Role of thromboxane A2 in airway microvascular leakage induced by inhaled platelet-activating factor.

We studied the effects of OKY-046 (1, 10, and 30 mg/kg iv), a selective thromboxane synthase inhibitor, and of ICI 192605 (0.5 mg/kg), a selective thromboxane A2 receptor antagonist, on airflow obstruction and airway microvascular leakage induced by inhaled platelet-activating factor (PAF). Extravasated Evans blue dye content was measured as a reflection of airway microvascular leakage. In control animals, PAF caused a significantly higher increase in extravasation of dye and significantly less increase in lung resistance (RL) than histamine. OKY-046 significantly inhibited both changes in RL and airway microvascular leakage after PAF in a dose-dependent manner, whereas it inhibited histamine-induced airway microvascular leakage only at main bronchi, without any significant effect on RL. ICI 192605 significantly inhibited both RL and airway microvascular leakage induced by PAF, but not after histamine. After both PAF and histamine, changes in RL correlated significantly with the degree of microvascular leakage. Airway microvascular leakage and airflow obstruction after PAF, but not after histamine, may be dependent on thromboxane A2 generation.     

Secondary release of thromboxane A2 in aerosol leukotriene C4-induced bronchoconstriction in guinea pigs

Effect of a thromboxane synthetase inhibitor (OKY-046) on bronchoconstriction induced by aerosol leukotriene C4 and histamine was studied in anesthetized, artificially ventilated guinea pigs in order to examine whether secondary release of thromboxane A2 is produced by aerosol leukotriene C4 or not. 0.01-1.0 micrograms/ml of leukotriene C4 and 12.5-400 micrograms/ml of histamine inhaled from ultrasonic nebulizer developed for small animals caused dose-dependent increase of pressure at airway opening (Pao) which is considered to be an index representing bronchial response. Pretreatment of the animals with intravenous OKY-046 (100mg/kg) significantly reduced the airway responses produced by inhalation of 0.1, 0.33 and 1.0 micrograms/ml of leukotriene C4, while the pretreatment did not affect the histamine dose-response curve. Based on these findings and previous reports (6,7), it is suggested that aerosol leukotriene C4 activates arachidonate cyclooxygenase pathway including thromboxane A2 synthesis and the released cyclooxygenase products have bronchodilating effect as a whole.     

Secondary release of thromboxane A2 in aerosol leukotriene C4-induced bronchoconstriction in guinea pigs

Effect of a thromboxane synthetase inhibitor (OKY-046) on bronchoconstriction induced by aerosol leukotriene C4 and histamine was studied in anesthetized, artificially ventilated guinea pigs in order to examine whether secondary release of thromboxane A2 is produced by aerosol leukotriene C4 or not. 0.01–1.0μg/ml of leukotriene C4 and 12.5–400μg/ml of histamine inhaled from ultrasonic nebulizer developed for small animals caused dose-dependent increase of pressure at airway opening (Pao) which is considered to be an index representing bronchial response. Pretreatment of the animals with intravenous OKY-046 (100mg/kg) significantly reduced the airway responses produced by inhalation of 0.1, 0.33 and 1.0μg/ml of leukotriene C4, while the pretreatment did not affect the histamine dose-response curve. Based on these findings and previous reports (6, 7), it is suggested that aerosol leukotriene C4 activates arachidonate cyclooxygenase pathway including thromboxane A2 synthesis and the released cyclooxygenase products have bronchodilating effect as a whole     

Significance of thromboxane generation in ozone-induced airway hyperresponsiveness in dogs

To determine whether thromboxane A2 may be involved in ozone (O3)-induced airway hyperresponsiveness, we studied the effect of a thromboxane synthase inhibitor (OKY-046, 100 micrograms X kg-1 X min-1 iv) in five dogs exposed to O3. Airway responsiveness was assessed by determining the provocative concentration of acetylcholine aerosol that increased total pulmonary resistance by 5 cmH2O X l-1 X s. O3 (3 ppm) increased airway responsiveness as demonstrated by a decrease in acetylcholine provocative concentration from 2.42 (geometric SEM = 1.64) to 0.14 mg/ml (geometric SEM = 1.30). OKY-046 significantly inhibited this effect without altering pre-O3 responsiveness or the O3-induced increase in neutrophils and airway epithelial cells in bronchoalveolar lavage fluid. To further examine the role of thromboxane A2, we studied the effect of a thromboxane A2 mimetic, U-46619, on airway responsiveness in five additional dogs. U-46619 in subthreshold doses (i.e., insufficient to increase base-line pulmonary resistance) caused a fourfold increase in airway responsiveness to acetylcholine. Subthreshold doses of histamine had no effect. These results suggest that thromboxane A2 may be an important mediator of O3-induced airway hyperresponsiveness.     

