Thromboxane Synthetase Inhibitor Research Articles

Pulmonary Pharmacology of DT-TX 30 SE, a Potent Selective Combined Thromboxane Synthetase Inhibitor and Receptor Antagonist, in Guinea Pigs

A novel chemical compound, DT-TX 30 SE (E-6-(4-(2-(4-chlorobenzenesulphonylamino)-ethyl)phenyl)-6-(3-pyridyl)-hex-5-enoic acid), was studied in various models of guinea pig pulmonary function. The compound was a potent inhibitor (ED50 0.019 mg/kg, i.v.) of bronchospasm induced by the thromboxane receptor agonist U-46619, indicating thromboxane receptor antagonism. At even lower doses (ED50 0.0036 mg/kg, i.v.), it blocked arachidonic acid-induced bronchospasm. Interpretation of the latter results as evidence for additional thromboxane synthetase inhibitory activity was supported by the inhibition of arachidonic acid- or bradykinin-induced thromboxane B2 production in an isolated lung preparation, although prostaglandin E2 and prostaglandin 6-oxo-F1α production measured at the same time were not inhibited. The potency of DT-TX 30 SE was compared with thromboxane receptor antagonists and synthetase inhibitors described in the literature. As a receptor antagonist, DT-TX 30 SE was significantly more potent than BM 13505 and BM 13177 (assessed by antagonism of U-46619-induced bronchospasm), but less potent than SQ 29548, while as a thromboxane synthetase inhibitor, it was significantly more potent than OKY 046 and UK 37248 as assessed by antagonism of arachidonic acid-induced bronchospasm or (OKY 046) inhibition of thromboxane production in isolated lung. The compound was active by the oral route as shown by its ability, at 10 mg/kg, p.o., to significantly reduce the immediate allergic response of sensitized guinea pigs to an ovalbumin aerosol.

Increased whole blood platelet aggregation in oral contraceptive users can be preventedin vitroby a thromboxane synthetase inhibitor

Click to increase image sizeClick to decrease image sizeKey Words: Oral ContraceptivesThromboxane SynthetasePlatelet Aggregation

Platelet Reactivity In Vitro in Relation to Thromboxane in Healthy Pregnancy

There is substantial evidence of increased platelet reactivity in vivo and in vitro during pregnancy. Previous in vitro studies suggest that platelets from pregnant women show increased sensitivity to agonists, the response to which has a thromboxane dependent component. The aim of this study was to determine whether this is due to increased activity of the thromboxane biosynthetic pathway or to increased platelet sensitivity to the effects of thromboxane. During pregnancy, platelets were more sensitive to the pro-aggregatory effects in vitro of the thromboxane mimetic U46619, in whole blood and in platelet rich plasma, compared to those from non-pregnant controls. The difference in extent of U46619-induced platelet aggregation between groups was abolished in the presence of a high concentration of the specific thromboxane antagonist ICI 192605, but not by prior incubation of blood with aspirin. Platelets from pregnant women were significantly less sensitive to inhibition of arachidonic acid induced activation by the thromboxane synthetase inhibitor dazmegrel, but there was no change in platelet cyclic AMP accumulation under these conditions. Arachidonic acid induced platelet thromboxane B2 production was similar in pregnant and non-pregnant subjects. In conclusion, platelets are more sensitive to the activating effects of thromboxane during pregnancy, but there is no change in the intrinsic reactivity of the thromboxane biosynthetic pathway.

Protective effect of thromboxane synthetase inhibitor on hypertensive renal damage in Dahl salt-sensitive rats.

1. The effects of OKY-046, a specific thromboxane (TX) synthetase inhibitor, on blood pressure, urinary excretion of TX and its release from blood platelets and renal papilla, and pathological change of glomeruli were evaluated in Dahl salt-sensitive rats. 2. Average daily intakes of OKY-046-treated rats were 0.93 mg/kg (low dose), 9.8 mg/kg (moderate dose), and 88 mg/kg (high dose). 3. Systolic blood pressure tended to decrease by 6.3, 11.4, and 10.9% in three OKY-treated groups. 4. OKY-046 suppressed the release of TX from platelets in a dose-dependent fashion. Both TX in urine and released from renal papilla decreased in OKY-treated groups with moderate and high dose. OKY-046 resulted no change in urinary excretion or release from renal papilla of prostaglandin E2 or 6-keto-prostaglandin F1alpha. 5. Glomerular sclerosis score decreased significantly in both groups treated with moderate and high doses of OKY-046. 6. An inhibition of renal TX synthesis by TX synthetase inhibitor has a protective effect on the development of hypertensive renal damage with minor antihypertensive effect in Dahl salt-sensitive rats.

