Hyperkalemia increases the corporation of ventricular fibrillation (VF) and may also terminate it by mechanisms that remain unclear. guinea pig hearts and improved the extracellular K+ concentration ([K+]o) from control (4 mM) to 7 mM (= 5) or 10 mM (= 7). Optical mapping enabled spatial characterization of excitation dominating frequencies (DFs) and wavebreaks and recognition of sustained rotors (>4 cycles). During VF hyperkalemia reduced the maximum DF of the remaining ventricle (LV) from 31.5 ± 4.7 Hz (control) to 23.0 ± 4.7 Hz (7.0 mM) or 19.5 ± 3.6 Hz (10.0 mM; < 0.006) the left-to-right DF gradient from 14.7 ± 3.6 Hz (control) to 4.4 ± 1.3 Hz (7 mM) and 3.2 ± 1.4 Hz (10 mM) the number of DF domains and the incidence of wavebreak in the LV and interventricular areas. During 10 mM [K+]o the rotation period and core part of sustained rotors in the LV improved and VF often terminated. Two-dimensional computer simulations mimicking experimental VF expected that clamping EK1 to normokalemic ideals during simulated hyperkalemia prevented all the hyperkalemia-induced VF changes. During hyperkalemia despite the shortening of the action potential period depolarization of EK1 improved refractoriness leading to a slowing of VF which efficiently superseded the influence of IK1 conductance variations on VF corporation. This reduced the left-to-right excitation gradients and heterogeneous wavebreak formation. Overall these results provide to our knowledge the 1st direct mechanistic insight into the corporation and/or termination of VF by hyperkalemia. and and a measure of excitability/refractoriness; APD action potential duration; DI diastolic interval Introduction Changes in extracellular K+ ([K+]o) are commonly observed in cardiac disease (1). Recent studies suggest that treatment with inhibitors of the renin-angiotensin-aldosterone system prospects to [K+]o elevation (hyperkalemia) in individuals with chronic heart failure (2). Hyperkalemia also happens during tachycardia and/or ischemia and is a harbinger of cardiac arrhythmias including ventricular fibrillation (VF) (3) ?a leading cause of sudden cardiac death (4). Paradoxically hyperkalemia has also been suggested to dampen the proarrhythmic effect of sympathetic activation and thus be a Epothilone D protecting element during or after exercise (5). A Epothilone D recent publication (6) reported a case study of a patient who underwent spontaneous defibrillation which the authors suggested may have been related to raises in potassium levels that are expected to occur during medical VF. These observations suggest that hyperkalemia also has important antifibrillatory effects. However the precise mechanisms by which raises in [K+]o cause antiarrhythmic effects remain unclear and are the main focus of this study. In experimental models the antifibrillatory effect of hyperkalemia on sustained VF has long been identified (7-10). Koller et?al. (8) proposed a mechanism linked to?the inhibition of alternans mediated by hyperkalemia-induced reduction of the action potential duration (APD) restitution curve slope. However as the authors pointed out (8) their data did not explain how the VF rate of recurrence was modified by hyperkalemia which may have been partially related to Epothilone D the modified dynamics of spiral waves. We recently showed that VF in the guinea pig heart is sustained by high-frequency Epothilone D rotors of excitation located in the remaining ventricle (LV) (11 12 Fibrillatory conduction emanating from such sources underlies activation of the right ventricle (RV) with the formation of wavebreak Epothilone D and a razor-sharp reduction in excitation rate of recurrence occurring predominantly in the dominating rate of recurrence (DF) domain boundaries including that in the LV-RV junction (11). Consequently Rabbit Polyclonal to Vitamin D3 Receptor (phospho-Ser51). we postulated that we could better understand the mechanism underlying [K+]o-induced VF changes by quantifying the properties of rotors/spiral waves which are thought to underlie VF in normal and pathophysiological conditions (13). Accordingly we used optical mapping and numerical approaches to study the effects of hyperkalemia on VF dynamics (corporation/termination) induced in the structurally normal guinea pig heart. Finally we evaluated the ionic mechanisms underlying these changes in VF difficulty via computer simulations. Our results indicate the development in VF corporation during an increase in [K+]o can be.