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      Cholinergic Signaling Exerts Protective Effects in Models of Sympathetic Hyperactivity-Induced Cardiac Dysfunction

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          Abstract

          Cholinergic control of the heart is exerted by two distinct branches; the autonomic component represented by the parasympathetic nervous system, and the recently described non-neuronal cardiomyocyte cholinergic machinery. Previous evidence has shown that reduced cholinergic function leads to deleterious effects on the myocardium. Yet, whether conditions of increased cholinergic signaling can offset the pathological remodeling induced by sympathetic hyperactivity, and its consequences for these two cholinergic axes are unknown. Here, we investigated two models of sympathetic hyperactivity: i) the chronic beta-adrenergic receptor stimulation evoked by isoproterenol (ISO), and ii) the α 2A2C-adrenergic receptor knockout (KO) mice that lack pre-synaptic adrenergic receptors. In both models, cholinergic signaling was increased by administration of the cholinesterase inhibitor, pyridostigmine. First, we observed that isoproterenol produces an autonomic imbalance characterized by increased sympathetic and reduced parasympathetic tone. Under this condition transcripts for cholinergic proteins were upregulated in ventricular myocytes, indicating that non-neuronal cholinergic machinery is activated during adrenergic overdrive. Pyridostigmine treatment prevented the effects of ISO on autonomic function and on the ventricular cholinergic machinery, and inhibited cardiac remodeling. α 2A2C-KO mice presented reduced ventricular contraction when compared to wild-type mice, and this dysfunction was also reversed by cholinesterase inhibition. Thus, the cardiac parasympathetic system and non-neuronal cardiomyocyte cholinergic machinery are modulated in opposite directions under conditions of increased sympathetic drive or ACh availability. Moreover, our data support the idea that pyridostigmine by restoring ACh availability is beneficial in heart disease.

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          Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study.

          Beta-blocking agents improve functional status and reduce morbidity in mild-to-moderate heart failure, but it is not known whether they produce such benefits in severe heart failure. We randomly assigned 2289 patients with symptoms of heart failure at rest or on minimal exertion and with an ejection fraction <25% (but not volume-overloaded) to double-blind treatment with either placebo (n=1133) or carvedilol (n=1156) for an average of 10.4 months. Carvedilol reduced the combined risk of death or hospitalization for a cardiovascular reason by 27% (P=0.00002) and the combined risk of death or hospitalization for heart failure by 31% (P=0.000004). Patients in the carvedilol group also spent 27% fewer days in the hospital for any reason (P=0.0005) and 40% fewer days in the hospital for heart failure (P<0.0001). These differences were as a result of both a decrease in the number of hospitalizations and a shorter duration of each admission. More patients felt improved and fewer patients felt worse in the carvedilol group than in the placebo group after 6 months of maintenance therapy (P=0.0009). Carvedilol-treated patients were also less likely than placebo-treated patients to experience a serious adverse event (P=0.002), especially worsening heart failure, sudden death, cardiogenic shock, or ventricular tachycardia. In euvolemic patients with symptoms at rest or on minimal exertion, the addition of carvedilol to conventional therapy ameliorates the severity of heart failure and reduces the risk of clinical deterioration, hospitalization, and other serious adverse clinical events.
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            Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats.