Role of thromboxane A2 and prostacyclin in uninephrectomy-induced attenuation of ischemic renal injury

Contralateral uninephrectomy attenuates unilateral renal ischemic injury. The present work was performed to elucidate whether the beneficial effect of uninephrectomy was mediated through the modification of the actions of thromboxane A2 (TxA2) or prostacyclin. Unilateral ischemic injury was provoked by a 60-minute left renal artery occlusion in right nephrectomized (Nx) and in sham-nephrectomized (Sham-Nx) rats. Inulin clearance (CIn) of left kidney 48 hours after ischemia was significantly higher in the Nx group than in the Sham-Nx group (0.11 +/- 0.07 vs. 0.00 +/- 0.00 ml/min/kidney, P < 0.05). Ischemia-induced tubular necrosis was also less in Nx animals. Proliferating cell nuclear antigen (PCNA) staining, a marker for cell proliferation, was found more markedly in Nx rats than in Sham-Nx animals. Forty-eight hours after ischemia, renal cortical TxB2 content was greater in Sham-Nx rats than in Nx rats (29.5 +/- 4.4 vs. 18.3 +/- 1.7 pg/mg protein, P < 0.05). No significant difference was found in the intrarenal content of 6-keto prostaglandin F1 alpha between two ischemia groups. A thromboxane synthetase inhibitor, OKY-046 (100 mg/kg/day, i.p.), significantly increased CIn 48 hours after ischemia (0.00 +/- 0.00 vs. 0.17 +/- 0.09 ml/min/kidney, P < 0.05) and attenuated ischemic tubular damage in Sham-Nx rats but not in Nx animals. Under OKY-046 treatment, no significant difference was found in postischemic CIn and ischemic tubular damage between the Nx and Sham-Nx groups. OKY-046 also increased PCNA expression in the cortex and outer stripe in Sham-Nx animals. These data suggest that less production of intrarenal TxB2 plays an important role for the uninephrectomy-induced attenuation of ischemic renal damage and for the facilitation of tubular recovery.

Heparin-Protamine Complexes Cause Pulmonary Hypertension in Goats

Protamine reversal of heparin-induced anticoagulation causes thromboxane release followed by pulmonary vasoconstriction in sheep and pigs. The aim of this study was to determine whether heparin-protamine (H-P) complexes are causative agents of thromboxane release followed by pulmonary hypertension associated with protamine reversal of heparin. We separated H-P complexes and non-heparin-protamine (non-H-P) complexes from heparinized defibrinated human plasma neutralized with protamine by chromatography and studied the changes in hemodynamics, airway pressure, and thromboxane B2 concentration after injection of H-P complexes or non-H-P complexes into seven goats. In addition, we studied whether these pulmonary responses were blocked in goats pretreated with cyclooxgenase inhibitor (Indomethacin, n = 5) or thromboxane synthetase inhibitor (OKY-046, n = 5). A very small dose of H-P complexes increased pulmonary arterial and peak airway pressures and was followed by thromboxane B2 release (from 12 [5.5-23] to 28 [16-44] mmHg, from 9.0 [7.5-15] to 12 [8-19] cmH2O, and from 0.85 [0.34-3.2] to 16.4 [1.4-39.3] ng.ml-1, respectively). On the other hand, animals that received non-H-P complexes showed no significant changes. Indomethacin totally blocked and OKY-046 partially blocked the increases in pulmonary arterial pressure and thromboxane B2 concentration. H-P complexes play a major role in pulmonary hypertension after protamine reversal of heparin, and thromboxane A2 is a main mediator of the pulmonary hypertensive response to H-P complexes in goats.

Prostaglandins and diabetic nephropathy

Abnormalities of renal prostaglandins (PGs) contribute to the pathogenesis of diabetic nephropathy through changes in renal hemodynamics. Our recent studies have demonstrated that urinary excretion ratio of 6-keto-PGF 1 α (6KF) to TXB 2 is decreased in patients with non-insulin-dependent diabetes mellitus (NIDDM). In the present study, we evaluated the clinical effects of some drugs on renal PG metabolism and diabetic nephropathy. Ozagrel, a specific thromboxane synthetase inhibitor, reduced urinary TXB 2 excretion, resulting in the improvement of the decreased urinary 6KF/TXB 2 ratio in NIDDM patients. Urinary albumin excretion was decreased and creatinine clearance (Ccr) was increased during ozagrel administration. The similar beneficial effect was also found in the administration of cilostazol, a phosphodiesterase inhibitor, whereas a stable analogue of PGI 2, beraprost sodium, reduced urinary albumin excretion in relation to the reduction of platelet aggregation rate. In conclusion, the drugs modulating renal and platelet PG S metabolism with direction to an increase in 6KF/TXB 2 ratio and an inhibition against platelet function might be beneficial for the treatment of diabetic nephropathy.

