rs-5186 and Coronary-Disease

We studied the effects of a thromboxane A2 synthetase inhibitor (RS-5186), a thromboxane A2 antagonist (ONO-3708), a 5-lipoxygenase inhibitor (AA-861) and a peptidoleukotriene antagonist (ONO-1078) on infarct size, polymorphonuclear leukocyte infiltration, gross myocardial hemorrhage and arrhythmias in the canine coronary occlusion (2 hour)-reperfusion model (5 hour). The infarct size and risk area were determined by a double staining technique. Thirty minutes prior to occluding the coronary arteries, dogs were randomly assigned to one of the following five groups: the thromboxane A2 synthetase inhibitor group (n = 11) receiving RS-5186 10 mg/kg i.v., the thromboxane A2 antagonist group (n = 12) receiving continuous intravenous infusion of ONO-3708 1 microgram/kg/min, the lipoxygenase inhibitor group (n = 11) receiving AA-861 3 mg/kg i.v., the peptidoleukotriene antagonist group (n = 11) receiving continuous intravenous infusion of ONO-1078 1 microgram/kg/min and the vehicle control group (n = 15). Except for ONO-3708, all the other drugs reduced the infarct size (RS-5186: 26.3 +/- 2.4% of risk area (mean +/- SEM), AA-861: 21.8 +/- 1.3%, ONO-1078: 22.5 +/- 4.4% vs control: 54.0 +/- 6.4%, p less than 0.01 respectively) as well as reducing the area of gross myocardial hemorrhage (RS-5186: 3.9 +/- 2.6% of infarct size, AA-861: 5.1 +/- 2.4%, ONO-1078: 5.2 +/- 2.5% vs control: 22.3 +/- 3.9%, p less than 0.01 respectively). RS-5186 and AA-861 reduced the intensity of polymorphonuclear leukocyte infiltration into the infarcted area, however, neither ONO-3708 nor ONO-1078 had any significant influence.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arrhythmias, Cardiac; Benzoquinones; Cardiomyopathies; Chromones; Coronary Disease; Dogs; Hemorrhage; Lipoxygenase Inhibitors; Male; Myocardial Infarction; Myocardium; Neutrophils; Quinones; SRS-A; Thiophenes; Thromboxane A2; Thromboxane-A Synthase

The effects of the new thromboxane A2 (TXA2) synthetase inhibitor sodium 6-(2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b]thiophene)carboxylate (RS-5186), 10 mg/kg i.v., on infarct size, polymorphonuclear leukocytes (PMNs) infiltration, gross myocardial hemorrhage and ventricular arrhythmias were studied using a canine coronary occlusion (2 h)-reperfusion (5 h) model. Infarct size (IS) and risk area (RA) were determined by a dual staining technique. 60 min before coronary occlusion dogs were randomly assigned to either the RS-5186 treated group (n = 11) or the control group (n = 15). RS-5186 reduced infarct size (RS-5186: 26.3 +/- 2.4% of RA (mean +/- SEM) vs control: 50.7 +/- 5.9%, p less than 0.01), and also reduced the area of gross myocardial hemorrhage (RS-5186: 3.9 +/- 2.6% of IS vs control: 22.4 +/- 4.0%, p less than 0.01). The drug also decreased the intensity of PMNs infiltration into the infarcted area (p less than 0.05). However, RS-5186 had no significant influence on the incidence of ventricular arrhythmias. These results suggest that the new thromboxane A2 synthetase inhibitor RS-5186 might be useful in salvaging ischemic myocardium.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Coronary Vessels; Dogs; Hemodynamics; In Vitro Techniques; Male; Neutrophils; Risk Factors; Thiophenes; Thromboxane A2; Thromboxane-A Synthase

This study was designed to determine the effect of sodium 6-(2-[1-(1H)-imidazolyl]methyl-4,5-dihydrobenzo[b] thiophene)carboxylate (RS-5186), a new thromboxane A2 (TXA2) synthetase inhibitor, on mitochondrial function and lysosomal integrity in ischemic myocardium. 17 anesthetized mongrel dogs were divided into 2 groups. In the control group (n = 11), the left anterior descending arteries (LAD) of the dogs were occluded for 2 h and physiological saline was infused until the end of the experiment. In the RS-5186 treated group (n = 6), 25 min prior to LAD occlusion, RS-5186, 10 mg/kg, was injected for 10 min. 2 h after occlusion, mitochondria were prepared from both ischemic and non-ischemic areas, which were confirmed by Evans' blue dye, and mitochondrial function (respiratory control index: RCI, and the rate of oxygen consumption in state III respiration: St.III O2) was measured polarographically with succinate as substrate. Fractionation of myocardial tissue from both ischemic and non-ischemic areas was also performed, and the activities of lysosomal enzymes (N-acetyl-beta-glucosaminidase: NAG, beta-glucuronidase: beta-gluc) of each fraction were measured. 2-h LAD occlusion induced a significant greater decrease in mitochondrial function from the ischemic area of the control group (RCI: 2.80 +/- 0.45, St.III O2: 133.5 +/- 35.6 natoms/mg protein/min) compared with those from the non-ischemic area (RCI: 4.49 +/- 0.46, St.III O2: 344.0 +/- 31.9).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood Pressure; Coronary Disease; Dogs; Female; Heart Rate; In Vitro Techniques; Lysosomes; Male; Mitochondria, Heart; Oxygen Consumption; Thiophenes; Thromboxane A2; Thromboxane-A Synthase; Time Factors