OKY-046 inhibits anaphylactic bronchoconstriction and reduces histamine level in bronchoalveolar lavage fluid in sensitized guinea pigs.

We investigated the effects of OKY-046, a potent and selective thromboxane A2 (TxA2) synthetase inhibitor, on anaphylactic bronchoconstriction and release of chemical mediators into airway lumen in sensitized guinea pigs in vivo. OKY-046 dose-dependently inhibited antigen-induced anaphylactic bronchoconstriction with or without mepyramine, a histamine H1 antagonist. In the presence of mepyramine, OKY-046 (300 mg/kg, p.o.) elicited significant reductions in histamine (1 min) and TxB2 increases (1-15 min) in bronchoalveolar lavage (BAL) fluid but significantly increased the plasma level of 6-keto-PGF1 alpha, a stable PGI2 metabolite, after antigen challenge. On the contrary, indomethacin only significantly reduced increases in TxB2 levels. These results suggest that the antiasthmatic effect of OKY-046 is probably due to inhibition of TxA2 synthesis and suppression of histamine release via a PGI2 shunting mechanism.     

The role of thromboxane A2 (TxA2) in allergic cutaneous reactions and the effect of (E)-3-[p-(1H-imidazol-1-ylmethyl) phenyl]-2-propenoic acid hydrochloride (OKY-046), a TxA2 synthetase inhibitor

To study the role of thromboxane A2 (TxA2) in cutaneous allergic reactions, the effect of (E)-3-[p-(1H-Imidazol-1-ylmethyl)phenyl]-2-propenoic acid hydrochloride (OKY-046), a selective TxA2 synthetase inhibitor, on cutaneous reactions in rats and mice was studied. Simultaneously, the effect of 9,11-methanoepoxy-prostaglandin H2 (U-46619), a stable analogue of TxA2, on capillary permeability in mouse and rat skin was investigated. Passive cutaneous anaphylaxis (PCA) in mouse ear was clearly inhibited by OKY-046 but not by indomethacin. The inhibitory action of OKY-046 was not influenced by pretreatment with indomethacin. Moreover, prostaglandin I2, which accumulated as a result of the inhibition of TxA2 synthetase, did not affect the PCA. But, the dye leakages caused by histamine, serotonin and leukotriene C4 in mouse ear were clearly inhibited by OKY-046. In addition, OKY-046 inhibited rat reversed cutaneous anaphylaxis, but its inhibitory action was not affected by pretreatment with indomethacin. Contrary to the above results, rat footpad passive Arthus reaction and mouse footpad tuberculin delayed hypersensitivity reaction were not affected by OKY-046. Additionally, U-46619 did not cause an increase of capillary permeability in either mouse and rat skin. These results suggest a slight role of TxA2 in cutaneous allergic reactions in mice and rats and the efficacy of OKY-046 on Type I and II reactions regardless of the inhibition of TxA2 synthetase activity.     

Protective actions of a new thromboxane synthetase inhibitor in arachidonate induced sudden death

A new thromboxane synthetase inhibitor, OKY-046, at doses of 0.5 and 1.0 mg/kg prevented mortality induced by sodium arachidonate in 100% of the rabbits studied. Sodium arachidonate at a dose of 1.25 mg/kg uniformly decreased mean arterial blood pressure to values approximately 0 mm Hg, stopped respiration and produced sudden death within 3-5 minutes in all rabbits studied. OKY-046 prevented all these sequelae of the sodium arachidonate. Untreated rabbits challenged with sodium arachidonate develop large increases in circulating thromboxane B2 (TxB2) and 6-keto PGF1 alpha of about 12- to 18-fold. In contrast, OKY-046 prevented the increase in TxB2 concentrations and the pulmonary thrombosis, but did not block the rise in 6-keto PGF1 alpha following arachidonate injection. These results suggest that the protective mechanism of OKY-046 in arachidonate induced sudden death is via selective inhibition of thromboxane synthesis.     