Ketoconazole to prevent acute respiratory distress syndrome in critically ill patients.

Ketoconazole appears to be an effective prophylactic measure in surgical patients at risk of developing ARDS. The beneficial effects may be caused by thromboxane synthetase inhibition because thromboxane B2 concentrations were decreased by ketoconazole in both studies. Two studies were unable to demonstrate a beneficial effect with the selective thromboxane synthetase inhibitor dazoxiben. Both studies consisted of a small number of subjects with already established ARDS, not prophylaxis in patients at risk of ARDS. Although the effects of ketoconazole on mortality in patients at risk of ARDS are conflicting, there may be reduced mortality in patients with sepsis. Several issues must be considered before ketoconazole is used in this setting. First, the studies to date have excluded patients at risk of hepatotoxicity, which is probably wise considering the potential hepatotoxicity with ketoconazole and the unknown benefit/risk ratio in these patients. Also, therapies that reduce gastric acidity should be avoided to ensure bioavailability. If ketoconazole is administered through a jejunostomy tube, it probably should be given with a dilute acid to enhance absorption. Furthermore, ketoconazole is a known inhibitor of the cytochrome P450 system, which results in a number of drug interactions. If ketoconazole is used, the patient's current drug therapy should be reviewed for potential interacting drugs. In light of the current studies, ketoconazole may be considered for surgical patients at risk of developing ARDS (especially patients with sepsis) with the previously noted considerations. Future research should seek to confirm ketoconazole's role for the prevention of ARDS in all critically ill patients. Additional studies also should clarify the role of various inflammatory mediators in the pathophysiology and therapy of ARDS.

P-196 Analysis of pathophysiology after hepatic resection combined with pancreatectomy-long-lasting catabolism following 50% hepatic resection combined with 70% pancreatectomy in rats

Reperfusion of ischemic tissue is responsible for production of metabolites with deleterious local vascular effects. Thromboxane A2, a potent vasoconstrictor and platelet aggregator, has been implicated as a mediator of the “reperfusion injury.” We studied the effect of an experimental thromboxane synthetase inhibitor, OKY-046, on coronary sinus thromboxane levels, ventricular irritability, myocardial contractility, infarct salvage, and histologic features of reperfusion. Sixteen sheep were randomized to OKY-046, 3 mg/kg, or saline vehicle before 3-hour occlusion and subsequent reperfusion of the left anterior descending artery. The OKY group demonstrated less ventricular irritability as measured by incidence of ventricular fibrillation and necessity for countershock to reverse tachyarrhythmias. Coronary sinus thromboxane levels were significantly lower in the OKY group compared with the control group. There is additional evidence to suggest that OKY increases infarct salvage and attenuates histologic features of microcirculatory damage.

The protective effect of thromboxane synthetase inhibitor UK 38485 against bile duct ligation induced liver injury

In order to elucidate the relation between tissue eicosanoids and liver injury due to bile duct obstruction, we have examined the effects of iloprost, a stable analogue of prostaglandin I 2 (PGI 2), and UK 38485 (UK), an inhibitor of thromboxane synthetase, on prostaglandin E 2 (PGE 2) and leukotriene C 4 (LTC 4) in guinea pig liver. 56 male guinea pigs were divided into the following groups: (i) sham operations (SHAM), (ii) bile duct ligated (BDL) group, (iii) guinea pigs given UK (5 μg/kg body wt intraperitoneally 10 min, 8 h and 16 h after bile duct ligation), and (iv) guinea pigs treated with iloprost (ILO) (2 μg/kg body wt intraperitoneally 10 min, 8 h and 16 h after bile duct ligation). Liver damage was assessed by blind quantitation of liver cell necrosis. Bile duct ligation caused an increase in tissue PGE 2-like activity and a decrease LTC 4-like activity. But the most pronounced elevation of PGE 2 was observed in ILO treated group. The LTC 4-like activity level improved significantly in the UK-treated BDL group compared with the BDL only and ILO treated animals. Also, UK was found to be beneficial in preventing the liver cell necrosis due to cholestasis. It is concluded that the ratio of PGE 2 LTC 4 in liver is a valuable marker for cholestatic injury.

