2-methyl-3-(4-(3-pyridinylmethyl)phenyl)-2-propenoic-acid and Thrombosis

Thromboxane has characteristics that signify potential importance in cardiovascular disease states. In models developed for studying thrombotic sudden death, thromboxane appears to be an important mediator. Thus, in arachidonic acid-induced sudden death, agents that either inhibit thromboxane generation or block thromboxane receptor activation prevent the occurrence of thrombotic death. Thromboxane mimetics are also useful in modeling sudden death; when injected i.v., these compounds elicit effects similar to those obtained with arachidonic acid. In this case, however, pretreatment with cyclooxygenase or thromboxane synthetase inhibitors confers no protection, whereas the thromboxane receptor antagonist retains its efficacy. Other factors that affect susceptibility to experimental sudden death include gender, species, and endocrine status. Thrombotic sudden death models have now been used to test, in vivo, the in vitro antiplatelet aggregatory effect of calcium-channel blockers. The data suggest that dihydropyridine agents such as nifedipine and nisoldipine are protective against thrombosis, whereas verapamil may have little such activity. Furthermore, sudden death induced by a variety of thrombotic challenges is prevented by pretreatment with nifedipine. The thrombotic sudden death models currently employed are useful for the in vivo study of the thrombotic process and for the evaluation of agents with potentially thrombotic or antithrombotic properties.

Topics: Angina Pectoris; Animals; Arachidonic Acid; Arachidonic Acids; Calcium Channel Blockers; Castration; Death; Estrogens; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Glucocorticoids; Humans; Male; Methacrylates; Prostaglandin Endoperoxides, Synthetic; Sex Factors; Testosterone; Thrombosis; Thromboxane A2; Thromboxane B2; Thromboxanes

The pathogenesis of intestinal damage caused by bolus intravenous injection of endotoxin (ETX; 3 mg/kg) was investigated. Administration of ETX to rats induced reddish discoloration suggestive of bleeding, increased hemoglobin amounts, and leakage of plasma protein in the intestine. However, light microscopic examination of the intestine demonstrated blood congestion of the microvessels. Plasma accumulation was partially inhibited by combined pretreatment with a histamine H1 antagonist and a serotonin (5-HT) antagonist. Neither a 5-lipoxygenase inhibitor, a soybean trypsin inhibitor, nor atropine was observed to inhibit plasma accumulation. Both the intestinal leakage of plasma and the accumulation of hemoglobin were completely inhibited by indomethacin, a selective thromboxane A synthetase inhibitor (OKY 1581), and a stable PGI2 analogue (beraprost). Intravital microscopic observation of the microvessels of the small intestinal villi demonstrated microthrombus formation within several minutes after the injection of ETX, and pretreatment with OKY 1581 attenuated the formation of microthrombus. Platelet counts decreased significantly 10 min after ETX administration, and the decrease was not inhibited by pretreatment with either OKY 1581 or beraprost. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were not prolonged. These observations thus suggest that microcirculatory disturbances by platelet thrombus, which are mediated by thromboxane A2 at least in part, play an important role in ETX-induced intestinal damage.

Topics: Animals; Capillary Leak Syndrome; Cyclooxygenase Inhibitors; Endotoxins; Enzyme Inhibitors; Epoprostenol; Escherichia coli; Gastrointestinal Hemorrhage; Indomethacin; Intestine, Small; Male; Methacrylates; Microcirculation; Platelet Activation; Rats; Rats, Sprague-Dawley; Shock, Septic; Specific Pathogen-Free Organisms; Thrombosis; Thromboxane A2; Thromboxane-A Synthase

Topics: Acrylates; Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Biological Assay; Blood Platelets; Cerebral Infarction; Haplorhini; Kinetics; Methacrylates; Muscle Contraction; Oxidoreductases; Platelet Aggregation; Rabbits; Rats; Thrombosis; Thromboxane A2; Thromboxane-A Synthase

To elucidate the role of thromboxane A2 in the development of endotoxin shock following administration of endotoxin, the effects of three thromboxane A2 synthetase inhibitors, (E)-3-(4-(1-imidazolyl)phenyl)-2-propenoic acid hydrochloride monohydrate (OKY-046), sodium (E)-3-(4-(3-pyridylmethyl)phenyl)-2-methylacrylate (OKY-1581) and imidazole were examined. Intravenous administration of E. Coli endotoxin (3 mg/kg) produced shock and all rats died within ten hours. Pretreatment with thromboxane A2 synthetase inhibitors markedly improved the survival rates. The untreated endotoxin shock group showed marked increase in thromboxane B2 levels in the venous blood, while no such changes were seen in the pretreated groups. There were no statistically significant differences in 6-keto prostaglandin F1 alpha levels in the venous blood. In the untreated shock group, microthrombi were observed in 64% of the glomeruli in the kidneys two hours after endotoxin injection. In the groups pretreated with OKY-046, OKY-1581 and imidazole, microthrombi were seen only in 22, 19 and 24%, respectively. Thus, thromboxane A2 plays an important role in the development of endotoxin shock and thromboxane A2 synthetase inhibitors, in particular OKY-046 and -1581, are prophylactic.

Topics: Animals; Fibrinogen; Glucuronidase; Kidney; Male; Methacrylates; Oxidoreductases; Platelet Count; Rats; Rats, Inbred Strains; Shock, Septic; Thrombosis; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes