ozagrel and Myocardial-Infarction

Topics: Angina Pectoris; Aspirin; Coronary Disease; Epoprostenol; Humans; Hypertension; Methacrylates; Myocardial Infarction; Oxidoreductases; Platelet Aggregation; Thromboxane-A Synthase; Thromboxanes; Urokinase-Type Plasminogen Activator

Remote hind limb preconditioning (RIPC) is a protective strategy in which short episodes of ischemia and reperfusion in a remote organ (hind limb) protects the target organ (heart) against sustained ischemic reperfusion injury. The present study was designed to investigate the possible role of thromboxane A2 in RIPC-induced cardioprotection in rats. Remote hind limb preconditioning was performed by four episodes of 5 min of inflation and 5 min of deflation of pressure cuff. Occlusion of the hind limb with blood pressure cuff is most feasible, non-invasive, clinically relevant, and safe method for inducing RIPC. Isolated rat hearts were perfused on Langendorff apparatus and were subjected to global ischemia for 30 min followed by 120-min reperfusion. The levels of lactate dehydrogenase (LDH) and creatine kinase (CK) were measured in coronary effluent to assess the degree of myocardial injury. The extent of myocardial infarct size along with the functional parameters including left ventricular developed pressure (LVDP), dp/dtmax, and dp/dtmin were also measured. Ozagrel (thromboxane synthase inhibitor) and seratrodast (thromboxane A2 receptor antagonist) were employed as pharmacological modulators of thromboxane A2. Remote hind limb preconditioning significantly attenuated ischemia/reperfusion-induced myocardial injury and produced cardioprotective effects. However, administration of ozagrel and seratrodast completely abolished the cardioprotective effects of RIPC suggesting the key role of thromboxane A2 in RIPC-induced cardioprotection. It may be concluded that brief episodes of preconditioning ischemia and reperfusion activates the thromboxane synthase enzyme that produces thromboxane A2, which may elicit cardioprotection either involving humoral or neurogenic pathway.

Topics: Animals; Benzoquinones; Creatine Kinase; Female; Heart; Heptanoic Acids; Hindlimb; Ischemic Preconditioning; L-Lactate Dehydrogenase; Male; Methacrylates; Myocardial Infarction; Myocardial Reperfusion Injury; Rats, Wistar; Thromboxane A2; Thromboxane-A Synthase

Platelets are suggested to exacerbate ischemia-induced myocardial injury, which has led to the study of various antiplatelet therapies including thromboxane synthetase inhibitors (TXSI). Two such agents, benzylimidazole and OKY-046, reduce infarct size commensurate with a diminution in serum thromboxane B2 formation in anesthetized dogs subjected to 90 minutes of coronary artery occlusion followed by 5 hours of reperfusion. In contrast, platelet depletion with specific antiserum does not reduce infarct size but prevents the cardioprotection afforded by the TXSI. Platelet-derived prostaglandin endoperoxides (PGG2 and PGH2), which cannot be converted to thromboxane A2 in the inhibited platelet, can be transformed to PGE2 and PGD2 in plasma and to PGI2 by the blood vessel wall. These prostaglandins are considered "cardioprotective." Consequently, a low dose of aspirin (3-5 mg/kg) given 24 hours before coronary occlusion was used to selectively block the platelet cyclooxygenase enzyme. Aspirin, by itself, does not reduce infarct size, but it suppresses the myocardial salvage induced by OKY-046. Thus, TXSI reduce infarct size by platelet-dependent, aspirin-sensitive mechanism that depends on the redirection of platelet-derived PGG2 and PGH2 to protective metabolites, rather than inhibition of thromboxane A2 per se. Moreover, myocardial salvage induced by the TXSI is accompanied by a reduction in neutrophil accumulation in the myocardium, as indicated by the levels of the neutrophil-specific myeloperoxidase enzyme. Platelet depletion or pretreatment with aspirin prevents the TXSI-induced suppression of neutrophil accumulation. Consequently, it is proposed that the prostaglandin-mediated protective effects of TXSI can be resolved, at least in part, in terms of a braking action on neutrophil activation to prevent leukocyte-dependent tissue injury.

Topics: Acrylates; Animals; Aspirin; Biomechanical Phenomena; Blood Platelets; Coronary Disease; Cyclooxygenase Inhibitors; Dogs; Imidazoles; Methacrylates; Myocardial Infarction; Thromboxane-A Synthase

An experimental model of acute myocardial infarction is presented. Intracoronary thrombus was precipitated by a mock ruptured atheromatous plaque, which is a cholesterol-collagen mixture, protruding into the stenosed left anterior descending coronary artery. Twenty-five dogs, divided into two groups, were studied: a control group of 15 dogs and a treated group of 10 dogs. Intracoronary thrombus was precipitated by the mock atheromatous plaque in 13 of 15 control animals. Myocardial infarction was induced in 10 and sudden death in two. Coronary blood flow decreased gradually or cyclically to end in myocardial infarction. The model was utilized to investigate the effects of a thromboxane synthetase inhibitor, OKY-046, on 10 additional animals. OKY-046 could significantly decrease the incidence of occlusive thrombus formation and myocardial infarction when administered intravenously during coronary blood flow reduction (3 of 10 in the treated group vs 12 of 15 in the control group, p less than 0.02). Thromboxane B2 was significantly elevated in the coronary venous blood during reduction of the coronary blood flow, while thromboxane B2 was reduced and 6-ketoprostaglandin F1 alpha increased during OKY-046 administration. The reduction in thromboxane A2 production associated with increased prostacyclin appeared to be the major mechanism of the interruption of the thrombus formation by OKY-046.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Coronary Thrombosis; Dogs; Epoprostenol; Female; Male; Methacrylates; Myocardial Infarction; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Topics: Acrylates; Animals; Catecholamines; Dogs; Drug Evaluation, Preclinical; Epoprostenol; Methacrylates; Myocardial Infarction; Myocardium; Oxidoreductases; Prostanoic Acids; Thromboxane-A Synthase

Topics: Acrylates; Adult; Angina Pectoris; Female; Humans; Male; Methacrylates; Middle Aged; Myocardial Infarction; Oxidoreductases; Physical Exertion; Platelet Aggregation; Reference Values; Thromboxane B2; Thromboxane-A Synthase