Abstract
β-adrenergic receptor (β-AR) blockers may be administered during acute myocardial infarction (MI), as they reduce energy demand through negative chronotropic and inotropic effects and prevent ischemia-induced arrhythmogenesis. However, the direct effects of β-AR blockers on ventricular electrophysiology and intracellular Ca2+ handling during ischemia remain unknown. Using optical mapping of transmembrane potential (with RH237) and sarcoplasmic reticulum (SR) Ca2+ (with the low-affinity indicator Fluo-5N AM), the effects of 15 min of regional ischemia were assessed in isolated rabbit hearts (n = 19). The impact of β-AR inhibition on isolated hearts was assessed by pre-treatment with 100 nM propranolol (Prop) prior to ischemia (n = 7). To control for chronotropy and inotropy, hearts were continuously paced at 3.3 Hz and contraction was inhibited with 20 μM blebbistatin. Untreated ischemic hearts displayed prototypical shortening of action potential duration (APD80) in the ischemic zone (IZ) compared to the non-ischemic zone (NI) at 10 and 15 min ischemia, whereas APD shortening was prevented with Prop. Untreated ischemic hearts also displayed significant changes in SR Ca2+ handling in the IZ, including prolongation of SR Ca2+ reuptake and SR Ca2+ alternans, which were prevented with Prop pre-treatment. At 5 min ischemia, Prop pre-treated hearts also showed larger SR Ca2+ release amplitude in the IZ compared to untreated hearts. These results suggest that even when controlling for chronotropic and inotropic effects, β-AR inhibition has a favorable effect during acute regional ischemia via direct effects on APD and Ca2+ handling.
Highlights
Ventricular arrhythmias during the acute phase of myocardial infarction (MI) remain a leading cause of death (Henriques et al, 2005; Benjamin et al, 2017)
At 5 min ischemia, Prop pretreated hearts showed larger sarcoplasmic reticulum (SR) Ca2+ release amplitude in the ischemic zone (IZ) compared to untreated hearts. These results suggest that even when controlling for chronotropic and inotropic effects, β-adrenergic receptor (β-AR) inhibition has a favorable effect during acute regional ischemia via direct effects on action potential duration (APD) and Ca2+ handling
All procedures involving animals were approved by the Animal Care and Use Committee of the University of California, Davis and adhered to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No 85-23, revised 1996)
Summary
Ventricular arrhythmias during the acute phase of myocardial infarction (MI) remain a leading cause of death (Henriques et al, 2005; Benjamin et al, 2017). Recent evidence suggests that when administered prior to primary percutaneous coronary intervention (PCI), intravenous β-AR blocker therapy results in improved ejection fraction and fewer major adverse cardiac events compared to PCI without β-AR blocker pre-treatment (Halkin et al, 2004; Pizarro et al, 2014). The mechanisms underlying these improved outcomes are likely multi-factorial, but may stem in part from a global reduction in oxygen demand due to reductions in heart rate and contractility, as well as inhibition of β-AR signaling in the ischemic region. Locally enhanced β-AR stimulation may exacerbate the arrhythmogenic effects of ischemia by contributing to Ca2+ overload and additional APD shortening due to β-AR augmentation of repolarizing K+ currents
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