ATTENUATION OF THE ANTIARRHYTHMIC EFFECTS OF ISCHEMIC PRECONDITIONING BY BLOCKADE OF BRADYKININ B-2 RECEPTORS

1 The possibility that bradykinin is involved in the pronounced antiarrhythmic effects of ischaemic preconditioning in anaesthetized mongrel dogs was examined with the use of the selective B-2 antagonist, icatibant (Hoe-140). 2 Preconditioning, achieved by two 5 min occlusions of the left anterior descending coronary artery, followed 20 min later by a 25 min occlusion of the same artery resulted, during this prolonged occlusion, in less severe arrhythmias (VF 0% versus 47% in control non-preconditioned dogs), reductions in the incidence and number of episodes of ventricular tachycardia (VT) and in the number of ventricular premature beats and increased survival following reperfusion (50% versus 0% in the controls). 3 Hoe-140 was given in a dose of 300 mu g kg(-1) either before the preconditioning procedure or after preconditioning but before the prolonged occlusion. This dose of Hoe-140 had insignificant haemodynamic effects and failed to modify the increase in coronary blood flow that occurred in the circumflex coronary artery when the anterior descending branch was occluded. 4 It was difficult to precondition dogs in the presence of Hoe-140. There were more ventricular arrhythmias during the initial 5 min occlusion (44 +/- 12 versus 10 +/- 3) and a higher incidence of ventricular fibrillation (50% versus 21%) during the preconditioning procedure. There was also a more pronounced ST-elevation (recorded from epicardial electrodes) during the preconditioning occlusions in those dogs given Hoe-140. 5 In those dogs that survived to the long (25 min) occlusion, Hoe-140 prevented the antiarrhythmic effects of preconditioning (reduction in ventricular premature beats and in VT) although all the dogs survived the occlusion period. However on reperfusion, survival in the preconditioned dogs given Hoe-140 was less than in those dogs preconditioned without the B-2 antagonist. 6 Changes in the degree of inhomogeneity of conduction within the ischaemic area, which were markedly suppressed by preconditioning, were attenuated in those dogs preconditioned in the presence of Hoe-140. 7 These results suggest that bradykinin acts as both a 'trigger' for preconditioning and as one of the mediator protective (antiarrhythmic) substances generated by the myocardium under these conditions. Since the protection afforded both by preconditioning and by local intracoronary infusions of bradykinin is markedly attenuated by an inhibitor of the L-arginine nitric oxide pathway, we suggest that much of the protection afforded by ischaemic preconditioning results from the generation of nitric oxide, and that bradykinin, released early during ischaemia, acts as a stimulant for this generation.