scholarly journals Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca2+signaling

2014 ◽  
Vol 306 (10) ◽  
pp. H1385-H1397 ◽  
Author(s):  
Jie Liu ◽  
Syevda Sirenko ◽  
Magdalena Juhaszova ◽  
Steven J. Sollott ◽  
Shweta Shukla ◽  
...  
Keyword(s):  
Heart Rate ◽  
Cell Function ◽  
Ryanodine Receptors ◽  
Phosphodiesterase Inhibitor ◽  
Receptor Activation ◽  
Functional Changes ◽  
Adult Mice ◽  
Size Number ◽  
Pathway Activation ◽  
Beating Rate

A reduced sinoatrial node (SAN) functional reserve underlies the age-associated decline in heart rate acceleration in response to stress. SAN cell function involves an oscillatory coupled-clock system: the sarcoplasmic reticulum (SR), a Ca2+clock, and the electrogenic-sarcolemmal membrane clock. Ca2+-activated-calmodulin-adenylyl cyclase/CaMKII-cAMP/PKA-Ca2+signaling regulated by phosphodiesterase activity drives SAN cells automaticity. SR-generated local calcium releases (LCRs) activate Na+/Ca2+exchanger in the membrane clock, which initiates the action potential (AP). We hypothesize that SAN cell dysfunctions accumulate with age. We found a reduction in single SAN cell AP firing in aged (20–24 mo) vs. adult (3–4 mo) mice. The sensitivity of the SAN beating rate responses to both muscarinic and adrenergic receptor activation becomes decreased in advanced age. Additionally, age-associated coincident dysfunctions occur stemming from compromised clock functions, including a reduced SR Ca2+load and a reduced size, number, and duration of spontaneous LCRs. Moreover, the sensitivity of SAN beating rate to a cAMP stress induced by phosphodiesterase inhibitor is reduced, as are the LCR size, amplitude, and number in SAN cells from aged vs. adult mice. These functional changes coincide with decreased expression of crucial SR Ca2+-cycling proteins, including SR Ca2+-ATPase pump, ryanodine receptors, and Na+/Ca2+exchanger. Thus a deterioration in intrinsic Ca2+clock kinetics in aged SAN cells, due to deficits in intrinsic SR Ca2+cycling and its response to a cAMP-dependent pathway activation, is involved in the age-associated reduction in intrinsic resting AP firing rate, and in the reduction in the acceleration of heart rate during exercise.

scholarly journals Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice

2012 ◽  
Vol 96 (3) ◽  
pp. 372-380 ◽  
Author(s):  
M. J. Bround ◽  
P. Asghari ◽  
R. B. Wambolt ◽  
L. Bohunek ◽  
C. Smits ◽  
...  
Keyword(s):  
Heart Rate ◽  
Ryanodine Receptors ◽  
Adult Mice ◽  
Control Heart ◽  
Control Heart Rate

FUNCTIONAL STATUS AND ADAPTIVE POTENTIAL IN FOREIGN STUDENTS WITH DIFFERENT TYPES OF VEGETATIVE REGULATION DURING TUITION

2020 ◽  
pp. 118-126
Author(s):  
A.M. Satarkulova
Keyword(s):  
Heart Rate ◽  
Foreign Students ◽  
Autonomic Regulation ◽  
The Body ◽  
Functional Changes ◽  
Different Types ◽  
Type 3 ◽  
Adaptive Abilities

