Attenuation of the antiarrhythmic effects of ischaemic preconditioning by blockade of bradykinin B₂ receptors

Abstract

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 B2 antagonist, icatibant . 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 Ag kg-' 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 B2 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.

The Role of Bradykinin System in Type 2 Diabetes

“…The urinary and plasma BK-forming components are comprised of proteins that mediate their effects on vasculature by releasing BK [30][31][32][33]. It is also known that the tissue kallikrein present in the urine is originating from the kidney and it reflects the renal activity of BK [9]. Higher concentrations of prekallikrein levels may suggest the onset of renal abnormalities.…”

“…It seems that the kinins may be generated in parallel with the formation of thrombin at inflammatory sites, since inactive plasma kallikrein can be activated by coagulant Hageman factor. The tissue kallikrein multigene family comprises a closely related cluster of genes that vary in number between the different mammalian species: 24 genes have been identified in the mouse, 20 in the rat, 3 in humans and 3 in the hamster [9].…”

“…Tissue kallikrein is found in various organs such as the kidney, heart and synovial tissue [7,8]. These kallikreins differ from one another in molecular weight, biological function, physicochemical and immunological properties [9]. The tissue kallikrein is synthesized in the cells as a precursor and converted into active form by the cleavage of an amino terminal peptide [10].…”

Further evidence for the role of nitric oxide in the antiarrhythmic effect of ischaemic preconditioning: the effect of peroxynitrite and changes in NOS-dependent NO production

“…Furthermore, the blockade of A1 receptors abolished, whereas the administration of A1 agonist mimicked the cardioprotective effects of PC Thornton et al, 1992). Parallel with this adenosine hypothesis, our research group proposed that bradykinin (BK), formed rapidly after the onset of ischaemia, plays also an important trigger role in the antiarrhythmic effect of PC (Végh et al, 1991b(Végh et al, , 19931994b). The administration of BK (Végh et al, 1991b) and the combined ACE/NEP inhibitor Z13752A, which increases endogenous BK levels by inhibiting the degradation of BK mimicked, whereas the blockade of BK2 receptors with icatibant markedly attenuated the antiarrhythmic effect of PC (Végh et al, 1994b).…”

The effect of acute simvastatin administration on the ischaemia and reperfusion-induced ventricular arrhythmias in anesthetized dogs

“…It was shown that bradykinin, which is rapidly formed in the blood during hypoxia [21][22][23] plays an important trigger role in the preconditioning-induced protection, since it acting on the endothelial bradykinin B 2 receptors triggers the generation and release of other mediators, such as prostacyclin [14] and nitric oxide [24]. These diffusible mediators reaching the myocytes activate mechanisms, which are ultimately lead to the protection [25].…”