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Thromboxane Synthase Inhibition Blunts the Development of Pulmonary Hypertension and Vascular Remodeling in Hypoxic Neonatal Piglets
Author(s) -
HirenallurS. Dinesh K.,
Haworth Steven T.,
Gordon John B.,
Rusch Nancy J.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.933.9
Subject(s) - thromboxane a synthase , thromboxane , downregulation and upregulation , hypoxia (environmental) , pulmonary hypertension , vascular resistance , medicine , endocrinology , thromboxane a2 , atp synthase , nitric oxide synthase , chemistry , receptor , blood pressure , enzyme , nitric oxide , oxygen , biochemistry , platelet , organic chemistry , gene
The development of chronic hypoxia (CH)‐induced neonatal pulmonary hypertension (PH) is associated with increased production of thromboxane (TxA 2 ) and an upregulation of L‐type calcium (Ca L ) channels. Thus, we hypothesized that TxA 2 synthase inhibition may blunt the development of PH by mitigating the upregulation of Ca L channels. Newborn piglets were exposed to 21 days of normoxia (N), CH or CH plus the TxA 2 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 Ca L channels and anomalous Ca 2+ ‐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 TxA 2 synthase blunts the development of hypoxia‐induced neonatal PH by preserving vascular function and structural integrity. Funded by NIH R01 HL83013