y-20811 and Myocardial-Infarction

To examine effects of a new thromboxane synthetase inhibitor, Y-20811, on infarct size, neutrophil accumulation, and arrhythmias, coronary artery was occluded for 90 min and reperfused for 6 h in anesthetized dogs. Y-20811 administered intravenously (i.v.) 30 min before occlusion decreased serum thromboxane B2 (TBX2) formation by 98% 30 min later and by 79% at 6 h after reperfusion. Ventricular fibrillation (VF) developed in 1 of 15 control and 3 of 10 treated dogs during occlusion (p = NS), whereas after reperfusion it occurred in 7 of 14 control and none of seven treated dogs (p < 0.05). The number of arrhythmias during the first hour of reperfusion was significantly reduced in treated dogs (134 +/- 74 beats/min in control vs. 14 +/- 4 beats/min in treated dogs, p < 0.05). Hemodynamics, area at risk, and collateral flow to the ischemic region were similar for the two groups. The extent of myocardial necrosis was 28.0 +/- 10.0% (n = 7) of the area at risk in control dogs and 27.6 +/- 6.2% (n = 7) in treated dogs (p = NS). The relation between the ratio of myocardial necrosis to area at risk and collateral flow was similar. The degree of neutrophil accumulation did not differ but correlated with infarct size (r = 0.85). Thus, Y-20811 reduced reperfusion arrhythmias but failed to limit infarct size and neutrophil accumulation after coronary artery occlusion/reperfusion in dogs.

Topics: Animals; Arrhythmias, Cardiac; Coronary Circulation; Coronary Disease; Dogs; Female; Hemodynamics; Imidazoles; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Neutrophils; Thromboxane B2; Thromboxane-A Synthase

We examined the hypothesis that combined actions of anticoagulant (heparin) and Y-20811, thromboxane A2 synthetase inhibitor (TXSI), or S-1452, receptor blockade (TXRB), can provide better antithrombotic protection than TXSI or TXRB alone. In 20 of 33 dogs instrumented, placement of a critical stenosis at a focus of coronary vascular injury initiated a reproducible cyclic coronary flow reduction (CCFR). TXSI (1 mg/kg, IV) perfectly inhibited CCFR in 6 of 10 dogs (60%), and was associated with a significant decrease in 11-dehydro-TXB2 (85 +/- 8% of control; p < 0.05) and an increase in 6-keto-PGF1 alpha (155 +/- 38%; p < 0.05) in coronary sinus blood samples. In the remaining 4 dogs, additional administration of heparin (2000 IU) completely abolished CCFR. On the other hand, TXRB (1 mg/kg, IV) perfectly inhibited CCFR in 7 of 10 dogs (70%), and was accompanied by a significant increase in 6-keto-PGF1 alpha (214 +/- 65%; p < 0.05) and unchanged TXB2 level. In the remaining 3 dogs, additional administration of heparin (2000 IU) completely abolished CCFR. Thus, the combination of anticoagulant and TXSI or TXRB were more effective than TXSI or TXRB alone in abolishing thrombotic CCFR, suggesting that the combination might be effective for treating patients with impending myocardial infarction.

Topics: Animals; Bridged Bicyclo Compounds; Coronary Circulation; Dogs; Drug Synergism; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Heparin; Imidazoles; Myocardial Infarction; Receptors, Prostaglandin; Thromboxane-A Synthase