sq-29548 and Myocardial-Infarction

The effects of thromboxane A2 (TXA2)/prostaglandin endoperoxide receptor blockade on myocardial infarct size and cardiac dynamics were determined in a canine model of 24 h acute myocardial infarction. Anesthetized open-chest dogs were subjected to left anterior descending (LAD) coronary artery occlusion. Twenty minutes post-occlusion the dogs were given i.v. saline (0.9% NaCl solution) (n = 12) or the TXA2 receptor antagonist SQ 29548 (0.2 mg/kg i.v. loading dose +0.2 mg/kg/h i.v. for 4 h) (n = 10). SQ 29548 treatment resulted in a significant (P < 0.01) reduction in infarct size. Heart rate (HR) and systolic blood pressure (SAP) were not markedly affected by the drug. The sharp rise in the left ventricular end diastolic pressure (LVEDP) in the saline-treated animals was significantly lowered by SQ 29548 treatment and the correction of this variable was maintained till 24 h post-occlusion. The lowered maximal rate of rise of left ventricular pressure (LVdP/dt max) in the saline-treated animals was corrected albeit non-significantly by the drug treatment. Thus, SQ 29548 treatment resulted in a significant salvage of myocardial tissue and marked alterations in left ventricular dynamics. The study suggests a deleterious role for thromboxane A2 in ischemia; indicating that TXA2 blockade may have potential as a mode of therapy for ischemic heart disease.

Topics: Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Fatty Acids, Unsaturated; Female; Heart Rate; Hemodynamics; Hydrazines; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Necrosis; Receptors, Thromboxane; Thromboxane A2

The aim of this study was to assess whether prostaglandin endoperoxides, which continue to be formed in the setting of thromboxane A2 synthase inhibition, might influence the fate of ischemic myocardium in a model of coronary occlusion and reperfusion.. It was recently demonstrated that thromboxane A2 synthase inhibitors reduce ischemic myocardial injury through a redirection of prostaglandin (PG) endoperoxides toward the synthesis of "cardioprotective" prostaglandins, such as PGI2, PGE2 and PGD2. However, part of these prostaglandin endoperoxides may also stimulate a receptor, shared with thromboxane A2, mediating platelet aggregation and vasoconstriction.. New Zealand White rabbits were subjected to 30 min of coronary occlusion, followed by 5.5 h of reperfusion. Fifteen minutes before reperfusion, the animals were randomized to receive 1) saline solution (control animals, n = 8); 2) SQ 29548, a potent and selective thromboxane A2/PGH2 receptor antagonist (n = 8); 3) dazoxiben, a selective thromboxane A2 synthase inhibitor (n = 8); 4) R 68070 (Ridogrel), a drug with dual thromboxane A2 synthase-inhibiting and thromboxane A2/PGH2 receptor-blocking properties (n = 8); or 5) aspirin + R 68070 (n = 8).. Dazoxiben and R 68070, but not SQ 29548, significantly reduced thromboxane B2 formation and increased plasma levels of 6-keto-PGF1 alpha, PGE2 and PGF2 alpha. Ex vivo platelet aggregation induced by U46619 (a thromboxane A2 mimetic) was inhibited by SQ 29548 and R 68070 but not by dazoxiben. In control animals, infarct size determined at the end of the experiment by triphenyltetrazolium chloride staining averaged 57.7 +/- 3.2% of the area at risk of infarction. The administration of SQ 29548 did not significantly reduce infarct size compared with that in control animals, whereas dazoxiben and R 68070 significantly reduced infarct size to 36.7 +/- 2.8% and 16.6 +/- 3.6% of area at risk of infarction, respectively (p < 0.001 vs. control values). In rabbits treated with R 68070, infarct size was also significantly smaller than that of dazoxiben-treated rabbits (p < 0.01). This protective effect of R 68070 was completely abolished when the drug was administered with aspirin, infarct size in this group averaging 59.7 +/- 1.6% (p = NS vs. control values). No differences in regional myocardial blood flow, systemic blood pressure, heart rate or extent of area at risk were observed among groups.. Thus, prostaglandin endoperoxides play an important role in modulating the cardioprotective effects of thromboxane A2 synthase inhibitors. The simultaneous inhibition of thromboxane A2 synthase and blockade of thromboxane A2/PGH2 receptors by R 68070 identify a pharmacologic interaction of potential therapeutic importance.

