thromboxane-a2 and flunixin-meglumine

Endotoxin has previously been shown to induce platelet aggregation in equine heparinised whole blood. This study aimed to determine whether platelet-activating factor or products of cyclo-oxygenase metabolism (thromboxane A2 or prostaglandins) were important in mediating the response of platelets to endotoxin. The effects of the following drugs on endotoxin-induced aggregation were investigated: aspirin, flunixin meglumine and carprofen (non-steroidal anti-inflammatory drugs); CV-3988 and WEB2086 (platelet-activating factor receptor antagonists); quinacrine (phospholipase A2 inhibitor). The effects of quinacrine on platelet aggregation in citrated platelet-rich plasma induced by ADP and platelet-activating factor were also investigated. CV-3988 and WEB2086 caused a concentration-dependent inhibition of endotoxin-induced aggregation. The non-steroidal anti-inflammatories were without effect except flunixin meglumine which produced a small inhibition of endotoxin-induced aggregation. Quinacrine had a similar effect to the platelet-activating factor antagonists, but also non-competitively inhibited platelet aggregation in citrated platelet-rich plasma. It is concluded that platelet-activating factor is a critical mediator of endotoxin-induced platelet aggregation in the horse, but that products of cyclo-oxygenase metabolism are not of importance.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Azepines; Carbazoles; Clonixin; Endotoxins; Heparin; Horses; In Vitro Techniques; Phospholipases A; Phospholipases A2; Phospholipid Ethers; Platelet Activating Factor; Platelet Aggregation; Platelet Aggregation Inhibitors; Quinacrine; Thromboxane A2; Triazoles

Shock was induced in four groups of anesthetized ponies with an intravenous injection of Escherichia coli endotoxin [125 micrograms/kg]. Five minutes after endotoxin injection, the ponies were given no treatment (group A), flunixin meglumine (FM:1.1 mg/kg) (group B), dexamethasone (2 mg/kg) (group C), or prednisolone (10 mg/kg) (group D). Additionally, FM was given every 3 hours, and the steroids were given at 3, 9, and 24 hours following endotoxin. Hemodynamic measurements were made during the 4-hour anesthetic period. Blood samples were collected for the analysis of prostaglandins, blood chemicals, and enzymes until death. Microspheres labeled with one of four radionuclides were used to determine regional blood flow at 0, 0.1, 1, and 2 hours after endotoxin was given. Plasma levels of both thromboxane and prostaglandin I2 increased from less than 1 ng/ml to between 3 and 5 ng/ml following the injection of endotoxin. The elevated thromboxane corresponded with high pulmonary arterial pressure [between 35 and 55 mm Hg] and low mean systemic arterial pressure (between 40 and 65 mm Hg) during the first 5-10 minutes following endotoxin. Increased concentrations of prostaglandin I2 were temporally related to systemic arterial hypotension, which occurred 1-2 hours following endotoxin in all groups except group B. The rise of prostaglandin I2 and hypotension were not observed in the flunixin meglumine-treated ponies. Dexamethasone was less effective, and prednisolone was ineffective in preventing the synthesis of prostaglandin I2 and the accompanying hemodynamic changes that occurred during the first 2 hours following endotoxin. This is probably due to the fact that steroids require a longer period of time before prostaglandin synthesis is reduced. Although not statistically significant, increased survival trends were observed in ponies treated with flunixin meglumine.

Topics: Animals; Clonixin; Dexamethasone; Endotoxins; Epoprostenol; Escherichia coli; Female; Hemodynamics; Horses; Male; Nicotinic Acids; Prednisolone; Shock, Septic; Thromboxane A2

The efficacy of three agents which alter the metabolism of arachidonic acid was investigated in normal, conscious horses. A dose response evaluation was made of flunixin meglumine and phenylbutazone, two cyclo-oxygenase inhibitors, and of a selective thromboxane synthetase inhibitor, UK-38,485. Radioimmunoassay of thromboxane B2 (TxB2) and 6-keto prostaglandin F1 alpha (PGF1 alpha) was used to assess the concentrations of thromboxane A2 (TxA2) and prostacyclin (PGI2) respectively, in serum. Flunixin was the most potent inhibitor of serum TxB2 and 6-keto PGF1 alpha production. UK-38,485 also decreased serum TxB2 generation while significantly increasing serum 6-keto PGF1 alpha levels, thus confirming its selectivity as a thromboxane synthetase inhibitor.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Clonixin; Epoprostenol; Horses; Imidazoles; Male; Nicotinic Acids; Orchiectomy; Phenylbutazone; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

This study had 2 objectives: (i) to correlate plasma thromboxane and prostaglandin I2 (epoprostenol) concentrations with hemodynamic changes occurring in equine endotoxin shock, and (ii) to determine the effects of flunixin meglumine on plasma concentrations of these prostaglandins relative to hemodynamic changes. Shock was induced in 2 groups, each of 4 anesthetized ponies, and in a 3rd group of 2 ponies. Group A ponies were given endotoxin only (and were not treated), and group B ponies were given endotoxin and then treated with flunixin meglumine. Group C ponies were treated with flunixin meglumine 5 minutes before they were fiven endotoxin. Arterial, pulmonary arterial, and central venous pressures were measured and blood samples were collected at 0, 0.1, 0.25, 0.5, 1, 1, 3, and 4 hours after ponies were given the endotoxin. The plasma thromboxane and prostaglandin I2 concentrations were increased in equine endotoxic shock. Increased thromboxane concentration was associated with the high pulmonary arterial and central venous pressures and low arterial blood pressure in the minutes immediately after the ponies were given endotoxin. The increased prostaglandin I2 concentration was associated with systemic hypotension at 1 to 2 hours after endotoxin. Treatment of ponies with flunixin meglumine after endotoxin was given (group B) prevented the prostaglandin I2 rise and the associated hypotension. Treatment with fluixin meglumine before endotoxin was given prevented the increase of the plasma thromboxane and prostaglandin I2 values, along with the associated hemodynamic changes.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clonixin; Epoprostenol; Escherichia coli; Female; Hemodynamics; Horse Diseases; Horses; Male; Primates; Prostaglandin Antagonists; Prostaglandins; Rabbits; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxanes