New findings r What is the central question of this study?Ischaemia-reperfusion of peripheral tissues protects the heart from subsequent myocardial ischaemia-reperfusion-induced injury and cardiac dysfunction, a phenomenon referred to as 'remote ischaemic preconditioning' (rIPC). This study addressed whether activation of sensory afferent nerves in the ischaemic hindlimb and vagal efferent nerves innervating the heart mediate rIPC. This investigation was designed to determine the participation of the vagus nerve and muscarinic receptors in the remote ischaemic preconditioning (rIPC) mechanism. New Zealand rabbits were anaesthetized, and the femoral artery was dissected. After 30 min of monitoring, the hearts were isolated and subjected to 30 min of global no-flow ischaemia and 180 min of reperfusion (nonrIPC group). The ventricular function was evaluated, considering the left ventricular developed pressure and the left ventricular end-diastolic pressure. In the rIPC group, the rabbits were subjected to three cycles of hindlimb ischaemia (5 min) and reperfusion (5 min), and the same protocol as that used in non-rIPC group was then repeated. In order to evaluate the afferent neural pathway during the rIPC protocol we used two groups, one in which the femoral and sciatic nerves were sectioned and the other in which the spinal cord was sectioned (T9-T10 level). To study the efferent neural pathway during the rIPC protocol, the vagus nerve was sectioned and, in another group, atropine was administered. The effect of vagal stimulation was also evaluated. An infarct size of 40.8 ± 3.1% was obtained in the non-rIPC group, whereas in rIPC group the infarct size decreased to 16.4 ± 3.5% (P < 0.05). During the preconditioning protocol, the vagus nerve section and the atropine administration each abolished the effect of rIPC on infarct size. Vagal stimulation mimicked the effect of rIPC, decreasing infarct size to 15.2 ± 4.7% (P < 0.05). Decreases in infarct size were accompanied by improved left ventricular function.M. Donato and B. Buchholz contributed equally to this manuscript.

Sudden unexpected death in epilepsy (SUDEP) is the major cause of death in those patients suffering from refractory epilepsy (RE), with a 24-fold higher risk relative to the normal population. SUDEP risk increases with seizure frequency and/or seizure-duration as in RE and Status Epilepticus (SE). P-glycoprotein (P-gp), the product of the multidrug resistant ABCB1-MDR-1 gene, is a detoxifying pump that extrudes drugs out of the cells and can confer pharmacoresistance to the expressing cells. Neurons and cardiomyocytes normally do not express P-gp, however, it is overexpressed in the brain of patients or in experimental models of RE and SE. P-gp was also detected after brain or cardiac hypoxia. We have previously demonstrated that repetitive pentylenetetrazole (PTZ)-induced seizures increase P-gp expression in the brain, which is associated with membrane depolarization in the hippocampus, and in the heart, which is associated with fatal SE. SE can produce hypoxic-ischemic altered cardiac rhythm (HIACR) and severe arrhythmias, and both are related with SUDEP. Here, we investigate whether SE induces the expression of hypoxia-inducible transcription factor (HIF)-1α and P-gp in cardiomyocytes, which is associated with altered heart rhythm, and if these changes are related with the spontaneous death rate. SE was induced in Wistar rats once a week for 3 weeks, by lithium-pilocarpine-paradigm. Electrocardiograms, HIF-1α, and P-gp expression in cardiomyocytes, were evaluated in basal conditions and 72 h after SE. All spontaneous deaths occurred 48 h after each SE was registered. We observed that repeated SE induced HIF-1α and P-gp expression in cardiomyocytes, electrocardiographic (ECG) changes, and a high rate of spontaneous death. Our results suggest that the highly accumulated burden of convulsive stress results in a hypoxic heart insult, where P-gp expression may play a depolarizing role in cardiomyocyte membranes and in the development of the ECG changes, such as QT interval prolongation, that could be related with SUDEP. We postulate that this mechanism could explain, in part, the higher SUDEP risk in patients with RE or SE.