Vasoconstrictor mechanism of neuropeptides augmented after endothelial removal in isolated, perfused canine basilar arteries

In order to investigate the functional role of endothelium and vasoeffector mechanism in cerebrovascular responses to neuropeptides, the stainless steel cannula inserting method was applied to examine the responses to intraluminally-applied bradykinin, substance P and vasopressin in isolated and perfused canine basilar arteries. In control vessels with intact endothelium, each neuropeptide induced a monophasic dilation at lower doses, and a biphasic response, i.e., an initial dilation followed by a secondary constriction, at higher doses. The dilation was significantly reduced and the constriction was significantly enhanced, while the dilation to papaverine was not modified by endothelial removal with intraluminal saponin. The same tendency was observed in the responses after extraluminal treatment with oxyhaemoglobin. The monophasic constrictions to prostaglandin F2 alpha and potassium chloride were significantly potentiated by the endothelial removal. The augmented constrictions to the neuropeptides were significantly diminished by indomethacin (a cyclooxygenase inhibitor), OKY-046 (a thromboxane synthetase inhibitor) and nimodipine (a dihydropyridine calcium antagonist), but not by AA-861 (a lipoxygenase inhibitor). These results suggest that the neuropeptide causes an endothelium-dependent dilation and a constriction of smooth muscles, and that the enhanced constriction might be relevant in part with thromboxane A2, linked with calcium influx into smooth muscle cells in cerebral arteries.

Mechanism of Acetylcholine-Induced Constriction Enhanced by Endothelial Removal in Isolated, Perfused Canine Basilar Arteries

We examined the responses to intraluminally applied acetylcholine (ACh) in isolated and perfused canine basilar arteries by the stainless-steel cannula-inserting method. In control vessels with intact endothelium, ACh produced a slight vasodilatation followed by a long-lasting vasoconstriction in the absence of induced tone. Propranolol, a beta-adrenoceptor blocker, had no effect on the response to ACh. After endothelial removal with intraluminal saponin, the constrictor component of the response to ACh was significantly enhanced, and the constrictions to prostaglandin F2 alpha (PGF2 alpha) and potassium chloride (KCl) were significantly potentiated. After exposure to extraluminal oxyhemoglobin, the ACh-induced constriction was significantly augmented, whereas the dilator component of the response to calcium ionophore A23187 was significantly attenuated. The enhanced constriction to ACh after endothelial removal was significantly blocked by OKY-046 (a thromboxane synthetase inhibitor) and nimodipine (a dihydropyridine calcium antagonist), but was slightly though not significantly suppressed by AA-861 (a lipoxygenase inhibitor). The response to PGF2 alpha was not altered by OKY-046 or AA-861. These results suggest that the potentiation of ACh-induced constriction after endothelial removal may be mediated in part by thromboxane A2 (TXA2), linked with extracellular calcium entry in smooth muscle cells (SMC). This mechanism might be involved in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH).

Pulmonary Thromboxane Release Following Intestinal Reperfusion

Microvascular dysfunction is a prominent feature of the lung injury associated with intestinal reperfusion (IR). This study examines the hypothesis that IR induces pulmonary thromboxane A 2 (TxA 2) release, which contributes to pulmonary microvascular dysfunction. Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of reperfusion (IR). Sham-operated animals served as controls (SHAM). Following IR or SHAM, the lungs were perfused in vitro with a modified Krebs buffer and ventilated with room air. Eicosanoid levels within the pulmonary venous effluent and bronchoalveolar lavage (BAL) fluid were determined (TxB 2, 6-keto-PGF 1a, and PGE 2). Pulmonary artery pressure (PAP) was measured continuously and expressed as change from baseline in mm Hg. The dominant eicosanoid generated by the lungs in response to IR was TxB 2. TxB 2 levels in the pulmonary venous effluent of IR lungs were 75% greater than controls ( P = 0.005). Similarly, TxB 2 levels in the BAL were more than 2.5 times controls ( P = 0.001). The change in PAP of lungs from IR animals was significantly greater than that of controls (4.1 ± 1.5 vs 0.3 ± 0.54 mm Hg, IR vs SHAM, P = 0.01). The increased PAP associated with IR lungs was prevented by cyclooxygenase inhibition with indomethacin (-1.28 ± 0.29 mm Hg, P < 0.05) and thromboxane synthetase inhibition with imidazole (-1.75 ± 0.95 mm Hg, P < 0.05). These experiments support the hypothesis that IR up-regulates endogenous pulmonary TxA 2 release. Furthermore, the local release of TxA 2 by the lung may contribute to the microvascular dysfunction characteristic of IR-induced lung injury.

