Thromboxane does not mediate pulmonary hypertension in phorbol ester-induced acute lung injury in dogs.
Thromboxane (Tx) has been suggested to mediate the pulmonary hypertension of phorbol myristate acetate- (PMA) induced acute lung injury. To test this hypothesis, the relationship between Tx and pulmonary arterial pressure was evaluated in a model of acute lung injury induced with PMA in pentobarbital sodium-anesthetized male mongrel dogs. Sixty minutes after administration of PMA (20 micrograms/kg iv, n = 10), TxB2 increased 10-fold from control in both systemic and pulmonary arterial blood and 8-fold in bronchoalveolar lavage (BAL) fluid. Concomitantly, pulmonary arterial pressure (Ppa) increased from 14.5 +/- 1.0 to 36.2 +/- 3.5 mmHg, and pulmonary vascular resistance (PVR) increased from 5.1 +/- 0.4 to 25.9 +/- 2.9 mmHg.l-1.min. Inhibition of Tx synthase with OKY-046 (10 mg/kg iv, n = 6) prevented the PMA-induced increase in Tx concentrations in blood and BAL fluid but did not prevent or attenuate the increase in Ppa. OKY-046 pretreatment did, however, attenuate but not prevent the increase in PVR 60 min after PMA administration. Pretreatment with the TxA2/prostaglandin H2 receptor antagonist ONO-3708 (10 micrograms.kg-1.min-1 iv, n = 7) prevented the pressor response to bolus injections of 1-10 micrograms U-46619, a Tx receptor agonist, but did not prevent or attenuate the PMA-induced increase in Ppa. ONO-3708 also attenuated but did not prevent the increase in PVR. These results suggest that Tx does not mediate the PMA-induced pulmonary hypertension but may augment the increases in PVR in this model of acute lung injury.
Department of Pharmacology, St. Louis University School of Medicine, Missouri 63104.
A H
AH
Stephenson
R S
RS
Sprague
T E
TE
Dahms
A J
AJ
Lonigro
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001992:Bronchoalveolar Lavage Fluid / Q000378:metabolism; D004285:Dogs; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000209:etiology* / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D055370:Lung Injury; D008297:Male; D008689:Methacrylates / Q000494:pharmacology; D011651:Pulmonary Artery / Q000503:physiopathology; D013755:Tetradecanoylphorbol Acetate; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013929:Thromboxane B2 / Q000097:blood / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013931:Thromboxanes / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
D008689:Methacrylates; D013931:Thromboxanes; D013929:Thromboxane B2; D013928:Thromboxane A2; C049855:ONO 3708; D013930:Thromboxane-A Synthase; C034364:ozagrel; D013755:Tetradecanoylphorbol Acetate