icatibant and Tachycardia--Ventricular

Brief reversible ischemic episodes (ischemic preconditioning, IPC) protect the heart against arrhythmias during a subsequent prolonged low-flow ischemia. We have recently shown that this protection involves release of bradykinin, activation of bradykinin B2 receptors followed by opening of sarcolemmal, but not mitochondrial ATP-sensitive K+ channels. The goal of this study was to clarify a trigger and/or mediator role of bradykinin in the antiarrhythmic effects of IPC during low-flow ischemia.. Isolated perfused rat hearts underwent 60 minutes of low-flow ischemia induced by reducing perfusion pressure followed by 60 minutes of reperfusion. Preconditioning was induced by 2 x 5 minutes episodes of zero-flow ischemia. In yet other groups, preconditioned or non-preconditioned hearts were treated either with bradykinin (10 nmol/L) or with HOE 140 (bradykinin B2 receptor antagonist, 100 nmol/L).. IPC reduced the number of ventricular premature beats, as well as the incidence of ventricular tachycardia and of ventricular fibrillation during low-flow ischemia. In addition, this protection was abolished by HOE 140 given during low-flow ischemia. Pharmacological preconditioning using short bradykinin perfusion instead of IPC did not show antiarrhythmic effects. However, bradykinin administered during low-flow ischemia and reperfusion reduced the number of ventricular premature beats and the incidence of ventricular tachycardia and of ventricular fibrillation during low-flow ischemia.. Bradykinin is a mediator, but unlikely a trigger, of antiarrhythmic effects of IPC during low-flow ischemia.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Disease Models, Animal; Disease Progression; Electrocardiography; Heart Rate; Heart Ventricles; Ischemic Preconditioning, Myocardial; Male; Pilot Projects; Prognosis; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Ventricular Fibrillation

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 (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 micrograms 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 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, w

Topics: Animals; Arrhythmias, Cardiac; Bradykinin; Bradykinin Receptor Antagonists; Cardiac Complexes, Premature; Coronary Circulation; Coronary Vessels; Dogs; Electrocardiography; Epoprostenol; Female; Hemodynamics; Male; Myocardial Ischemia; Nitric Oxide; Tachycardia, Ventricular

Recent studies have shown that bradykinin decreases the incidence of ischaemic arrhythmias in dogs and may also mediate the antiarrhythmic effects of preconditioning in this species. We investigated the effects of exogenously administered bradykinin on the severity of ischemic arrhythmias and the role of endogenously released bradykinin, acting on B2-receptors, in preconditioning in anaesthetized rats.. In protocol 1, male rats were subjected to a single 30 min occlusion of the left main coronary artery and received left ventricular infusions of bradykinin (30 ng to 10 micrograms/kg/min) or saline. In protocol 2, rats were pretreated with the B2-receptor antagonist HOE 140 (40 and 400 micrograms/kg intravenous bolus) 10 min before coronary artery occlusion. In protocol 3, rats were preconditioned by a 3 min coronary occlusion followed by 10 min of reperfusion before a sustained 30 min occlusion. Saline or HOE 140 was given 10 min before the preconditioning protocol. In all groups, the number and severity of ventricular arrhythmias were determined during the 30 min coronary occlusion.. In protocol 1, none of the doses of bradykinin had any significant effect on the total number of ventricular ectopic beats (1512 +/- 252 in saline-treated controls versus 1337 +/- 302 with the highest dose of bradykinin tested) or on the incidence of ventricular tachycardia or ventricular fibrillation. The two higher doses of bradykinin (1 and 10 micrograms kg/min) caused a reduction in blood pressure soon after infusion began, although this was not maintained for the duration of the experiment. In protocol 2, HOE 140, in doses that produced a sustained antagonism to the depressor response to bradykinin, had no effect on either arrhythmia count or the incidence of ventricular fibrillation in rats subjected to a single 30 min coronary occlusion. In protocol 3, a 3 min preconditioning occlusion in saline-treated rats reduced arrhythmia counts from 1046 +/- 196 in non-preconditioned rats to 76 +/- 44 in preconditioned rats, and reduced the incidences of ventricular tachycardia and ventricular fibrillation from 100 to 50% and from 75 to 7%, respectively. Neither dose of HOE 140 tested reversed these antiarrhythmic effects of preconditioning.. These results suggest that bradykinin is not protective against ischaemic arrhythmias in rats in vivo, whether given exogenously or released endogenously. Furthermore, in contrast to other species, bradykinin does not appear to play a role in the antiarrhythmic effect of ischaemic preconditioning.

Topics: Adrenergic beta-Antagonists; Animals; Arrhythmias, Cardiac; Blood Pressure; Bradykinin; Dose-Response Relationship, Drug; Heart Rate; Male; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Ventricular Fibrillation