The effects of thromboxane A2 inhibitors (OKY-046 and ONO-3708) and leukotriene inhibitors (AA-861 and LY-171883) on CCl4-induced chronic liver injury in mice

The effects of OKY-046, a selective thromboxane A2 (TxA2) synthetase inhibitor, ONO-3708, a novel TxA2 receptor antagonist, AA-861, a selective 5-lipoxygenase inhibitor and LY-171883, a peptide leukotrienes (p-LTs) receptor antagonist on the chronic liver injury were investigated in mice. The chronic liver injury was induced by the injection of carbon tetrachloride (CCl4) two times a week for twelve weeks in mice. In chronic liver injury models, significant histopathological changes in the liver and extensive elevation of glutamate transaminase (GOT and GPT) activity were observed. Administration of OKY-046, ONO-3708, AA-861 and LY-171883 for 12 weeks suppressed the elevation of serum GOT and GPT levels and histopathological changes in CCl4-induced chronic liver injury. These results suggest that TxA2 and LTs inhibitors are effective for the onset and development of chronic liver injury in mice.     

Effects of OKY-046, a selective thromboxane synthetase inhibitor, on blood pressure and thromboxane synthesis in spontaneously hypertensive rats

The effects of OKY-046, a specific thromboxane (TX) synthetase inhibitor, on blood pressure, urinary TX excretion, TX synthesis in blood platelets, kidney slices and aortic strips, were evaluated in adult spontaneously hypertensive rats (SHR). OKY-046 was dissolved in drinking water at concentrations of 1, 10, 100 mg/dl. The average intakes of OKY-046 were 1.4 +/- 0.1, 13.0 +/- 1.1, and 147 +/- 12 mg/kg/day, in rats who took 1, 10, 100 mg/dl of OKY-046 solutions for drinking water, respectively. The systolic blood pressure was significantly decreased by 34 mmHg only with the high dose of OKY-046 (147 mg/kg/day). OKY-046 suppressed the platelet aggregability to ADP and the release of TX B2, a stable metabolite of TX A2, from blood platelets in a dose-dependent fashion. Urinary excretion of TX B2 decreased significantly in both groups treated with moderate (13.0 mg/kg/day) and high doses of OKY-046 (147 mg/kg/day). The release of TX B2 from kidney slices was decreased only by the high dose of OKY-046, while the release of TX B2 from aortic strips was not changed even by the high dose of OKY-046. OKY-046 had no effect on urinary excretion of 6-keto-prostaglandin F1 alpha, a stable metabolite of prostacyclin, or, on its release from the kidney slices and aortic strips. These results suggest that the effect of OKY-046 on TX synthesis has organ specificity and that the antihypertensive effect of this drug in SHR is related to reduced renal TX synthesis.     

A formyl peptide contracts guinea pig lung: role of arachidonic acid metabolites

We studied the role of cyclooxygenase and lipoxygenase products of arachidonic acid metabolism in mediating N-formyl-methionyl-leucyl-phenylalanine- (FMLP) induced contractions of guinea pig lung parenchymal strips. The cyclooxygenase inhibitors indomethacin (10(-5) M) and aspirin (3 X 10(-5) to 10(-4) M), the lipoxygenase inhibitor nordihydroguaiaretic acid (10(-5) to 3 X 10(-5) M), and the combined cyclooxygenase/lipoxygenase inhibitors 1-phenyl-3-pyrazolidinone (Phenidone) (3 X 10(-5) to 3 X 10(-4) M) and BW 755C (10(-5) to 10(-4) M) each caused a decrease in the maximum force induced by FMLP (Fmax) and an increase in the concentration of FMLP required to produce 50% of Fmax (EC50). The thromboxane synthesis inhibitor imidazole (3 X 10(-3) M) also decreased Fmax. The leukotriene D4 receptor antagonist FPL 55712 (5.7 X 10(-6) to 1.9 X 10(-5) M) increased the EC50 for FMLP, whereas desensitization of lung parenchymal strips to leukotriene B4 by pretreatment with this leukotriene (10(-7) M) had no effect on FMLP-induced contraction. After exposure to FMLP (10(-6) M), guinea pig lung produced (as determined by high-performance liquid chromatography and radioimmunoassay) leukotrienes C4 and B4, thromboxane A2 (as measured by its stable degradation product thromboxane B2), and prostaglandin F2 alpha. Lung strips not exposed to FMLP showed no evidence of leukotriene production. We conclude that thromboxane A2 and leukotriene C4 generated in response to FMLP mediate a substantial fraction of the force induced by this peptide in guinea pig lung parenchymal strips.     