Topics: Animals; Aspirin; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Female; Hydrazines; Imidazoles; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Pentanoic Acids; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Pyridines; Rabbits; Receptors, Thromboxane; Thromboxane-A Synthase

Since thromboxane A2 (TXA2) release may relate to the extension of myocardial injury following coronary ligation, the authors examined the effects of pretreatment with a selective TXA2 synthetase inhibitor U-63,557A, or a TXA2 receptor antagonist SQ-29,548, on myocardial infarct size forty-eight hours following left coronary ligation in rats. Myocardial infarct size (as percent of left ventricle, LV) was decreased from 44 +/- 3% in saline-treated control animals to 34 +/- 4% (P less than 0.05) in U-63,557A-treated animals and to 32 +/- 4% (P less than 0.05) in SQ-29,548 treated animals (U-63,557A-treated vs SQ-29,548-treated, P = NS). LV creatine kinase (CK) was 5.08 +/- 0.42 IU/mg protein in noninfarcted untreated rats and 1.79 +/- 0.21 IU/mg protein in saline-treated infarcted rats. LV CK was 2.86 +/- 0.40 IU/mg protein in U-63,557A-treated rats and 3.11 +/- 0.51 IU/mg protein in SQ-29,548-treated infarcted rats (both P less than 0.05 compared with saline-treated rats). The beneficial effects of U-63,557A and of SQ-29,548 were not accompanied by reduction in indices of myocardial oxygen demand (heart rate and arterial pressure). However, neutrophil accumulation in the infarcted myocardium was markedly decreased by U-63,557A and SQ-29,548 pretreatment. Myocardial myeloperoxidase activity, a specific marker of neutrophil infiltration, was also decreased (P less than 0.02) in U-63,557A- and SQ-29,548-treated animals (0.09 +/- 0.03 and 0.07 +/- 0.02 units/100 mg, respectively) compared with saline-treated infarcted rats (0.19 +/- 0.04 units/100 mg). In vitro incubation of U-63,557A and SQ-29,548 caused a significant and similar reduction in f-MLP-induced neutrophil chemotaxis, and U-63,557A increased prostacyclin formation in whole blood. These data suggest that reduction in the extent of myocardial injury by TXA2 synthetase or receptor inhibitors may, in part, relate to a decrease in neutrophil accumulation in the infarcted tissue. In spite of differences in mechanisms of action of U-63,557A and SQ-29,548, both agents exert a similar protective effect on the extent of myocardial injury following coronary ligation. Reduction in neutrophil accumulation in the infarcted zone, as well as in f-MLP-directed chemotaxis in vitro, suggests that TXA2 inhibition may modulate neutrophil migration.

Topics: Animals; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Chemotaxis, Leukocyte; Creatine Kinase; Epoprostenol; Fatty Acids, Unsaturated; Hydrazines; Male; Myocardial Infarction; Myocardium; Neutrophils; Peroxidase; Platelet Aggregation; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

The effect of thromboxane A2/prostaglandin endoperoxide receptor blockade on infarct size following myocardial ischemia plus reperfusion was determined in dogs. In anesthetized dogs SQ 29,548 (0.2 mg/kg/h) caused a 1,000-fold shift in the dose flow-response curve of renal and mesenteric beds to U-46619, indicating potent receptor blockade. The vasoconstrictor response of the left circumflex coronary artery (LCX) to U-46619 was completely inhibited by SQ 29,548. Three additional groups of anesthetized dogs were subjected to LCX occlusion and 10 min later were given (a) SQ 29,548 (0.2 mg/kg loading dose + 0.2 mg/kg/h infusion intravenously, i.v., n = 7), a thromboxane A2/prostaglandin endoperoxide receptor antagonist; (b) vehicle (n = 7); and (c) SQ 28,585 (0.2 mg/kg loading dose + 0.2 mg/kg/h infusion i.v., n = 3), an inactive compound structurally related to SQ 29,548. After 90 min of occlusion, the LCX was reperfused for 5 h. The area at risk and infarct size were then determined. The cardiac area at risk was similar in size for all groups. Infarct size as a percentage of the total area at risk was large, 79 +/- 2% in vehicle controls, but this was markedly reduced to 45 +/- 8% with SQ 29,548 treatment. SQ 28,585 did not alter infarct size as compared with vehicle controls. Area at risk and infarct size were highly correlated (r = 0.95) in vehicle-treated animals. None of the drug treatments resulted in a significantly altered hemodynamic status. Thus, blockade of thromboxane A2/prostaglandin endoperoxide receptors during ischemia plus reperfusion resulted in a significant salvage of myocardial tissue and suggests a deleterious role for thromboxane A2 in ischemia.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Fatty Acids, Unsaturated; Female; Hydrazines; Male; Myocardial Infarction; Prostaglandin Endoperoxides, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Regional Blood Flow; Thromboxane A2

