A. Vegh et al., ATTENUATION OF THE ANTIARRHYTHMIC EFFECTS OF ISCHEMIC PRECONDITIONINGBY BLOCKADE OF BRADYKININ B-2 RECEPTORS, British Journal of Pharmacology, 113(4), 1994, pp. 1167-1172
1 The possibility that bradykinin is involved in the pronounced antiar
rhythmic effects of ischaemic preconditioning in anaesthetized mongrel
dogs was examined with the use of the selective B-2 antagonist, icati
bant (Hoe-140). 2 Preconditioning, achieved by two 5 min occlusions of
the left anterior descending coronary artery, followed 20 min later b
y a 25 min occlusion of the same artery resulted, during this prolonge
d occlusion, in less severe arrhythmias (VF 0% versus 47% in control n
on-preconditioned dogs), reductions in the incidence and number of epi
sodes of ventricular tachycardia (VT) and in the number of ventricular
premature beats and increased survival following reperfusion (50% ver
sus 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 preconditioni
ng but before the prolonged occlusion. This dose of Hoe-140 had insign
ificant haemodynamic effects and failed to modify the increase in coro
nary blood flow that occurred in the circumflex coronary artery when t
he anterior descending branch was occluded. 4 It was difficult to prec
ondition 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 pronoun
ced ST-elevation (recorded from epicardial electrodes) during the prec
onditioning occlusions in those dogs given Hoe-140. 5 In those dogs th
at survived to the long (25 min) occlusion, Hoe-140 prevented the anti
arrhythmic effects of preconditioning (reduction in ventricular premat
ure beats and in VT) although all the dogs survived the occlusion peri
od. However on reperfusion, survival in the preconditioned dogs given
Hoe-140 was less than in those dogs preconditioned without the B-2 ant
agonist. 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 (antiarrhyth
mic) substances generated by the myocardium under these conditions. Si
nce the protection afforded both by preconditioning and by local intra
coronary infusions of bradykinin is markedly attenuated by an inhibito
r of the L-arginine nitric oxide pathway, we suggest that much of the
protection afforded by ischaemic preconditioning results from the gene
ration of nitric oxide, and that bradykinin, released early during isc
haemia, acts as a stimulant for this generation.