A study on the effectiveness of a thromboxane synthetase inhibitor (OKY-046) in increasing the survival length of skin flaps

In an experimental study to test the thromboxane (TX) synthetase inhibitor OKY-046, two random-pattern skin flaps, each measuring 15.5 x 2 cm, and caudally based, were elevated on the backs of rabbits, and the effect of the test drug on their survival length was evaluated. The results indicated that the survival length of the skin flaps was 4.5 +/- 0.2 cm in the control group and 6.8 +/- 0.3 cm in the OKY-046-treated group, hence exceeding the control value by more than 50 percent, which was statistically significant. A laser speckle flow-meter showed that the OKY-046-treated flaps had significantly greater blood flow as compared with the control group both at 1 and 48 hours after operation. Whereas the blood flow values were significantly lower at 48 hours than at 1 hour after operation in the control group, no such reduction was noted in the OKY-046-treated group. On the other hand, while plasma TXB2 was found elevated at 1 hour postoperatively in the control group, such a response to the surgical intervention was blocked and the plasma TXB2/6-keto prostaglandin (PG) F1a ratio was decreased in the OKY-046-treated group. These results clearly indicated that OKY-046 suppressed a plasma thromboxane elevation induced by surgery, it augmented the flap blood flow, and it thereby increased flap survival length, suggesting that the drug might be helpful clinically and that further investigation must be carried out concerning its application.     

Endothelium-dependent contraction induced by nicotine in isolated canine basilar artery--possible involvement of a thromboxane A2 (TXA2) like substance

The present experiments were undertaken to determine whether the response to nicotine in the isolated canine cerebral artery is endothelium-dependent. Changes in the tension of arterial strips were recorded isometrically. Removal of the endothelium was carried out by gentle rubbing, and confirmed by scanning electron microscopy. Rubbing procedure did not affect the contractile response of the strips to serotonin. Treatment of unrubbed strips with nicotine (10(-4)M) caused a transient contraction. This response was abolished by removal of endothelium and attenuated by hexamethonium (5 x 10(-6)M) and atropine (10(-6)M). The nicotine-induced contraction was attenuated also by aspirin (5 x 10(-5)M), a cyclooxygenase inhibitor, OKY-046 (5 x 10(-5)M), a thromboxane A2 (TXA2) synthetase inhibitor and ONO-3708 (5 x 10(-9)M), a TXA2 antagonist. These results indicate that the nicotine-induced contraction in canine cerebral artery is endothelium-dependent, and suggest that the endothelium-derived contracting factor (EDCF) in the nicotine-induced response is a TXA2-like substance.     

Thromboxane mediates pulmonary hypertension and lung inflammation during hyperacute lung rejection.

The role of thromboxane (Tx) in hyperacute rejection of pig lung by human blood was studied in an ex vivo model, wherein lungs from juvenile piglets were perfused with fresh heparinized human blood. In this model, hyperacute lung rejection was characterized by an abrupt rise in pulmonary vascular resistance (PVR; >1 cmH2O x ml(-1) x min) and prolific Tx elaboration (>15 ng/ml) within 5 min and loss of function within 10 min. Although papaverine significantly blunted the rise in PVR (<0.2 cmH2O x ml(-1) x min), Tx production was not inhibited (>20 ng/ml), and florid tracheal edema was usually evident within 20 min. In contrast, both inhibition of Tx synthesis (Tx < 3 ng/ml) with OKY-046 and blockade of the Tx receptor with SQ-30741 (Tx > 20 ng/ml) were not only associated with significantly lower peak PVRs (<0.2 cmH2O x ml(-1) x min) but also with attenuated increase in lung wet-to-dry ratio and airway edema. In concert, elaboration of histamine and tumor necrosis factor was blunted, and median survival increased >10-fold to 2 h (SQ-30741) and >4 h (OKY-046). Depletion of the pig lung macrophages with dichloromethyl bisphosphonate in liposomes, but not Pall filtration of the human blood or liposomes alone, significantly inhibited Tx elaboration (<0.2 vs. >8 ng/ml for Pall filtration or liposomes) and blunted PVR elevation (<0.3 cmH(2)O x ml(-1) x min) during initial perfusion. C3a and histamine elaboration were inhibited, and median survival was significantly prolonged (>4 h). These findings implicate Tx in the inflammation associated with hyperacute lung rejection and demonstrate that pulmonary intravascular macrophages are critical to its elaboration.     

Identification and specific blockade of histaminergic receptors in guinea pig vasa deferentia

Histamine produces contractions of the guinea pig vas deferens. The present investigation was undertaken to characterize the nature of histaminergic receptors in this tissue. Histamine (1.6 X 10(-6) M to 3.2 X 10(-5) M) produced dose-related contractions of guinea pig vas deferens (GPVD). Mepyramine (5.3 X 10(-8) M and 1 X 10(-9) M) blocked the responses to histamine competitively. Metiamide (1.23 X 10(-5) M) did not block the responses to histamine significantly. Specific H1 and H2 receptor agonists, namely 2-(2'-pyridyl)ethylamine (PEA) (2.55 X 10(-6) M to 3.0 X 10(-5) M) and 4-methylhistamine (4-MH) (2.52 X 10(-5) M to 3.0 X 10(-4) M), respectively, produced dose-related contractions of GPVD. The responses to PEA were blocked competitively by mepyramine, whereas the responses to 4-MH were blocked by metiamide. Reserpine pretreatment (5 mg/kg, i.p., 24 h) did not alter the responses to histamine and PEA. Our data suggest the presence of both H1 and H2 receptors in the GPVD which are excitatory in nature.     

Thromboxane synthase inhibition and cardiopulmonary function during endotoxemia in sheep.

We studied the cardiopulmonary response to endotoxin (lipopolysaccharide, LPS) in sheep with and without the administration of a thromboxane synthase inhibitor, OKY-046. The animals were instrumented for crystalographic dimension analysis of the left ventricle (LV) and for measurement of LV, aortic, left atrial, and pulmonary arterial pressures and cardiac index, as well as lung lymph flow. They received 1.0 micrograms/kg of Escherichia coli LPS with (n = 8) and without (n = 8) OKY-046 (10 mg/kg bolus, then 10 micrograms.kg-1.min-1). OKY-046 prevented the increase of pulmonary arterial pressure and the decrease of cardiac index that occurred during the early phase of endotoxemia. Between 8 and 12 h after LPS, cardiac index increased from 6.8 +/- 0.7 to 8.9 +/- 0.51.min-1.m-2. Concomitantly, the end-systolic pressure-diameter relationship (ESPDR, sensitive myocardial contractility index) significantly decreased from 14.7 +/- 0.6 to 7.7 +/- 0.7. Other indexes of the LV contractility (+dP/dtmax) were also reduced. OKY-046 prevented the decreases of ESPDR and +dP/dtmax. OKY-046 also attenuated the increased lung lymph flow changes seen with LPS.     

Involvement of thromboxane A(2) in airway mucous cells in asthma-related cough.

