OKY-046 prevents increases in LTB4 and pulmonary edema in phorbol ester-induced lung injury in dogs.
Thromboxanes (Txs) were implicated as possible participants in the altered microvascular permeability of acute lung injury when the Tx synthase inhibitor, OKY-046, was reported to prevent pulmonary edema induced by phorbol myristate acetate (PMA). Recently, however, we found that OKY-046, at a dose just sufficient to block Tx synthesis in intact dogs, did not prevent PMA-induced pulmonary edema but rather merely reduced it modestly. The present study was designed to explore other mechanisms whereby OKY-046 might prevent PMA-induced pulmonary edema. The finding that 5-lipoxygenase (5-LO) metabolites of arachidonic acid were increased within the lung after PMA administration, coupled with the report that OKY-046 inhibited slow-reacting substance of anaphylaxis formation, permitted formulation of the hypothesis that OKY-046, at a dose in excess of that required to inhibit Tx synthesis, inhibits the formation of a product(s) of 5-LO and, thereby, prevents edema formation. In vehicle-pretreated pentobarbital-anesthetized male mongrel dogs (n = 4), PMA (20 micrograms/kg i.v.) increased pulmonary vascular resistance (PVR) from 4.4 +/- 0.3 to 26.3 +/- 8.8 mmHg.l-1 x min (P < 0.01) and extravascular lung water from 6.7 +/- 0.5 to 19.1 +/- 6.2 ml/kg body wt (P < 0.05). Concomitantly, both TxB2 and leukotriene B4 (LTB4) were significantly increased in the lung. Pretreatment with OKY-046 (100 mg/kg i.v., n = 8) prevented PMA-induced increases in TxB2, LTB4, and pulmonary edema formation but did not prevent the increase in PVR.(ABSTRACT TRUNCATED AT 250 WORDS)
Sprague
R S
RS
Department of Medicine, Saint Louis University School of Medicine, Missouri 63104.
Stephenson
A H
AH
Lonigro
A J
AJ
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D015633:Extravascular Lung Water; D007958:Leukocyte Count; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D008689:Methacrylates / Q000494:pharmacology*; D010100:Oxygen / Q000097:blood; D011654:Pulmonary Edema / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D013755:Tetradecanoylphorbol Acetate; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013931:Thromboxanes / Q000378:metabolism
D008689:Methacrylates; D013931:Thromboxanes; D007975:Leukotriene B4; D015121:6-Ketoprostaglandin F1 alpha; D001094:Arachidonate 5-Lipoxygenase; D013930:Thromboxane-A Synthase; C034364:ozagrel; D013755:Tetradecanoylphorbol Acetate; D010100:Oxygen