BLOCKADE OF THE TP RECEPTOR PREVENTS 60% O2-MEDIATED
PULMONARY HYPERTENSION IN NEWBORN RATS
Jankov RP1, Belcastro R1, Ovcina E1, Cabacungan J1,
Tanswell AK1, 2, 3.
1CIHR Group in
Lung Development and Lung Biology Programme, Hospital for Sick Children
Research Institute, and Departments of 2Paediatrics and 3Physiology,
University of Toronto, Ontario, Canada
Background: Increased expression of endothelin-1
(ET-1) is critical to the development of 60% O2-mediated
pulmonary hypertension (PHT).
Objective: To test the hypotheses that blockade of
the thromboxane (TX) A2 (TP) receptor will prevent PHT through
inhibition of 8-isoprostane-mediated ET-1 up-regulation.
Methods: Newborn
rat pups were given daily i.p. injections of the TP receptor antagonist,
L670596 (0.5 mg/kg), DFU, a COX-2 antagonist (10 mg/kg), or inert vehicle
during 14 d of 60% O2 or air exposure. TXB2, a stable
derivative of TXA2, and 8-isoprostane, a bioactive product of
lipid peroxidation, were quantified by enzyme immunoassay of purified lung
homogenates. ET-1 and COX-2
were measured by Western blot.
Results: ET-1,
COX-2, 8-isoprostane, and TXB2 were increased (p<0.05
compared to air controls) by 60% O2 exposure. Compared to
vehicle-treated animals in 60% O2, L670596-treated animals did not
develop right ventricular hypertrophy (RVH), a marker of PHT. DFU prevented
the 60% O2-mediated rise in lung TXB2, but had no
effect on RVH. None of the
interventions prevented the 60% O2-mediated increase in lung
8-isoprostane. Increased lung
ET-1 expression in 60% O2-exposed animals was attenuated by
L670596 (p<0.05 compared to vehicle-treated controls).
Conclusions: TP
receptor activation, by contributing to up-regulation of ET-1, is important
in the pathogenesis of PHT in this model. 8-Isoprostane contributes to ET-1
up-regulation during 60% O2 exposure by acting as an incidental
ligand of the TP receptor.
This work was supported by the CIHR.