Arachidonic Acid Cascade and the Generation of Ischemia- and Reperfusion-Induced Ventricular Arrhythmias

This article reviews the evidence we found in our study that the local generation of thromboxane and prostacyclin is one important factor involved in determining the severity of the ventricular arrhythmias that result from acute myocardial ischaemia and subsequent reperfusion. The hypothesis examined is that thromboxane release, presumably from platelets, is harmful in the early stages of ischaemia (perhaps because this induces further platelet aggregation and/or a reduction in blood flow as a result of both active vasoconstriction and of mechanical obstruction) and that prostacyclin generation (presumably mainly from endothelial cells) is beneficial at this time. The evidence is that in anaesthetised greyhound dogs, blockade of the thromboxane receptor (AH 23848) or inhibition of thromboxane synthesis (with a variety of “specific” inhibitors of thromboxane syn-thetase such as dazoxiben, dazmegrel, and “low-dose” aspirin) slightly reduces the severity of ischaemia-induced arrhythmias and markedly increases survival after myocardial reperfusion by reducing reperfusion-induced ventricular fibrillation (e.g., from 80% in control dogs to <20% in treated dogs). The evidence that prostacyclin generation is helpful in this situation comes from studies with locally infused prostacyclin or iloprost and with na-fazatrom, a drug that increases the amount of prostacyclin released into local coronary venous blood soon after the onset of myocardial ischaemia; these procedures also reduce the number of ventricular extrasystoles occurring during ischaemia and the incidence of reperfusion-induced ventricular fibrillation. These findings do not imply that arachidonic acid derivatives are the only, or even the main, biochemical factor involved in the generation of these arrhythmias. Noradrenaline release is clearly also important. They do, however, suggest that, because more than one biochemical mediator may be involved, combination therapy offers the best approach to dealing with this consequence of myocardial ischaemia and reperfusion. Some evidence for this comes from the extra benefit obtained with a combination of a thromboxane synthetase inhibitor and a β-adrenoceptor blocking drug.