            Diminished cardiac vagal activity and higher heart rate predict a high mortality rate of chronic heart failure (CHF) after myocardial infarction. We investigated the effects of chronic electrical stimulation of the vagus nerve on cardiac remodeling and long-term survival in an animal model of CHF after large myocardial infarction. Two weeks after the ligation of the left coronary artery, surviving rats were randomized to vagal- and sham-stimulated groups. Using an implantable miniature radio-controlled electrical stimulator, we stimulated the right vagal nerve of CHF rats for 6 weeks. The intensity of electrical stimulation was adjusted for each rat, so that the heart rate was lowered by 20 to 30 beats per minute. The treated rats had significantly lower left ventricular end-diastolic pressure (17.1+/-5.9 versus 23.5+/-4.2 mm Hg, P<0.05) and higher maximum dp/dt of left ventricular pressure (4152+/-237 versus 2987+/-192 mm Hg/s, P<0.05) than the untreated rats. Improvement of cardiac pumping function was accompanied by a decrease in normalized biventricular weight (2.75+/-0.25 versus 3.14+/-0.22 g/kg, P<0.01). Although the 140-day survival of the untreated group was only half, vagal stimulation markedly improved the survival rate (86% versus 50%, P=0.008). Vagal stimulation therapy achieved a 73% reduction in a relative risk ratio of death. Vagal nerve stimulation markedly improved the long-term survival of CHF rats through the prevention of pumping failure and cardiac remodeling.
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              Mice deficient for the vesicular acetylcholine transporter are myasthenic and have deficits in object and social recognition.

              An important step for cholinergic transmission involves the vesicular storage of acetylcholine (ACh), a process mediated by the vesicular acetylcholine transporter (VAChT). In order to understand the physiological roles of the VAChT, we developed a genetically altered strain of mice with reduced expression of this transporter. Heterozygous and homozygous VAChT knockdown mice have a 45% and 65% decrease in VAChT protein expression, respectively. VAChT deficiency alters synaptic vesicle filling and affects ACh release. Whereas VAChT homozygous mutant mice demonstrate major neuromuscular deficits, VAChT heterozygous mice appear normal in that respect and could be used for analysis of central cholinergic function. Behavioral analyses revealed that aversive learning and memory are not altered in mutant mice; however, performance in cognitive tasks involving object and social recognition is severely impaired. These observations suggest a critical role of VAChT in the regulation of ACh release and physiological functions in the peripheral and central nervous system.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                3 July 2014
                : 9
                : 7
                : e100179
                Affiliations
                [1 ]Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
                [2 ]Department of Biochemistry, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
                [3 ]Department of Morphology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
                [4 ]National Institute of Science and Technology in Nanobiopharmaceutics, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
                [5 ]School of Physical Education and Sport, Universidade de São Paulo, São Paulo, Brazil
                [6 ]Robarts Research Institute, University of Western Ontario, Department of Physiology and Pharmacology, Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Canada
                University of Milan, Italy
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SG MAMP RASS MAPF PCB. Performed the experiments: MG PWMA AL CRR DDD AML PMM MBM RRR ML. Analyzed the data: MG PWMA AL CRR DDD AML PMM MBM RRR ML MAPF SG. Contributed reagents/materials/analysis tools: RASS MAPF PCB RRR MAMP SG PMM. Wrote the paper: SG MAMP MG.

                Article
                PONE-D-13-40406
                10.1371/journal.pone.0100179
                4081111
                24992197
                23335c05-7613-4819-9c57-450a17315ca2
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 1 October 2013
                : 23 May 2014
                Page count
                Pages: 9
                Funding
                This work was supported by grants from NIH R03TW008425 from the Fogarty International Center (Guatimosim S), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado de Minas Gerais, PRONEX ( APQ-04334-10 ) and National Institute of Science and Technology in Nanobiopharmaceutics. MAMP is supported by the Heart and Stroke Foundation of Ontario (Grant-in aid NA6656). Gavioli, M is recipient of CNPq PhD fellowship at the Post-graduation Program in Biological Science: Physiology and Pharmacology at UFMG. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Anatomy
                Cardiovascular Anatomy
                Biochemistry
                Neurochemistry
                Neurochemicals
                Cell Biology
                Cell Physiology
                Molecular Cell Biology
                Genetics
                Gene Expression
                Organisms
                Animals
                Vertebrates
                Mammals
                Rodents
                Rats
                Neuroscience
                Cellular Neuroscience
                Physiology
                Cardiovascular Physiology
                Blood Circulation
                Medicine and Health Sciences
                Cardiology
                Heart Failure
                Diagnostic Medicine
                Diagnostic Radiology
                Ultrasound Imaging
                Echocardiography
                Research and Analysis Methods
                Model Organisms
                Animal Models

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