Sympathetic stimulation increased maximum slope of restitution and electrical alternans but decreased ERP and VF threshold whilst vagus nerve stimulation had opposite effects. The interaction between action potential duration and beat-to-beat interval may play an important role in the autonomic modulation of VF initiation.

It is well recognised that stimulation of the sympathetic nervous system exerts a positive chronotropic effect on the heart, speeding the rate of discharge of the intrinsic pacemaker, which is usually the sino-atrial node, whilst parasympathetic stimulation has opposite effects (Levy & Zieske, 1969). Atrioventricular (AV) conduction is also affected, with sympathetic stimulation speeding conduction (positive dromotropy) and parasympathetic stimulation delaying conduction (negative dromotropy) (Warner et al. 1986). Autonomic stimulation also affects myocardial mechanical performance but the cause of this effect is less straightforward. Whilst it is generally accepted that sympathetic stimulation exerts a positive inotropic effect on the heart with increased contractility, the effect of vagal stimulation on cardiac mechanical performance is less well defined (Xenopoulos & Applegate, 1994). At the molecular level, the sympathetic and parasympathetic nervous systems modulate cardiac function by means of the neurotransmitters, catecholamines and acetylcholine, respectively (Levy, 1997), interacting with receptors located on the sarcolemma of the cardiac myocyte. The cellular mechanisms by which stimulation of the autonomic nervous system affect the various processes involved in excitation-contraction coupling have not been fully investigated. The ability to investigate how nerves influence these mechanisms is limited by the type of preparation available.Experimental data relating to the effect of autonomic nerve activity on cardiac function have been obtained in vivo where direct stimulation of autonomic nerves may be confounded by influences from circulating hormones and haemodynamic reflexes. On the other hand, in vitro studies on isolated heart preparations have used exogenous pharmacological agents and chemical analogues, such as isoprenaline, to mimic stimulation of autonomic nerves. The disadvantage of both of these approaches may be overcome by an isolated heart preparation in which both sets of autonomic nerves are intact and available for stimulation. In this paper we describe a novel, isolated Langendorff perfused rabbit heart preparation with intact dual autonomic innervation that allows the study of the effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart. To demonstrate the viability of the preparation, we have described the effects of direct stimulation of the sympathetic outflow and vagus nerves on the intrinsic heart rate and AV conduction at varying stimulus strengths and frequencies.Effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart -a novel model of isolated Langendorff perfused rabbit heart with intact dual autonomic innervation A novel isolated Langendorff perfused rabbit heart preparation with intact dual autonomic innervation is described. This preparation allows the study of the effects of direct sympathetic and vagus nerve stimulation on the physiology of the whole heart. These hearts (n = 10) had baseline h...

BackgroundIvabradine is a specific bradycardic agent used in coronary artery disease and heart failure, lowering heart rate through inhibition of sinoatrial nodal HCN‐channels. This study investigated the propensity of ivabradine to interact with KCNH2‐encoded human Ether‐à‐go‐go–Related Gene (hERG) potassium channels, which strongly influence ventricular repolarization and susceptibility to torsades de pointes arrhythmia.Methods and ResultsPatch clamp recordings of hERG current (IhERG) were made from hERG expressing cells at 37°C. IhERG was inhibited with an IC50 of 2.07 μmol/L for the hERG 1a isoform and 3.31 μmol/L for coexpressed hERG 1a/1b. The voltage and time‐dependent characteristics of IhERG block were consistent with preferential gated‐state‐dependent channel block. Inhibition was partially attenuated by the N588K inactivation‐mutant and the S624A pore‐helix mutant and was strongly reduced by the Y652A and F656A S6 helix mutants. In docking simulations to a MthK‐based homology model of hERG, the 2 aromatic rings of the drug could form multiple π‐π interactions with the aromatic side chains of both Y652 and F656. In monophasic action potential (MAP) recordings from guinea‐pig Langendorff‐perfused hearts, ivabradine delayed ventricular repolarization and produced a steepening of the MAPD90 restitution curve.ConclusionsIvabradine prolongs ventricular repolarization and alters electrical restitution properties at concentrations relevant to the upper therapeutic range. In absolute terms ivabradine does not discriminate between hERG and HCN channels: it inhibits IhERG with similar potency to that reported for native If and HCN channels, with S6 binding determinants resembling those observed for HCN4. These findings may have important implications both clinically and for future bradycardic drug design.

We show that the vagal anti-fibrillatory action in the rabbit ventricle occurs via post-ganglionic efferent nerve fibres, independent of muscarinic receptor activation, VIP, and the endothelium. Together with our previous publications, our data support the possibility of a novel ventricular nitrergic parasympathetic innervation and highlight potential for new therapeutic targets to treat ventricular dysrhythmias.