The assessment and dynamic control over students’ status is a very important task. It allows timely detection of prenosological status prior to pathology and health maintenance in students. The objective of the paper is to assess the adaptive abilities of the body, to analyze changes in heart rate variability indicators in students with various types of autonomic regulation, to identify prenosological status and precursory pathological symptoms. Materials and Methods. The study enrolled 302 students from India, aged 21.54±1.43. Programming complex «Psychophysiologist» was used to register the main HRV parameters within 5 minutes. Health status was evaluated according to the index of functional changes and the scale of functional states. Results. N.I. Shlyk (2009) distinguished two groups of students with different types of autonomic regulation: type 1 (53 %) with moderate and type 2 (5 %) with marked characteristics of central regulation profile, type 3 (35 %) with moderate and type 4 (7 %) with marked characteristics of autonomous regulation profile. Main parameters of HRV and adaptation potential were defined for each student.All the parameters characterized functional and health status. Conclusions. It was shown that 82 % of trial subjects (type 1), 53 % (type 2), 94 % (type 3) and 95 % (type 4) demonstrated satisfactory adaptation and their physiological processes were at an optimal level. 18 % of students (type 1) demonstrated reduced adaptive abilities of the body. Moreover, they were under moderate stress. 47 % of subjects (type 2) were also under a significant stress, which was proven by excessively high SI, low SDNN and TP, and an increased index of functional changes. 5 % of students (type 4) revealed dysfunctional characteristics in the heart rhythm, peculiar to pathology. Keywords: foreign students, heart rate variability, types of autonomic regulation, adaptation potential, functional status. Оценка состояния студентов и динамический контроль за ним является важной задачей, поскольку позволяет своевременно выявлять у студентов донозологические состояния, предшествующие патологии, и способствовать сохранению здоровья. Цель. Оценка адаптивных возможностей организма, анализ изменений показателей вариабельности сердечного ритма у студентов с различными типами вегетативной регуляции, выявление донозологических состояний и ранних признаков патологии. Материалы и методы. В исследовании участвовало 302 студента в возрасте 21,54+1,43 года из Индии. Регистрировались основные параметры ВСР в течение 5 мин с использованием программно-аппаратного комплекса «Психофизиолог». Состояние и уровень здоровья оценивались по индексу функциональных изменений и шкале функциональных состояний. Результаты. По способу, предложенному Н.И. Шлык, выделены группы студентов с различными типами вегетативной регуляции: I (53 %) и II типы (5 %) – с умеренным и выраженным преобладанием центрального контура регуляции соответственно, III (35 %) и IV типы (7 %) – с умеренным и выраженным преобладанием автономного контура регуляции соответственно. У каждого из студентов определены основные параметры ВСР и адаптационного потенциала, характеризующие функциональное состояние и уровень здоровья. Выводы. Показано, что для 82 % обследуемых с I типом, 53 % со II типом, 94 % c III типом и 95 % с IV типом регуляции характерно состояние удовлетворительной адаптации, физиологические процессы сохраняются на оптимальном уровне. В группе студентов I типа у 18 % студентов адаптивные возможности организма снижены, выявлено состояние умеренного напряжения. У 47 % обследуемых II типа также зафиксировано состояние резко выраженного напряжения, индикатором которого является чрезмерно высокое значение SI, низкие величины SDNN и ТP, повышенное значение индекса функциональных изменений. В группе студентов с IV типом у 5 % учащихсяв регуляции ритма сердца выявлены дисфункциональные признаки, характерные для патологии. Ключевые слова: иностранные студенты, вариабельность сердечного ритма, типы вегетативной регуляции, адаптационный потенциал, функциональное состояние.

scholarly journals Dopamine Transporter Genetic Reduction Induces Morpho-Functional Changes in the Enteric Nervous System

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 465
Author(s):  
Silvia Cerantola ◽  
Valentina Caputi ◽  
Gabriella Contarini ◽  
Maddalena Mereu ◽  
Antonella Bertazzo ◽  
...  
Keyword(s):  
Nervous System ◽  
Small Intestine ◽  
Enteric Nervous System ◽  
Dopamine Transporter ◽  
Myenteric Plexus ◽  
Receptor Activation ◽  
D1 Receptor ◽  
Functional Changes ◽  
Neurochemical Coding ◽  
The Impact

Antidopaminergic gastrointestinal prokinetics are indeed commonly used to treat gastrointestinal motility disorders, although the precise role of dopaminergic transmission in the gut is still unclear. Since dopamine transporter (DAT) is involved in several brain disorders by modulating extracellular dopamine in the central nervous system, this study evaluated the impact of DAT genetic reduction on the morpho-functional integrity of mouse small intestine enteric nervous system (ENS). In DAT heterozygous (DAT+/−) and wild-type (DAT+/+) mice (14 ± 2 weeks) alterations in small intestinal contractility were evaluated by isometrical assessment of neuromuscular responses to receptor and non-receptor-mediated stimuli. Changes in ENS integrity were studied by real-time PCR and confocal immunofluorescence microscopy in longitudinal muscle-myenteric plexus whole-mount preparations (). DAT genetic reduction resulted in a significant increase in dopamine-mediated effects, primarily via D1 receptor activation, as well as in reduced cholinergic response, sustained by tachykininergic and glutamatergic neurotransmission via NMDA receptors. These functional anomalies were associated to architectural changes in the neurochemical coding and S100β immunoreactivity in small intestine myenteric plexus. Our study provides evidence that genetic-driven DAT defective activity determines anomalies in ENS architecture and neurochemical coding together with ileal dysmotility, highlighting the involvement of dopaminergic system in gut disorders, often associated to neurological conditions.

