The effects of R 68070 an oxime-alkane carboxylic acid derivative combining specific thromboxane A2 (TXA2) synthetase inhibition with TXA2/prostaglandin endoperoxide receptor blockade in one molecule, on thrombus formation in a coronary artery following electrically-induced endothelial injury and on its myocardial repercussions were examined in dogs. In an open-chest model in anaesthetized dogs, a stainless steel electrode was inserted into the left anterior descending coronary artery (LAD) distally (+ 1 cm) from an electromagnetic flow probe. ECG and heart rate were derived from limb leads. Serum TXB2 levels were measured by RIA on venous spontaneously coagulated blood (1 h, 37°C). Endothelial cell injury in the LAD coronary artery was induced by the application of an anodal current of 300 μA during 30 min; after an additional 60 min observation period, the thrombus wet weight was determined.In comparison with solvent treatment (n = 8), R 68070 (1.25 mg/kg I.V. 10 min before electrical stimulation, n = 7), significantly reduced the thrombus mass (solvent : 43 mg; R 68070 : 18 mg median value, p < 0.05), the incidence of ECG changes indicative for myocardial ischemia (fibrillation : solvent 1/8; R 68070 0/7; arrhythmias : solvent 3/8; R 68070 2/7; ST changes : solvent 7/8; R 68070 1/7, p < 0.05) and the decrease in coronary blood flow after electrical stimulation (solvent : from 13 to 6.5 ml/min; R 68070 : from 13 to 11 ml/min median values, p < 0.05). Serum TXB2 levels were reduced by 92 % at 100 min after the injection of the active compound (median value, n = 7).Heart rate and coronary blood flow measured before the induction of the endothelial injury were not modified by R 68070.The present study thus demostrates that R 68070 exerts a potent anti-thrombotic effect in canine coronary arteries. The relative contributions to this effect of TXA2 synthetase inhibition and of TXA2/prostaglandin endoperoxide receptor blockade exerted by the compound are being investigated.
Effect of acute atrial fibrillation on phasic coronary blood flow pattern and flow reserve in humans