Effect of phorbol myristate acetate-induced lung injury on airway blood flow

The effects of phorbol myristate acetate (PMA) induced lung injury on the pulmonary and systemic blood flow contributions to the trachea and main bronchi (upper airways) were assessed in anesthetized dogs by injecting 15 μm radiolabeled microspheres into the right and left heart, respectively. Upper airway blood flow was studied in lungs given the following treatments: (1) PMA; (2) PMA in lungs pretreated with the thromboxane synthetase inhibitor OKY-046, and (3) PMA in lungs pretreated with the antioxidant catalase. After microsphere injections, the tracheal cartilage, tracheal muscle-mucosa, and main bronchi were excised. The results of this study indicate that under normal conditions, tracheal mucosa [33–52 ml·min −·(100 g) −1] and tracheal cartilage [18–27 ml·min −1·(100 g) −1] blood flow is primarily systemic while both the systemic [12–18 ml·min −1·(100 g) −1] and pulmonary [6–12 ml·min −1·(100 g) −1] circulations contribute substantial amounts of blood flow to the main bronchi. PMA significantly decreased the systemic blood flow contribution to the tracheal cartilage and muscle-mucosa, and both the systemic and pulmonary blood flow contributions to the main bronchi to less than 50% of control values, an effect that was inhibited by catalase, but not by OKY-046. These results suggest that the effect of PMA-induced lung injury on the pulmonary and systemic blood flow contributions to the upper airways is at least partially mediated by oxygen radical production, probably hydrogen peroxide (H 2O 2), but not by the production of the arachidonic acid metabolite thromboxane.

Pharmacokinetic and Pharmacodynamic Modeling of a Novel Thromboxane Synthetase Inhibitor, DP-1904, in Human.

Pharmacokinetic and pharmacodynamic (PK/PD) analyses for a novel thromboxane synthetase inhibitor, DP-1904, were performed to predict its PK/PD profiles in human after single and repeated oral administration. The pharmacodynamics of DP-1904 was characterized by serum levels of thromboxane B2(TXB2), a pharmacological marker for thromboxane synthetase inhibition. Based on a quantitative relationship between the plasma DP-1904 and serum TXB2 concentrations after single oral dosage, IC50 and Emax values were estimated to be 0.54 ng/ml and 94%, respectively. An integrated, simple PK/PD model was developed to simulate the changes in serum TXB2 levels after single oral administration of DP-1904 at various doses, and the simulation curves corresponded well with the observed data. The PK/PD model was then used to predict a pharmacological profile of DP-1904 after repeated oral doses in human; the predicted curves were in relatively good agreement with the observed data. Thus, it is suggested that our PK/PD model is feasible and practical for developing optimum dosing regimens of DP-1904 in clinical situations.

Role of thromboxane A 2 synthetase inhibitors in the treatment of patients with bronchial asthma

Asthma results from complex interactions among inflammatory cells, mediators, and the cells and tissues resident in the airways and is characterized by airway obstruction, airway inflammation, and airway hyperresponsiveness. Treatment of asthma should address not only the airway obstruction but also the chronic inflammation that may lead to hyperresponsiveness. In Japan, where the death rate from asthma has not increased despite increasing numbers of patients, treatment of bronchial asthma relies on the use of oral prophylactic antiasthma drugs, such as thromboxane synthetase inhibitors. Thromboxanes may facilitate the effect of acetylcholine on the airways and may be involved in hyperresponsiveness. Experiments using animal models have shown that thromboxane synthetase inhibitors have prevented increased airway reactivity after exposure to allergens and irritants. Double-blind clinical trials have shown that treatment with the thromboxane A 2 synthetase inhibitor ozagrel hydrochloride significantly reduced the need for concomitant steroid therapy, compared with treatment with azelastine hydrochloride. This review discusses the role of thromboxane A 2 synthetase inhibitors in the treatment of patients with bronchial asthma.

Sodium orthovanadate increases phospholipase A2 activity in isolated rat fat pads: a role of phospholipase A2 in the vanadate-stimulated release of lipoprotein lipase activity.

