One of the most common causes of pre-hospital mortality in patients with myocardial infarction is the onset of ventricular arrhythmias (VAs). Despite the advances in the understanding of underlying molecular mechanisms of VAs, the search for novel preventive treatment of VAs remains a priority. The impact of parasympathetic control to the prevention of VAs provided by the vagus nerve through the parasympathetic ganglia remains insufficiently studied. It has been previously demonstrated that glucagon-like peptide-1 receptors (GLP-1R) are located on both vagal post-ganglionic neurones and ventricular cardiomyocytes. Moreover, their activation using the GLP-1R agonist, Exendin-4, resulted in prolonged effective refractory period (ERP) and, thereby, reduced arrhythmia inducibility (Ang et al., 2018). This antiarrhythmic effect is mediated through muscarinic receptors and nitric oxide (NO), suggesting a complex interaction between GLP-1R signalling and classical parasympathetic neurotransmitters, including acetylcholine, NO, and vasoactive intestinal peptide (VIP).
To assess the left ventricular electrophysiological responses to sympathetic and parasympathetic agonists we used a mouse isolated Langendorff perfused heart model. For stimulation we used S1-S2 protocol at cycle lengths (CL) of 40 ms, 60 ms, 80 ms, 120 ms, 160 ms. Interestingly, no rate-dependent shortening of ERP was observed. Mean (±SD) values for ERP were therefore calculated over all the CLs measured. The mean ERP in control group (n=10) was 35.0±11.4 ms, was significantly prolonged by carbachol (n=7, 1 µM: ERP 40.8±11.2 ms; p<0.05), and shortened by isoprenaline (ISO, 1 µM, n=8, ERP 28.4±5.0 ms; p<0.05). We hypothesised that the opening of KATP channels contributed to the ERP shortening upon sympathetic stimulation (Kim et al., 2012). The effects of ISO on ERP were completely abolished in the presence of KATP channel blocker glibenclamide (n=5, 10 µM, ERP 36.7±12.3 ms; p=0.437), indicating potential antiarrhythmic properties of this antidiabetic drug. We will examine the involvement of KATP channels in the effects of GLP-1R activation. Further research on the modulation of VT/VF susceptibility by GLP-1R agonists and downstream signalling mechanisms in normoxic and ischaemic conditions could ultimately lead to the development of new therapeutic approaches for the treatment and prevention of ventricular tachyarrhythmias.