The aim of this study was to elucidate the role of thromboxane A(2) (TxA(2)) on asthma-related cough in guinea pigs. Animals were immunosensitized and repeatedly challenged with ovalbumin as an antigen. Coughs were induced by the inhalation of 10(-5) M capsaicin solution for 10 min. Thromboxane synthetase (TxS) inhibitor OKY-046 and thromboxane-receptor antagonist AA-2414 significantly inhibited cough responses in repeatedly challenged animals. Inhalation of TxA(2) mimic STA-2- potentiated cough responses in normal and immunosensitized animals but not in repeatedly challenged ones. Moreover, STA-2-potentiated coughs were inhibited by administration of neurokinin-receptor antagonist FK-224. In repeatedly challenged animals, concentration of TxB(2) in airway lavage fluid, expression of TxS mRNA in tracheal epithelia, and the immunostaining intensity against TxS in mucous cells of the epithelium significantly increased compared with normal and sensitized animals. These results suggest that TxA(2) derived from mucous cells potentiated cough responses to capsaicin in allergic airway inflammation.     

Synthesis of prostaglandin F by cultured human endometrial cells

Human endometrial cells were dispersed with collagenase and maintained in culture overnight. The synthesis of PGF by the dispersed cells incubated at 37 degrees C in serum-free medium was stimulated by estradiol (10(-7)M - 10(-5)M), histamine (5X10(-7)M - 5X10(-5)M), bradykinin (10(-6)M), phorbol myristate (PMA, 3X10(-8)M) and arachidonate (5X10(-6)M). Preincubation of the cells for 3 h with cortisol (5X10(-7)M - 5X10(-5)M), progesterone (10(-6)M) or mepacrine (10(-6)M - 2X10(-4)M) inhibited the response to histamine, bradykinin and PMA but not to arachidonate. Perfusion of the cultured cells in filtration chambers yielded similar results to those obtained in the incubation system but differences in the onset and duration of the responses to stimuli were found. In the perifusion system the responses to histamine and bradykinin were rapid and of short duration (peak response in less than 60 min) while the responses to PMA and arachidonate were of longer duration with a slower onset. We conclude that these observations using dispersed endometrial cells are consistent with previous work showing that histamine, bradykinin and PMA act by stimulating acylhydrolase activity, thereby liberating precursors such as arachidonic acid which are converted to prostaglandins by the cyclo-oxygenase complex.     

Effects of thromboxane synthase inhibition on air emboli lung injury in sheep

We tested the effects of OKY-046, a thromboxane synthase inhibitor, on lung injury induced by 2 h of pulmonary air infusion (1.23 ml/min) in the pulmonary artery of unanesthetized sheep with chronic lung lymph fistula so as to assess the role of thromboxane A2 (TxA2) in the lung injury. We measured pulmonary hemodynamic parameters and the lung fluid balance. The concentrations of thromboxane B2 (TxB2) and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) in plasma and lung lymph were determined by radioimmunoassay. Air infusion caused sustained pulmonary hypertension and an increase in pulmonary vascular permeability. The levels of TxB2 and 6-keto-PGF1 alpha in both plasma and lung lymph were significantly elevated during the air infusion. TxB2 concentration in plasma obtained from the left atrium was higher than that from the pulmonary artery at 15 min of air infusion. When sheep were pretreated with OKY-046 (10 mg/kg iv) prior to the air infusion, increases in TxB2 were prevented. The pulmonary arterial pressure, however, increased similarly to that of untreated sheep (1.8 X base line). The increase in lung lymph flow was significantly suppressed during the air infusion. Our data suggest that the pulmonary hypertension observed during air embolism is not caused by TxA2.     

Endothelium-independent and -dependent contractions induced by endothelin-1 in canine basilar arteries

Endothelium-dependence of contractile responses to endothelin-1 was examined in isolated canine basilar arteries. Within 2 hrs after mounting tissue preparations, endothelin-1 (10(-9) M) caused a monophasic tonic contraction that developed very slowly and was sustained in intact and endothelium-removed arteries. More than 5 hrs after tissue mounting, endothelin-1 (10(-9) M) caused a biphasic contraction consisting of phasic and tonic components in intact arteries, and caused a monophasic tonic contraction in endothelium-removed arteries. This phasic component was significantly decreased by aspirin (5 x 10(-5) M,), OKY-046 (10(-5) M) (a TXA2 synthetase inhibitor) and ONO-3708 (10(-8) M) (a TXA2 antagonist). The present experiments demonstrate that endothelin-1 causes an endothelium-independent tonic contraction and an endothelium-dependent phasic contraction in canine basilar arteries, and suggest that TXA2 plays a role as an endothelium-derived contracting factor.     

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)