Phospholipase (PL) A2 activity prepared from isolated rat fat pads incubated with sodium orthovanadate (vanadate) was increased in a time- and dose-dependent manner. The increasing effect of vanadate was reduced in the presence of tyrosine kinase inhibitors. Under the inhibition of protein synthesis by cycloheximide, vanadate still showed a full effect on the increase in PL A2 activity. Various PL A2 inhibitors, such as manoalide, quinacrine and p-bromophenacyl bromide, suppressed the stimulatory release of lipoprotein lipase (LPL) activity from the fat pads by vanadate. Moreover, the vanadate-stimulated release of LPL activity was decreased by the cyclooxygenase and thromboxane synthetase inhibitors, and a thromboxane A2 receptor antagonist, but was never suppressed by a lipooxygenase inhibitor. The stimulatory release of LPL activity by vanadate was also decreased in the presence of tyrosine kinase inhibitors. These results suggest that vanadate increases PL A2 activity, and the increase in PL A2 activity is partly involved in the vanadate-stimulated release of LPL activity with an association to the membrane tyrosine kinase.

Resolution of enantiomers of a novel thromboxane synthetase inhibitor by HPLC on a chiral stationary phase.

Resolution of enantiomers of a novel thromboxane synthetase inhibitor by HPLC on a chiral stationary phase.

Possible role of thromboxane A2 in hyperresponsiveness of isolated rat lung tissue in a Sephadex-induced eosinophilia model.

Antigen-stimulated contraction and release of chemical mediators were examined in saline- or Sephadex-treated rat lung parenchymal strips. Sephadex treatment caused eosinophilia in the blood and the lung tissue. Antigen challenge of the isolated parenchymal strips in Sephadex-treated rat was followed by passive sensitization, resulted in an augmented contraction and elevated releases of thromboxane (TX) B2 and peptide-leukotrienes (p-LTs) in bath fluid compared with those of saline-treated control. Although 5-hydroxytryptamine (5-HT) and histamine were significantly released after antigen challenge, the levels were not different between saline- and Sephadex-treated groups. DP-1904, a selective thromboxane synthetase inhibitor, and methysergide but not atropine significantly reduced the augmented contraction and inhibited the elevated TXB2 release in the Sephadex-treated group. Similar increased contraction and the elevated TXB2 release above were observed when Sephadex-treated rat lung strips were stimulated by exogenous 5-HT and LTD4. These augmented contractions were closely correlated with the increase in TXB2 level (r = 0.83; p < 0.01). In addition, contraction to U-46619, a thromboxane mimetic, was significantly greater in Sephadex-treated rat lung strips. Our results indicate that the ability of Sephadex-treated rat lung tissue to synthesize newly generated mediators such as TXA2 and p-LTs is increased, and the spasmogenic susceptibility of the lung tissue to TXA2 itself is modified by Sephadex treatment, suggesting these are due to the augmented contraction in an established hyperresponsiveness state induced by Sephadex.

Inhibitory Effect of a Selective Thromboxane Synthetase Inhibitor, OKY-046, on Acetaldehyde-Induced Bronchoconstriction in Asthmatic Patients

We recently reported that inhaled acetaldehyde causes bronchoconstriction indirectly via histamine release in patients with asthma. The purpose of this study was to investigate a role of thromboxane A2 in acetaldehyde-induced bronchoconstriction in asthmatic airways. We investigated the bronchial response to inhalation of ascending doses (5, 10, 20, and 40 mg/ml) of acetaldehyde in nine asthmatic subjects who were treated with placebo or OKY-046, a selective thromboxane A2 synthetase inhibitor, of 200 mg twice a day for 3 days, and 200 mg on the fourth day (test day) in a double-blind, randomized, placebo-controlled, crossover fashion. Percentage decreases in FEV1 caused by 20 and 40 mg/ml of acetaldehyde inhalation were significantly (p < 0.05 and p < 0.01, respectively) prevented by the pretreatment with OKY-046. Geometric mean value (geometric standard error of the mean) of acetaldehyde concentration producing a 20 percent fall in FEV1 (PC20-Ac-CHO) was significantly (p < 0.01) greater with the OKY-046 pretreatment (72.2 [1.1] mg/ml) than with the placebo pretreatment (19.8 [1.2] mg/ml). We conclude that thromboxane A2 is one of contributors to acetaldehyde-induced bronchoconstriction in asthmatic subjects. It suggests that thromboxane A2 may play an important role in endogenous histamine-induced bronchoconstriction caused by acetaldehyde in asthmatic airways. We believe that this is a first report on the interaction between endogenous histamine and thromboxane A2 in asthmatic subjects.