Beneficial effects of BAY u3405, a novel thromboxane A2 receptor antagonist, in splanchnic artery occlusion shock.
Splanchnic artery occlusion shock was induced in male anaesthetized rats by clamping the splanchnic artery for 45 min. The arteries were then released and survival rate, mean survival time, mean arterial blood pressure, plasma levels of thromboxane B2 and 6-keto-PGF1 alpha, macrophage phagocytosis activity and plasma levels of myocardial depressant factor were evaluated. In addition, the neutrophilic infiltrate was quantified in the ileum and lung using a myeloperoxidase (MPO) assay. Sham splanchnic-artery-occlusion-shocked rats were used as controls. Splanchnic-artery-occlusion-shocked rats died within 93 +/- 7 min, while all sham-shocked animals survived more than 3 h. Splanchnic artery occlusion shock caused changes in mean arterial blood pressure, significantly increased the plasma levels of thromboxane B2 (7.5 +/- 1.3 ng/ml; p < 0.001 vs. sham), 6-keto-PGF1 alpha (8.9 +/- 1.7 ng/ml; p < 0.001 vs. sham) and myocardial depressant factor (114 +/- 11 U/ml), and reduced macrophage phagocytosis. Furthermore, MPO activity was significantly elevated (0.12 +/- 0.03 x 10(-3) and 1.8 +/- 0.5 x 10(-3) U/g protein in the ileum and lung, respectively) 70 min after starting reperfusion. Administration of BAY u3405, a novel thromboxane A2 receptor antagonist (30 mg/kg i.v., 30 min before occlusion), significantly increased survival time (187 +/- 3.7 min) and survival rate, improved mean arterial blood pressure, reduced the plasma levels of myocardial depressant factor (54 +/- 3 U/ml), partially restored macrophage phagocytosis and lowered MPO activity in both the ileum and the lung. Our data are consistent with an involvement of thromboxane A2 in splanchnic artery occlusion shock and suggest that BAY u3405 might be of benefit in low-flow states such as circulatory shock.
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Institute of Pharmacology, School of Medicine, University of Messina, Italy.
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D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D001794:Blood Pressure / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008264:Macrophages / Q000502:physiology; D008297:Male; D009201:Myocardial Depressant Factor / Q000097:blood; D009195:Peroxidase / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012769:Shock / Q000188:drug therapy* / Q000503:physiopathology; D013152:Splanchnic Circulation / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D015996:Survival Rate; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D013929:Thromboxane B2 / Q000097:blood
D002227:Carbazoles; D009201:Myocardial Depressant Factor; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D009195:Peroxidase; C063119:ramatroban