Abstract
Dantrolene was reported to suppress ventricular fibrillation (VF) in failing hearts with acute myocardial infarction, but its antiarrhythmic efficacy in regional ischemia-reperfusion (IR) hearts remains debatable. Heart failure (HF) was induced by right ventricular pacing. The IR rabbit model was created by coronary artery ligation for 30 min, followed by reperfusion for 15 min in vivo in both HF and non-HF groups (n = 9 in each group). Simultaneous voltage and intracellular Ca2+ (Cai) optical mapping was then performed in isolated Langendorff-perfused hearts. Electrophysiological studies were conducted and VF inducibility was evaluated by dynamic pacing. Dantrolene (10 μM) was administered after baseline studies. The HF group had a higher VF inducibility than the control group. Dantrolene had both antiarrhythmic (prolonged action potential duration (APD) and effective refractory period) and proarrhythmic effects (slowed conduction velocity, steepened APD restitution slope, and enhanced arrhythmogenic alternans induction) but had no significant effects on ventricular premature beat (VPB) suppression and VF inducibility in both groups. A higher VF conversion rate in the non-HF group was likely due to greater APD prolonging effects in smaller hearts compared to the HF group. The lack of significant effects on VPB suppression by dantrolene suggests that triggered activity might not be the dominant mechanism responsible for VPB induction in the IR model.
Highlights
Reperfusion therapy by thrombolysis or immediate percutaneous coronary intervention is commonly performed for acute myocardial infarction (AMI)
We previously reported that dantrolene is effective in preventing ventricular fibrillation (VF) storm by suppressing ventricular premature beats (VPBs) in isolated failing rabbit hearts with AMI [9]
Ortiz et al reported that dantrolene protects the myocardium against myocardial stunning and IR arrhythmias in Wistar rat hearts [10]; other studies have reported that dantrolene has no significant effects on IR arrhythmia in canine hearts [11] and BioMed Research International on IR injury in rabbits in vivo [12]
Summary
Reperfusion therapy by thrombolysis or immediate percutaneous coronary intervention is commonly performed for acute myocardial infarction (AMI). It has been reported that intracellular Ca2+ (Cai) overload is involved in the development of fatal arrhythmias postischemia-reperfusion (IR) injury [1, 2]. The elevated Cai in IR myocardium may enhance triggered activity [3], thereby contributing to IR arrhythmias [4] Both IR and heart failure (HF) impair sarcoplasmic reticulum (SR) Ca2+ ATPase pump activity [5, 6], which results in decreased SR Ca2+ load and elevated diastolic Ca2+ to facilitate afterdepolarizations induction and triggered activity [7]. We previously reported that dantrolene is effective in preventing ventricular fibrillation (VF) storm by suppressing ventricular premature beats (VPBs) in isolated failing rabbit hearts with AMI [9]. We performed simultaneous membrane voltage (Vm) and Cai mapping to investigate the electrophysiological and Cai changes during dantrolene infusion in Langendorff-perfused rabbit hearts with IR injury
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