estimate the diameter-independent distensibility term, α (% change in diameter per Torr). Pulmonary arterial distensibility in isolated lungs of CH piglets (α=1.0±0.1% per Torr) was lower than that of N piglets (α=1.5±0.1% per Torr) indicative of vascular remodeling. Arterial distensibility was partially restored in furegrelate-treated CH piglets (α =1.2±0.1% per Torr) and microscopic evidence showing muscularization of small pulmonary arteries also was less prominent in these animals. Finally, isolated lungs of furegrelate-treated piglets showed lower basal and vasodilator-induced transpulmonary pressures compared to CH animals. These findings suggest that pharmacological inhibition of TxA2 synthase activity by furegrelate blunts the development of hypoxia-induced PAH in an established neonatal piglet model primarily by preserving the structural integrity of the pulmonary vasculature.

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Topics

Animal Models
Fetal and Neonatal Lung - Development-Function and Disease/BPD
Hypoxia/ Intermittent Hypoxia/ Hypoxia-Ischemia and Ischemia-Reperfusion Injury

Authors

Dinesh K. Hirenallur-S, Neil D. Detweiler, Steven T. Haworth, Jeaninne T. Leming, John B. Gordon, Nancy J. Rusch

Published in:

Pulmonary Circulation Vol 2: No 2 cover image

June 2012

Pulmonary Circulation Vol 2: No 2

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