Inositol 1,4,5-trisphosphate and reperfusion arrhythmias

1. The present review focuses on the role of the Ca2+-releasing second mess enger inositol 1,4,5-trisphosphate (IP3) in initiating arrhythmias during e arly reperfusion following a period of myocardial ischaemia, 2, Evidence for an arrhythmogenic action of IP3 was provided by studies sho wing a correlation between the extent of the increase in IP3 and the incide nce of arrhythmias in early reperfusion, In addition, phospholipase C inhib itors selective for thrombin receptor stimulation were anti-arrhythmic only when arrhythmias were thrombin initiated. 3. Mechanisms by which IP3 could initiate arrhythmias are discussed, with p articular emphasis on the role of slow and unscheduled Ca2+ release. 4. The reperfusion-induced IP3 and arrhythmogenic responses can be initiate d through either alpha(1)-adrenoceptors or thrombin receptors, but endothel in receptor stimulation was ineffective, Further studies have provided evid ence that the noradrenaline-mediated response was mediated by alpha(1A)-rec eptors, while the alpha(1B)-adrenoceptor subtype appeared to be protective, 5. Reperfusion-induced IP3 responses could be inhibited by procedures known to reduce the incidence of arrhythmias under these conditions, including p reconditioning, inhibiting Na+/H+ exchange or by dietary supplementation wi th n-3 polyunsaturated fatty acids, 6, Inositol 1,4,5-trisphosphate generation in cardiomyocytes can be facilit ated by raising intracellular Ca2+ and it seems Likely that the rise in Ca2 + in ischaemia and reperfusion is responsible for the generation of IP3, wh ich will, in turn, further exacerbate Ca2+ overload.