Effects of dazoxiben on arrhythmias and ventricular fibrillation induced by coronary artery occlusion and reperfusion in anaesthetised greyhounds.

Abstract

1 The effects of the thromboxane synthetase inhibitor dazoxiben (UK 37248) on haemodynamics, blood gases, thromboxane and prostacyclin release and on arrhythmias were examined in anaesthetised greyhounds subject to acute coronary artery occlusion and reperfusion. 2 Ten minutes after the administration of UK 37248 2 mg/kg intravenously, the plasma concentration of thromboxane B2 in the coronary sinus was significantly reduced whereas the 6-keto-prostaglandin Fln concentration was increased.3 UK 37248 did not significantly alter the number of arrhythmias or the incidence of ventricular fibrillation resulting from coronary artery occlusion. There was evidence, however, that in some drug-treated animals there may have been incomplete inhibition of thromboxane synthesis during coronary artery occlusion.4 A further dose of 1 mg/kg UK 37248 was administered intravenously 5min before the release of the 40 min coronary artery occlusion. Seven out of eight control dogs died in ventricular fibrillation following reperfusion whereas only one out of eight drug-treated animals fibrillated. 5 This latter result suggests that thromboxane may be an important factor in reperfusion induced ventricular fibrillation and that dazoxiben may be a useful drug in clinically related situations.

Preservation of myocardium in transient ischemia by the thromboxane synthetase inhibitor UK 38.485

“…Consistent with this concept are earlier results which demonstrate that imidazole, a non-specific thromboxane synthetase inhibitor, pinane TxA2, a thromboxane receptor antagonist with some thromboxane synthetase inhibitor properties, and dazoxiben, a specific thromboxane synthetase inhibitor, show some protection in acute myocardial ischemia [3,6,27,28]. Thromboxane synthesis capacity of platelets has been found to be increased in patients with coronary heart disease [22] and, as compared to normal persons, TxB2 levels were significantly higher in venous blood [17].…”

“…Now, the new imidazole derivative UK 38.485 retains the selectivity but has the advantages of greater potency and a longer duration of action [23]. For two reasons, thromboxane levels in ischemia before and after therapy were not measured in our study: (a) the efficacy of the drug in blocking the thromboxane synthetase is well documented [9] and (b) an elevation of TxB2 levels during a 3-min occlusion can be expected only in local coronary venous blood [6]. However, in mongrel dogs cannulation of local surface veins accompanying the coronary artery branches is extremely difficult allowing measurements only in coronary sinus blood, which must remain without evidence for the valuation of the effectiveness of the drug.…”

“…Despite great efficacy and specificity, an appropriate modification of the drug seemed to be necessary regarding the relatively short duration of action which must be considered as disadvantageous for experimental and, especially, for clinical purposes [6]. Now, the new imidazole derivative UK 38.485 retains the selectivity but has the advantages of greater potency and a longer duration of action [23].…”

“…One of the earliest consequences of myocardial ischemia is a rapid, localized release of thromboxane A2 (TxA2) within the ischemic region leading to a significant elevation of thromboxane B2, the degradation product of TxA2, in local coronary venous blood for about 50% within i min of coronary artery occlusion [5,6]. In man, increased levels of thromboxane B2 have been demonstrated in patients with Prinzmetal [18], vasotonic [25] and unstable anginas [13], although it remained unclear whether the release was cause or effect.…”

AH23848, a thromboxane antagonist, suppresses ischaemia and reperfusion‐induced arrhythmias in anaesthetized greyhounds

“…We have shown previously that drugs (e.g. prostacyclin) do gain access to the ischaemic myocardium (Coker & Parratt, 1983a) so we have assumed that this would also be true for AH23848. Although thromboxane receptors were presumably blocked after late administration of AH23848, reperfusion of the ischaemic myocardium still caused ventricular fibrillation.…”