Lidoflazine in the Early Stages of Acute Myocardial Ischaemia

Abstract

Gl 1XW1 Pretreatment of anaesthetized rats with intravenously administered lidoflazine (an antianginal agent) reduced the incidence and severity of ventricular arrhythmias which resulted from acute coronary artery ligation. Ventricular fibrillation was completely prevented by doses of 50 pg/kg and 2 mg/kg and no animal so treated died (contrast 50% incidence of fibrillation in the controls and 30% mortality). 2 In anaesthetized greyhound dogs, lidoflazine (2 mg/kg) administration resulted in transient reductions in systemic arterial pressure, LV dP/dt max and cardiac output. Coronary sinus P02 was markedly increased, indicating pronounced coronary vasodilatation. 3 Lidoflazine pretreatment inhibited the increase in epicardial ST-segment elevation which resulted, in dogs, from short (3 min) occlusions of the left anterior descending coronary artery. This effect was especially marked at sites where, in control occlusions, ST-segment elevation was most pronounced. 4 Lidoflazine greatly reduced the number of ventricular ectopic beats which usually resulted from more prolonged (30 min) periods of acute coronary artery occlusion. There was no ventricular fibrillation in these dogs (contrast 25% incidence in the controls). (1980). There has been renewed interest in lidoflazine because of the evidence that it protects cardiac muscle against the deleterious effects of ischaemia and subsequent reperfusion (Nayler, 1980; Flameng, Daenen, Xhonneux, Van de Water & Van Belle, 1980;Flameng, Daenen, Borgers, Thone, Xhonneux, Van de Water & Van Belle, 1981). The mechanism of this protection is unclear but lidoflazine interferes with the slow channel transport of Ca2+, at least in smooth muscle, and it is possible that lidoflazine alleviates myocardial damage, at least in part, by preventing mitochondrial calcium overload (Flameng et al., 1981).Despite some evidence (de Geest, Kesteloot & Piessens, 1979) that prolonged treatment with lidoflazine is of some benefit in the long term management of patients following myocardial infarction, little is known about the effects of the drug on the 0007-1188/82/060347-08 $01.00 early life-threatening ventricular arrhythmias which are a consequence of acute myocardial ischaemia. Schaper, Xhonneux, Jageneau & Janssen (1966) showed in dogs that prolonged oral treatment with the drug reduced the incidence of ventricular fibrillation following abrupt coronary artery occlusion whereas Carmeliet & Xhonneux (1971) found that lidoflazine was ineffective in reversing ventricular arrhythmias 24 h after coronary artery ligation. The aim of the present studies was three fold. Firstly to determine whether lidoflazine is effective against the early life-threatening arrhythmias that occur soon after coronary artery occlusion. Secondly, to determine if it reduces the incidence of arrhythmias following reperfusion and thirdly to examine, using epicardial mapping techniques, whether lidoflazine reduces the severity of myocardial ischaemic damage. Methods Studies in anaesthetized ratsThe effect of lidoflazine...

The antiarrhythmic effects of the nucleoside transporter inhibitor, R75231, in anaesthetized pigs

“…Previous studies with the few existing nucleoside transport inhibitors such as dipyridamole (Wainwright & Parratt, 1988) and lidoflazine (Coker et al, 1982) have indeed shown protection against ventricular arrhythmias during coronary occlusion in dogs. Furthermore, dipyridamole (Blumenthal et al, 1981), lidoflazine (Flameng et al, 1981), mioflazine (Wood et al, 1985) and dilazep (Gupta et al, 1989) have all been shown to reduce infarct size and/or improve functional recovery after myocardial ischaemia in canine hearts.…”

Purine metabolism in the heart

“…Anti-arrhythmic actions have been reported in a coronary occlusion model in dogs for dipyridamole [65] and lidoflazine [66] and in pigs for R 75 231 [67]. In the latter study, 9 out of 10 control animals died from ventricular fibrillation, while 8 out of 10 survived when pretreated with R 75 231.…”

The case for low-dose aspirin for the prevention of myocardial infarction: But how low is low?

“…The aspirin studies, conducted almost entirely in anesthetized dogs [32], suggest that the selective inhibition of thromboxane (and the "sparing" of prostacyclin) is the most likely explanation of the antiarrhythmic effect of lower doses of aspirin (e.g., 1 mg/ kg). What is of particular interest in all these experiments is that the selective inhibition of thromboxane release leads particularly to suppression of ventricular fibrillation that occurs following reperfusion.…”