SUPPRESSION OF VENTRICULAR ARRHYTHMIAS DURING ISCHEMIA-REPERFUSION BY AGENTS INHIBITING INS(1,4,5)P-3 RELEASE

Background Reperfusion following myocardial ischemia causes a rapid and transient release of inositol (1,4,5)triphosphate [Ins(1,4,5)P-3]. The aim of this study was to test whether this increased Ins(1,4,5)P-3 release was important for the development of ventricular arrhythmias and whether agents that inhibit this signal transduction pathway, such as aminoglycoside antibiotics, suppress arrhythmias. Methods and Results In perfused rat hearts, ventricular tachycardia (VT), ventricular fibrillation (VF), and accumulation of Ins(1,4,5)P-3 were measured during early reperfusion. A number of different compounds, including neomycin, gentamicin, streptomycin, spermine, reserpine, and prazosin, were effective in inhibiting the reperfusion-induced Ins(1,4,5)P-3 release and the onset of VT and VF in parallel. A strong correlation existed between Ins(1,4,5)P-3 content, measured at 2 minutes of reperfusion, and the incidence of reperfusion VT and VF. In addition, intravenous gentamicin suppressed the onset of arrhythmias under ischemic and reperfusion conditions in vivo. Conclusions Our results are consistent with the view that Ins(1,4,5)P-3 release plays a pivotal role in mediating arrhythmias during early reperfusion. Agents inhibiting Ins(1,4,5)P-3 release are antiarrhythmic and may have potential use clinically.