Bradykinin is a mediator, but unlikely a trigger, of antiarrhythmic effects of ischemic preconditioning.

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: Bradykinin is a mediator, but unlikely a trigger, of antiarrhythmic effects of IPC during low-flow ischemia.

Toward intelligent nanosize bioreactors: a pH-switchable, channel-equipped, functional polymer nanocontainer.

To develop an intelligent sensor-effector functionality on the nanoscale, a pH-switchable, controlled nanoreactor based on amphiphilic copolymer membranes was built. The nanovesicles were equipped with bacterial transmembrane ompF pore proteins and the pH-sensitive enzyme acid phosphatase, resulting in a switchable substrate processing at pH 4-6.5. Ideal pH and substrate concentrations for the reaction were determined experimentally. In future, the reactor might be used for self-regulating targeted diagnostic and therapeutic applications in medicine.

Antiarrhythmic effect of ischemic preconditioning during low-flow ischemia. The role of bradykinin and sarcolemmal versus mitochondrial ATP-sensitive K(+) channels.

Short episodes of ischemia (ischemic preconditioning) protect the heart against ventricular arrhythmias during zero-flow ischemia and reperfusion. However, in clinics, many episodes of ischemia present a residual flow (low-flow ischemia). Here we examined whether ischemic preconditioning protects against ventricular arrhythmias during and after a low-flow ischemia and, if so, by what mechanism(s). Isolated rat hearts were subjected to 60 min of low-flow ischemia (12% residual coronary flow) followed by 60 min of reperfusion. Ischemic preconditioning was induced by two cycles of 5 min of zero-flow ischemia followed by 5 and 15 min of reperfusion, respectively. Arrhythmias were evaluated as numbers of ventricular premature beats (VPBs) as well as incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF) during low-flow ischemia and reperfusion. Ischemic preconditioning significantly reduced the number of VPBs and the incidence of VT and of VF during low-flow ischemia. This antiarrhythmic effect of preconditioning was abolished by HOE 140 (100 nM), a bradykinin B(2) receptor blocker. Similar to preconditioning, exogenous bradykinin (10 nM) reduced the number of VPBs and the incidence of VT and of VF during low-flow ischemia. Furthermore, the antiarrhythmic effects of both ischemic preconditioning and bradykinin were abolished by glibenclamide (1 microM), a non-specific blocker of ATP-sensitive K(+) (K(ATP)) channels. Finally, the antiarrhythmic effects of both ischemic preconditioning and bradykinin were abolished by HMR 1098 (10 microM), a sarcolemmal K(ATP) channel blocker but not by 5-hydroxydecanoate (100 microM), a mitochondrial K(ATP) channel blocker. In conclusion, ischemic preconditioning protects against ventricular arrhythmias induced by low-flow ischemia, and this protection involves activation of bradykinin B(2) receptors and subsequent opening of sarcolemmal but not of mitochondrial K(ATP) channels.

Losartan but not enalaprilat acutely reduces reperfusion ventricular tachyarrhythmias in hypertrophied rat hearts after low-flow ischaemia.

Based on clinical and experimental studies, angiotensin II receptor blockers and angiotensin converting enzyme inhibitors have been proposed to exert acute anti-arrhythmic effects in heart failure patients. Therefore, the goal of this study was to assess acute anti-arrhythmic effects of losartan and enalaprilat in hypertrophied rat hearts during low-flow ischaemia and reperfusion. In dose-finding experiments in non-hypertrophied isolated perfused hearts, we performed dose-response curves of losartan and enalaprilat studying monophasic action potential duration at 90% repolarisation (MAPD(90%)) and ventricular fibrillation (VF) threshold. Subsequently, we determined the effects of losartan and enalaprilat (in therapeutically relevant concentrations) on ventricular tachyarrhythmias induced by low-flow ischaemia/reperfusion in hearts demonstrating left ventricular (LV) hypertrophy 70 days after aortic banding. We found that neither drug significantly affected MAPD(90%) (1 nM-1 mM) or VF threshold (1 microM losartan and 10 microM enalaprilat) in non-hypertrophied hearts. Similarly in hypertrophied hearts, neither drug significantly affected the incidence or the duration of ventricular tachyarrhythmias (ventricular tachycardia and VF) during low-flow ischaemia. However, 1 microM losartan significantly reduced the duration of ventricular tachyarrhythmias during reperfusion. In conclusion, neither losartan nor enalaprilat is acutely anti-arrhythmic in hypertrophied rat hearts during low-flow ischaemia. During reperfusion, however, losartan but not enalaprilat exerts acute anti-arrhythmic effects.