Thromboxane A2 (TXA2) receptor antagonists can limit infarct size in models of coronary occlusion and reperfusion, but it was unknown if these compounds can mitigate reperfusion injury. Anesthetized open chest dogs were subjected to left circumflex coronary (LCX) occlusion for 90 min. Two minutes before reperfusion, the dogs were given iv saline (0.9% NaCl) or the TXA2 antagonist SQ 29,548 (0.2 mg/kg + 0.2 mg/kg/hr). Reperfusion was instituted for 5 hr at which time infarct size was determined. Regional myocardial blood flow was determined before, during, and after occlusion. SQ 29,548 treatment resulted in a significant reduction in infarct size (57 +/- 7 and 34 +/- 8% of the left ventricular area at risk infarcted in the saline and SQ 29,548 groups, respectively). No differences in collateral flow during occlusion were observed between groups, but SQ 29,548 treatment resulted in a significantly higher subendocardial reperfusion flow (54 +/- 10 and 93 +/- 14 ml/min/100g for the saline and SQ 29,548 groups, respectively). Thus, TXA2 seems to play a role in exacerbating reperfusion injury and TXA2 receptor blockade may have potential as a mode of therapy for ischemia-reperfusion damage.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Coronary Circulation; Dogs; Fatty Acids, Unsaturated; Female; Hemodynamics; Hydrazines; Male; Myocardial Infarction; Receptors, Prostaglandin; Receptors, Thromboxane; Regional Blood Flow; Thromboxane A2

Thromboxane A2 (TxA2) has been implicated as a potential mediator of myocardial damage during acute ischemia. A potent and specific TxA2 receptor antagonist, SQ-29,548 (2 mg/kg bolus + 2 mg/kg/h) was tested in a cat acute coronary ligation model of myocardial ischemia over a 5-h observation period. Those cats given the TxA2 receptor antagonist had a significant reduction in elevated S-T segment from 0.32 to 0.17 mV (p less than 0.01) in contrast to cats given only vehicle which showed a progressive increase in S-T segment elevation over the 5-h course of the experiment. Furthermore, the rise in plasma creatine kinase (CK) activity during myocardial ischemia was significantly attenuated after SQ-29,548 administration (p less than 0.05). This was confirmed by direct myocardial biopsies which demonstrated a reduction in the loss of myocardial CK and nitrogenous compounds from the ischemic region. Because heart rate (HR), mean arterial blood pressure (MABP), and the pressure rate index (PRI) were unaffected by SQ-29,548 administration, its mechanism of protection probably does not occur through reduction of myocardial oxygen demand. Furthermore, specificity of SQ-29,548 for thromboxane/endoperoxide receptors was demonstrated in the isolated cat coronary arteries. These data suggest that SQ-29,548 reduces the damage associated with myocardial ischemia through direct TxA2 receptor antagonism. The data are also consistent with an important role of TxA2 in the pathophysiology of myocardial ischemia.

Topics: Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Cats; Creatine Kinase; Fatty Acids, Unsaturated; Heart; Heart Rate; Hydrazines; Isoenzymes; Male; Myocardial Infarction; Myocardium; Platelet Aggregation; Receptors, Prostaglandin; Receptors, Thromboxane