ozagrel 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

We have previously shown that superoxide anion (O2-) stimulates the release of vasoconstrictor prostanoids and induces a prolonged rise in coronary perfusion pressure (CPP) that persists even after removal of O2-. In this study, we tested the hypothesis that the increased CPP is mediated by activation of TxA2/ PGH2 (TP) receptors and protein kinase C (PKC)-dependent mechanisms. In Langendorff perfused rat hearts, O2- was applied for 15 min and then washed out over a period of 20 min. Application of O2- increased the release of vasoconstrictive (TxA2 and PGF2alpha) and decreased vasodilating (PGI2 and PGE2) prostanoids. Although indomethacin (10 microM), a cyclooxygenase inhibitor, attenuated the rise in CPP during O2- perfusion, the increase was not completely blocked. OKY 046Na (10 microM), a thromboxane synthase inhibitor, had no effect on O2--induced increases in CPP, whereas ONO 3708 (10 microM), a TP receptor antagonist, suppressed this effect. PKC activity was also elevated by more than 50% by O2- perfusion. CPP typically increased throughout the O2- wash-out. This post-O2- vasoconstriction was not inhibited by indomethacin, nitroglycerin or nitrendipine. In contrast, ONO 3708 (10 microM) and two PKC inhibitors, staurosporine (10 nM) and calphostin C (100 nM), completely blocked the rise in CPP, and even elicited vasodilation. PDBu enhanced the post-O2- vasoconstriction. We conclude that O2--induced coronary vasoconstriction is initially mediated by TP receptors, but activation of PKC sustains the response.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Calcium Channel Blockers; Cardiovascular Agents; Coronary Disease; Dinoprost; Enzyme Inhibitors; In Vitro Techniques; Indomethacin; Male; Methacrylates; Naphthalenes; Perfusion; Prostaglandins; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Staurosporine; Superoxides; Thromboxane A2; Thromboxane-A Synthase; Vasoconstrictor Agents

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

Effects of the administration of a thromboxane A2 (TXA2) analogue (STA2), a leukotriene C4 (LTC4), and a leukotriene D4 (LTD4) on regional myocardial blood flow (RMBF) and hemodynamics were studied in anesthetized, open-chest dogs. The blocking ability of a recently synthesized TXA2 selective antagonist, ONO-3708, and a peptidoleukotriene-selective antagonist, ONO-1078, was also investigated. RMBF was measured continuously in three areas: the left anterior descending coronary artery (LAD) area, the circumflex artery (Cx) area, and the area between LAD and Cx. STA2, LTC4, and LTD4 caused a significant dose-dependent reduction of the RMBF in the LAD area. The peak percentage decrease in RMBF followed by a 10 micrograms dose of STA2, 1 micrograms dose of LTC4, and 1 micrograms dose of LTD4 is 38.6% +/- 3.0%, 39.0% +/- 3.1%, and 36.2% +/- 2.4%, respectively. ED50 for the action of LTC4, LTD4, and STA2 on RMBF is 3, 3, and 50 micrograms, respectively. Pretreatment with the newly developed TXA2 antagonist, ONO-3708 (1 micrograms/kg/min for 10 min), completely inhibited the RMBF reduction induced by STA2 (10 micrograms). Pretreatment with the peptidoleukotriene antagonist, ONO-1078 (1 mg), inhibited the RMBF reduction induced by LTC4 or LTD4 (0.3-3 micrograms). Following pretreatment with a 1 mg dose of ONO-1078, the peak percentage decrease of RMBF caused by a 1 micrograms dose of LTC4 and LTD4 was reduced to 21.1% +/- 2.3% and 19.8% +/- 3.1%, respectively. However, the LTC4 (1 micrograms)-induced reduction of the RMBF was not affected by pretreatment with a TXA2 antagonist, ONO-3708, or an inhibitor of the endogenous production of TXA2, OKY-046.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Flow Velocity; Chromones; Coronary Circulation; Coronary Disease; Dogs; Male; Methacrylates; SRS-A; Thromboxane A2; Thromboxane-A Synthase

Reperfusion of ischemic tissue is responsible for production of metabolites with deleterious local vascular effects. Thromboxane A2, a potent vasoconstrictor and platelet aggregator, has been implicated as a mediator of the "reperfusion injury." We studied the effect of an experimental thromboxane synthetase inhibitor, OKY-046, on coronary sinus thromboxane levels, ventricular irritability, myocardial contractility, infarct salvage, and histologic features of reperfusion. Sixteen sheep were randomized to OKY-046, 3 mg/kg, or saline vehicle before 3-hour occlusion and subsequent reperfusion of the left anterior descending artery. The OKY group demonstrated less ventricular irritability as measured by incidence of ventricular fibrillation and necessity for countershock to reverse tachyarrhythmias. Coronary sinus thromboxane levels were significantly lower in the OKY group compared with the control group. There is additional evidence to suggest that OKY increases infarct salvage and attenuates histologic features of microcirculatory damage.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Coronary Circulation; Coronary Disease; Disease Models, Animal; Methacrylates; Microcirculation; Myocardial Contraction; Random Allocation; Sheep; Thromboxane B2; Thromboxane-A Synthase; Ventricular Fibrillation

Topics: Acrylates; Animals; Coronary Disease; Dogs; In Vitro Techniques; Methacrylates; Mitochondria, Heart; Oxygen Consumption; Thromboxane A2; Thromboxane-A Synthase

We studied the levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), platelet aggregability, beta-thromboglobulin and platelet factor 4 in 30 coronary artery disease (CAD) patients and 21 normal subjects during exercise. During treadmill exercise, 13 of 30 CAD patients reported chest pain. We administered a selective thromboxane synthetase inhibitor (OKY-046) for 2 weeks to 10 CAD patients with exercise-induced chest pain and studied its effects. At rest, the plasma TXB2 levels and platelet aggregation were significantly lower in normal subjects than in CAD patients, and there was no difference between CAD patients with and without exercise-induced chest pain. On treadmill testing, plasma TXB2 levels and platelet aggregation increased significantly only in the CAD patients with exercise-induced chest pain. Plasma 6-keto-PGF1 alpha levels in normal subjects were significantly higher than those in CAD patients both at rest and during exercise. After administration of OKY-046, mean exercise time increased significantly from 7.5 to 8.6 min (p less than 0.001). Plasma TXB2 level and platelet aggregation decreased significantly after OKY-046 administration both at rest and during exercise. These results suggest that a marked increase in TXA2, with only a minimal change in PGI2, during exercise may contribute to exercise-induced myocardial ischemia, and that OKY-046 is useful in the treatment of CAD patients.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Angina Pectoris; Coronary Disease; Epoprostenol; Female; Humans; Male; Methacrylates; Physical Exertion; Platelet Aggregation; Thromboxane B2; Thromboxane-A Synthase; Vasoconstriction

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Angina Pectoris; Coronary Disease; Humans; Methacrylates; Oxidoreductases; Physical Exertion; Platelet Aggregation; Prostaglandins; Thromboxane B2; Thromboxane-A Synthase

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Coronary Circulation; Coronary Disease; Dogs; Heart; Indomethacin; Kinetics; Lactates; Lactic Acid; Methacrylates; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes