Control of the Heart by Neurones of the Dorsal Motor Nucleus of the Vagus Nerve (DVMN) in Health and Disease

The strength, functional significance and origins of parasympathetic (vagal) control of left ventricular function remain controversial. Experimental studies conducted on rats and mice using methods of genetic neuronal targeting, functional neuroanatomical mapping, and pharmaco- and optogenetics were employed to test the hypothesis that parasympathetic control of the left ventricle is provided by vagal preganglionic neurones of the dorsal motor nucleus (DVMN). The results of the experiments described in this thesis suggest that (i) activity of the DVMN vagal preganglionic neurones are responsible for tonic parasympathetic control of ventricular excitability, likely to be mediated by nitric oxide; (ii) synuclein deficiency (a model relevant to Parkinson’s disease) results in a reduction in the activity of the DVMN neurones affecting the electrophysiological properties of the ventricle; (iii) tonic muscarinic influence on left ventricular contractility is provided by a subpopulation of vagal preganglionic neurones located in the caudal region of the left DVMN; (iv) reduced activity of the DVMN neurones is associated with a severely compromised aerobic exercise capacity; (v) increased activity of the DVMN neurones improves left ventricular performance and exercise capacity; and (vi) recruitment of the DVMN activity is sufficient to preserve exercise capacity and left ventricular function in heart failure developing after a myocardial infarction. These findings provide the first insight into the central nervous substrate that underlies functional parasympathetic innervation of the ventricles and highlight its importance in controlling cardiac function. The data obtained suggest that the DVMN neuronal projections provide tonic restraining influence on the ventricular arrhythmic potential and contractility, and have a trophic effect maintaining the ability of the heart to mount an appropriate inotropic response during exercise. As such, DVMN activity has a significant beneficial effect on the healthy left ventricle as well as ventricular myocardium compromised by occlusion of a major coronary artery

Origins of the vagal drive controlling left ventricular contractility

The strength, functional significance and origins of direct parasympathetic innervation of the left ventricle (LV) remain controversial. In the present study we used an anaesthetized rat model to first confirm the presence of tonic inhibitory vagal influence on LV inotropy. Using genetic neuronal targeting and functional neuroanatomical mapping we tested the hypothesis that parasympathetic control of LV contractility is provided by vagal preganglionic neurones located in the dorsal motor nucleus (DVMN). It was found that under systemic β-adrenoceptor blockade (atenolol) combined with spinal cord (C1) transection (to remove sympathetic influences), intravenous administration of atropine increases LV contractility in rats anaesthetized with urethane, but not in animals anaesthetized with pentobarbital. Increased LV contractility in rats anaesthetized with urethane was also observed when DVMN neurones targeted bilaterally to express an inhibitory Drosophila allatostatin receptor were silenced by application of an insect peptide allatostatin. Microinjections of glutamate and muscimol to activate or inhibit neuronal cell bodies in distinct locations along the rostro-caudal extent of the left and right DVMN revealed that vagal preganglionic neurones which have an impact on LV contractility are located in the caudal region of the left DVMN. Changes in LV contractility were only observed when this subpopulation of DVMN neurones was activated or inhibited. These data confirm the existence of a tonic inhibitory muscarinic influence on LV contractility. Activity of a subpopulation of DVMN neurones provides functionally significant parasympathetic control of LV contractile function. This article is protected by copyright. All rights reserved

Cardiac vagal preganglionic neurones: An update

The autonomic nervous system controls the heart by dynamic recruitment and withdrawal of cardiac parasympathetic and sympathetic activities. These activities are generated by groups of sympathoexcitatory and vagal preganglionic neurones residing in a close proximity to each other within well-defined structures of the brainstem. This short essay provides a general overview and an update on the latest developments in our understanding of the central nervous origins and functional significance of cardiac vagal tone. Significant experimental evidence suggests that distinct groups of cardiac vagal preganglionic neurones with different patterns of activity control nodal tissue (controlling the heart rate and atrioventricular conductance) and the ventricular myocardium (modulating its contractility and excitability)

PINK1 deficiency in β-cells increases basal insulin secretion and improves glucose tolerance in mice

The Parkinson's disease (PD) gene, PARK6, encodes the PTEN-induced putative kinase 1 (PINK1) mitochondrial kinase, which provides protection against oxidative stress-induced apoptosis. Given the link between glucose metabolism, mitochondrial function and insulin secretion in β-cells, and the reported association of PD with type 2 diabetes, we investigated the response of PINK1-deficient β-cells to glucose stimuli to determine whether loss of PINK1 affected their function. We find that loss of PINK1 significantly impairs the ability of mouse pancreatic β-cells (MIN6 cells) and primary intact islets to take up glucose. This was accompanied by higher basal levels of intracellular calcium leading to increased basal levels of insulin secretion under low glucose conditions. Finally, we investigated the effect of PINK1 deficiency in vivo and find that PINK1 knockout mice have improved glucose tolerance. For the first time, these combined results demonstrate that loss of PINK1 function appears to disrupt glucose-sensing leading to enhanced insulin release, which is uncoupled from glucose uptake, and suggest a key role for PINK1 in β-cell function

Brainstem hypoxia contributes to the development of hypertension in the spontaneously hypertensive rat.

Systemic arterial hypertension has been previously suggested to develop as a compensatory condition when central nervous perfusion/oxygenation is compromised. Principal sympathoexcitatory C1 neurons of the rostral ventrolateral medulla oblongata (whose activation increases sympathetic drive and the arterial blood pressure) are highly sensitive to hypoxia, but the mechanisms of this O2 sensitivity remain unknown. Here, we investigated potential mechanisms linking brainstem hypoxia and high systemic arterial blood pressure in the spontaneously hypertensive rat. Brainstem parenchymal PO2 in the spontaneously hypertensive rat was found to be ≈15 mm Hg lower than in the normotensive Wistar rat at the same level of arterial oxygenation and systemic arterial blood pressure. Hypoxia-induced activation of rostral ventrolateral medulla oblongata neurons was suppressed in the presence of either an ATP receptor antagonist MRS2179 or a glycogenolysis inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol, suggesting that sensitivity of these neurons to low PO2 is mediated by actions of extracellular ATP and lactate. Brainstem hypoxia triggers release of lactate and ATP which produce excitation of C1 neurons in vitro and increases sympathetic nerve activity and arterial blood pressure in vivo. Facilitated breakdown of extracellular ATP in the rostral ventrolateral medulla oblongata by virally-driven overexpression of a potent ectonucleotidase transmembrane prostatic acid phosphatase results in a significant reduction in the arterial blood pressure in the spontaneously hypertensive rats (but not in normotensive animals). These results suggest that in the spontaneously hypertensive rat, lower PO2 of brainstem parenchyma may be associated with higher levels of ambient ATP and l-lactate within the presympathetic circuits, leading to increased central sympathetic drive and concomitant sustained increases in systemic arterial blood pressure

Cardiac Vagus and Exercise.

Lower resting heart rate and high autonomic vagal activity are strongly associated with superior exercise capacity, maintenance of which is essential for general well-being and healthy aging. Recent evidence obtained in experimental studies using the latest advances in molecular neuroscience, combined with human exercise physiology, physiological modeling, and genomic data suggest that the strength of cardiac vagal activity causally determines our ability to exercise

The Role Of Parafacial Neurons In The Control Of Breathing During Exercise

Neuronal cell groups residing within the retrotrapezoid nucleus (RTN) and C1 area of the rostral ventrolateral medulla oblongata contribute to the maintenance of resting respiratory activity and arterial blood pressure, and play an important role in the development of cardiorespiratory responses to metabolic challenges (such as hypercapnia and hypoxia). In rats, acute silencing of neurons within the parafacial region which includes the RTN and the rostral aspect of the C1 circuit (pFRTN/C1), transduced to express HM4D (Gi-coupled) receptors, was found to dramatically reduce exercise capacity (by 60%), determined by an intensity controlled treadmill running test. In a model of simulated exercise (electrical stimulation of the sciatic or femoral nerve in urethane anaesthetised spontaneously breathing rats) silencing of the pFRTN/C1 neurons had no effect on cardiovascular changes, but significantly reduced the respiratory response during steady state exercise. These results identify a neuronal cell group in the lower brainstem which is critically important for the development of the respiratory response to exercise and, determines exercise capacity

Molecular Mechanisms Linking Autonomic Dysfunction and Impaired Cardiac Contractility in Critical Illness

Objectives: Molecular mechanisms linking autonomic dysfunction with poorer clinical outcomes in critical illness remain unclear. We hypothesized that baroreflex dysfunction alone is sufficient to cause cardiac impairment through neurohormonal activation of (NADPH oxidase-dependent) oxidative stress resulting in increased expression of G-protein coupled receptor kinase (GRK)-2, a key negative regulator of cardiac function. Design: Laboratory/clinical investigations. Setting: University laboratory/medical centers. Subjects: Adult rats; wild-type/NAPDH oxidase subunit-2 (NOX-2) deficient mice; elective surgical patients. Interventions: Cardiac performance was assessed by transthoracic echocardiography following experimental baroreflex dysfunction (BD, sino-aortic denervation) in rats and mice. Immunoblots assessed GPCR recycling proteins expression in rodent cardiomyocytes and patient mononuclear leukocytes. In surgical patients, heart rate recovery after cardio-pulmonary exercise testing, time/frequency measures of parasympathetic parameters were related to the presence/absence of BD (defined by spontaneous baroreflex sensitivity of <6ms.mmHg(-1)). The associations of BD with intraoperative cardiac function and outcomes were assessed. Measurements and Main Results: Experimental BD in rats and mice resulted in impaired cardiac contractility and upregulation of GRK-2 expression. In mice, genetic deficiency of gp91 NADPH-oxidase (NOX-2) subunit prevented upregulation of GRK-2 expression in conditions of BD and preserved cardiac function. BD was present in 81/249 (32.5%) patients, and was characterized by lower parasympathetic tone and increased GRK-2 expression in mononuclear leukocytes. BD in patients was also associated with impaired intraoperative cardiac contractility. Critical illness and mortality were more frequent in surgical patients with BD (relative risk: 1.66 [95%CI:1.16-2.39]; p=0.006). Conclusions: Reduced baroreflex sensitivity is associated with NOX-2 mediated upregulation of GRK-2 expression in cardiomyocytes and impaired cardiac contractility. Autonomic dysfunction predisposes patients to the development of critical illness and increases mortality.Objectives: Molecular mechanisms linking autonomic dysfunction with poorer clinical outcomes in critical illness remain unclear. We hypothesized that baroreflex dysfunction alone is sufficient to cause cardiac impairment through neurohormonal activation of (NADPH oxidase-dependent) oxidative stress resulting in increased expression of G-protein coupled receptor kinase (GRK)-2, a key negative regulator of cardiac function. Design: Laboratory/clinical investigations. Setting: University laboratory/medical centers. Subjects: Adult rats; wild-type/NAPDH oxidase subunit-2 (NOX-2) deficient mice; elective surgical patients. Interventions: Cardiac performance was assessed by transthoracic echocardiography following experimental baroreflex dysfunction (BD, sino-aortic denervation) in rats and mice. Immunoblots assessed GPCR recycling proteins expression in rodent cardiomyocytes and patient mononuclear leukocytes. In surgical patients, heart rate recovery after cardio-pulmonary exercise testing, time/frequency measures of parasympathetic parameters were related to the presence/absence of BD (defined by spontaneous baroreflex sensitivity of <6ms.mmHg(-1)). The associations of BD with intraoperative cardiac function and outcomes were assessed. Measurements and Main Results: Experimental BD in rats and mice resulted in impaired cardiac contractility and upregulation of GRK-2 expression. In mice, genetic deficiency of gp91 NADPH-oxidase (NOX-2) subunit prevented upregulation of GRK-2 expression in conditions of BD and preserved cardiac function. BD was present in 81/249 (32.5%) patients, and was characterized by lower parasympathetic tone and increased GRK-2 expression in mononuclear leukocytes. BD in patients was also associated with impaired intraoperative cardiac contractility. Critical illness and mortality were more frequent in surgical patients with BD (relative risk: 1.66 [95%CI:1.16-2.39]; p=0.006). Conclusions: Reduced baroreflex sensitivity is associated with NOX-2 mediated upregulation of GRK-2 expression in cardiomyocytes and impaired cardiac contractility. Autonomic dysfunction predisposes patients to the development of critical illness and increases mortality