In a previous research, we described that vagal stimulation increases the infarct size by sympathetic co-activation. The aim of this study was to determine if hemodynamic changes secondary to the vagal stimulation are able to activate sympathetic compensatory neural reflexes, responsible for increasing the infarct size. A second goal was to determine if intermittent vagal stimulation avoids sympathetic activation and reduces infarct size by muscarinic activation of the Akt/glycogen synthase kinase 3 β (GSK-3β) pathway. Rabbits were subjected to 30 min of regional myocardial ischemia and 3 h of reperfusion without vagal stimulation, or the following protocols of right vagus nerve stimulation for 10 min before ischemia: (a) continuous vagal stimulation and (b) intermittent vagal stimulation (cycles of 10 s ON/50 s OFF). Continuous vagal stimulation increased the infarct size (70.7 ± 4.3 %), even after right vagal section (68.6 ± 4.1 %) compared with control group (52.0 ± 3.7 %, p < 0.05). Bilateral vagotomy, pacing, and esmolol abolished the deleterious effect, reaching an infarct size of 43.3 ± 5.1, 43.5 ± 2.1, and 46.0 ± 4.6 % (p < 0.05), respectively. Intermittent stimulation reduced the infarct size to 29.8 ± 3.0 % (p < 0.05 vs I/R). This effect was blocked with atropine (50.2 ± 3.6 %, p < 0.05). Continuous vagal stimulation induced bradycardia and increased the loading conditions and wall stretching of the atria. These changes provoked the co-activation reflex of the sympathetic nervous system, observed by the rise in plasmatic catecholamine levels, which increased the infarct size. Sympathetic co-activation was abolished by continuous vagal stimulation with constant heart rate or parasympathetic deafferentation. Intermittent vagal stimulation attenuated the sympathetic tone and reduced the infarct size by the muscarinic activation of the Akt pathway and GSK-3β inhibition. Continuous stimulation only phosphorylated Akt and GSK-3β when esmolol was administered.

The trigeminal nerve and heart are strongly related through somato-autonomic nervous reflexes that induce rapid changes in cardiovascular function. Several trigeminal reflexes have been described, but the diving and trigeminocardiac reflexes are the most studied. The heart is a target organ dually innervated by the sympathetic and parasympathetic systems. Thus, how cardiac function is regulated during the trigeminal reflexes is the result of the combination of an increased parasympathetic response and increased, decreased, or unaltered sympathetic activity. Various hemodynamic changes occur as a consequence of these alterations in autonomic tone. Often in the oxygen-conserving physiological reflexes such as the diving reflex, sympathetic/parasympathetic co-activation reduces the heart rate and either maintains or increases blood pressure. Conversely, in the trigeminocardiac reflex, bradycardia and hypotension due to parasympathetic activation and sympathetic inactivation tend to be observed. These sudden cardiac innervation disturbances may promote the generation of arrhythmias or myocardial ischemia during surgeries in the trigeminal territory. However, the function and mechanisms involved in the trigeminal reflexes remain to be fully elucidated. The current review provides a brief update and analysis of the features of these reflexes, with special focus on how the autonomic nervous system interacts with cardiovascular function.

Vagal stimulation (VS) during myocardial ischemia and reperfusion has beneficial effects. However, it is not known whether short-term VS applied before ischemia or at the onset of reperfusion protects the ischemic myocardium. This study was designed to determine whether short-term VS applied before ischemia or at the onset of reperfusion reduces myocardial infarct size (IS), mimicking classic preconditioning and postconditioning. A second objective was to study the participation of muscarinic and nicotinic receptors in the protection of both preischemic and reperfusion stimulation. FVB mice were subjected to 30 min of regional myocardial ischemia followed by 2 h of reperfusion without VS, with 10-min preischemic VS (pVS), or with VS during the first 10 min of reperfusion (rVS). pVS reduced IS, and this effect was abolished by atropine and wortmannin. rVS also reduced IS in a similar manner, and this effect was abolished by the α-nicotinic acetylcholine receptor blocker methyllycaconitine. pVS increased Akt and glycogen synthase kinase (GSK)-3β phosphorylation. No changes in Akt and GSK-3β phosphorylation were observed in rVS. Stimulation-mediated IS protection was abolished with the JAK2 blocker AG490. rVS did not modify IL-6 and IL-10 levels in the plasma or myocardium. Splenic denervation and splenectomy did not abolish the protective effect of rVS. In conclusion, pVS and rVS reduced IS by different mechanisms: pVS activated the Akt/GSK-3β muscarinic pathway, whereas rVS activated α-nicotinic acetylcholine receptors and JAK2, independently of the cholinergic anti-inflammatory pathway. NEW & NOTEWORTHY Our data suggest, for the first time, that vagal stimulation applied briefly either before ischemia or at the beginning of reperfusion mimics classic preconditioning and postconditioning and reduces myocardial infarction, activating different mechanisms. We also infer an important role of α-nicotinic receptors for myocardial protection independent of the cholinergic anti-inflammatory pathway.

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