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

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

Topics: Adult; Angina, Unstable; Anticoagulants; Coronary Disease; Coronary Vessels; Electrocardiography; Female; Humans; Male; Methacrylates; Middle Aged; Myocardial Infarction; Perfusion; Stroke Volume; Thiophenes; Thromboxane A2; Thromboxane B2; Ticlopidine; Tomography, Emission-Computed; Urokinase-Type Plasminogen Activator

OKY-1581, a new thromboxane synthetase inhibitor, was studied in a conscious canine model of coronary thrombosis. After thoracotomy with placement of a left circumflex coronary artery flow probe and implantation of an electrode into the circumflex artery, animals were assigned randomly to the following groups: 0.9% NaCl vehicle control or OKY-1581 1 mg/kg every 4 intravenously for 24 h. During the drug treatment period, a 50 microA anodal current was passed through the circumflex electrode, and venous blood was obtained for platelet aggregation studies. As compared to control animals, the OKY-1581 treated animals developed a greater mean coronary flow at the end of the treatment period, smaller thrombi by wet weight, smaller infarcts, and fewer ventricular arrhythmias. Ex vivo platelet aggregation studies revealed significant inhibition of aggregation to standard aggregating agents for the drug treated group only. OKY-1581 is an effective antithrombotic agent which maintains coronary flow after a thrombogenic stimulus, presumably via blockade of the synthesis of thromboxane by blood platelets.

Topics: Acrylates; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Circulation; Coronary Disease; Dogs; Male; Methacrylates; Oxidoreductases; Platelet Aggregation; Thromboxane-A Synthase

OKY-1581, a new thromboxane synthetase inhibitor, at an infusion rate of 1.5 mg/kg/hr inhibited the ischemia-induced increase in circulating thromboxane B2 in cats. Although OKY-1581 failed to restore the S-T segment of the electrocardiogram toward normal values after the onset of ischemia, it prevented the rise in plasma creatine kinase activity usually observed during myocardial ischemia. In addition, OKY-1581 reduced the loss of myocardial creatine kinase activity in the ischemic region of those cats treated with OKY-1581 indicating a significant cardioprotection. No significant effects of OKY-1581 were observed on heart rate, mean arterial blood pressure or the product of the two, the pressure-rate index. Therefore, this agent does not protect by reducing myocardial oxygen demand. The mechanism of the protective action of OKY-1581 in acute myocardial ischemia appears to be either due to prevention of the constrictor and cytolytic actions of thromboxane A2 or to metabolic and cellular actions of OKY-1581 unrelated to thromboxane synthetase inhibition.

Topics: Acrylates; Animals; Cats; Coronary Disease; Creatine Kinase; Electrocardiography; Heart; Male; Methacrylates; Oxidoreductases; Oxygen Consumption; Thromboxane-A Synthase

Topics: Acrylates; Coronary Disease; Humans; Methacrylates; Oxidoreductases; Platelet Aggregation; Thromboxane-A Synthase

Isolated cat hearts were perfused with blood-free Krebs-Henseleit solution for 165 min. Ischemia was induced by reducing perfusion to 0.02 ml/min/g wet heart weight for 2 h followed by reperfusion at controls flows for 30 min. Hearts perfused with the thromboxane synthetase inhibitor OKY-1581 at concentrations of 5 X 10(-6) M were spared from the increases in circulating thromboxane B2 occurring in untreated ischemic hearts. After reperfusion, cardiac contractile force increased to a higher level in OKY-1581 treated hearts. This was associated with a lower coronary vascular resistance than in untreated ischemic hearts. OKY-1581 treated ischemic hearts exhibited lower perfusate and higher myocardial creatine kinase (CK) activity than untreated ischemic hearts, indicative of preservation of cellular integrity. Also, OKY-1581 treated ischemic hearts showed improved lysosomal stability as evidenced by a lower tissue percent free cathepsin D activity than untreated ischemic hearts. These results are consistent with a significant role of thromboxanes in the propagation of myocardial cellular damage during ischemia.

Topics: Acrylates; Animals; Cathepsin D; Cathepsins; Cats; Coronary Circulation; Coronary Disease; Creatine Kinase; Female; Hemodynamics; In Vitro Techniques; Lysosomes; Male; Methacrylates; Oxidoreductases; Thromboxane-A Synthase; Time Factors

Topics: Acrylates; Animals; Aspirin; Blood Platelets; Coronary Disease; Cyclic AMP; Cyclooxygenase Inhibitors; Dogs; Epoprostenol; Female; Ibuprofen; Indomethacin; Male; Methacrylates; Oxidoreductases; Platelet Aggregation; Prostaglandins; Prostaglandins H; Thromboxane-A Synthase