Abstract 280: Deficiency of FKBP12 in the Heart Leads to Impaired Contractility and Pregnancy Induced Cardiomyopathy

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Joshua Oakes ◽  
Susan Hamilton
Keyword(s):  
Ejection Fraction ◽  
Ryanodine Receptors ◽  
Left Ventricular ◽  
Heart Weight ◽  
Mild Phenotype ◽  
Adult Mice ◽  
Significant Difference ◽  
Fk506 Binding Proteins ◽  
Deficient Mice ◽  
Fractional Shortening

FK506 Binding Proteins (FKBPs) are a family of cis-trans prolyl isomerases that bind rapamycin and FK506. FKBP12 and 12.6 interact with ryanodine receptors (RyR), homotetrameric transmembrane ion channels that regulate Ca2+ release from the sarcoplasmic reticulum (SR). FKBP12 interacts with RyR1 in skeletal muscle and FKBP12.6 interacts with RyR2 in cardiac muscle to regulate the Ca2+ leak properties of these channels. Recently it has been suggested that FKBP12 also plays a role in regulating RyR2 activity. Using mice with a cardiac specific deficiency in FKBP12, we analyzed the role of FKBP12 in cardiac function. We found that both male and female mice with a α-MyHC Cre/Lox mediated deficiency in FKBP12 in the heart (FKBP12 KD) developed a mild dilated cardiomyopathy, with enlarged left ventricular diameter both during systole and diastole, decreased ejection fraction and decreased fractional shortening. To elucidate the mechanism for these effects we assessed Ca2+ sparks in isolated cardiomyocytes. We found an increase in both Ca2+ spark frequency and spark amplitude in FKBP12 cardiac deficient mice without a change in spark duration. Despite a mild phenotype in adult mice, we found that approximately 25% of all pregnancies (26/106) in the FKBP12 deficient mice resulted in the mothers dying following the birth. Autopsies show that these cardiac specific FKBP12 deficient mice had increased heart weight and significantly dilated ventricles compared to female Cre mice. Our data suggest that a cardiac specific deficiency in FKBP12 leads to the development of pregnancy induced cardiomyopathy. Echocardiography on FKBP12 deficient mice one day after giving birth found that there was no significant difference in ejection fraction or fractional shortening compared to α-MyHC Cre control mice. FKBP12 deficient females, however, had larger hearts and 50% (2/4) displayed heart failure and died. In conclusion, we show that FKBP12 does indeed alter Ca2+ handling in the heart and that a loss of FKBP12 leads to the development of pregnancy induced cardiomyopathies in females.

Cardiac enkephalins attenuate vagal bradycardia: interactions with NOS-1-cGMP systems in canine sinoatrial node

2003 ◽  
Vol 285 (5) ◽  
pp. H2001-H2012 ◽  
Author(s):  
Martin Farias ◽  
Keith Jackson ◽  
Michael Johnson ◽  
James L. Caffrey
Keyword(s):  
Heart Rate ◽  
Phosphodiesterase Inhibitor ◽  
Endogenous Opioids ◽  
Muscarinic Agonist ◽  
No Donor ◽  
Parasympathetic Nerve ◽  
Sa Node ◽  
Vagal Control ◽  
Nos Inhibitors ◽  
Vagal Bradycardia

Endogenous opioids and nitric oxide (NO) are recognized modulators of cardiac function. Enkephalins and inhibitors of NO synthase (NOS) both produce similar interruptions in the vagal control of heart rate. This study was conducted to test the hypothesis that NO systems within the canine sinoatrial (SA) node facilitate local vagal transmission and that the endogenous enkephalin methionine-enkephalin-arginine-phenylalanine (MEAP) attenuates vagal bradycardia by interrupting the NOS-cGMP pathway. Microdialysis probes were inserted into the SA node, and they were perfused with nonselective ( Nω-nitro-l-arginine methyl ester) and neuronal (7-nitroindazole) NOS inhibitors. The right vagus nerve was stimulated and both inhibitors gradually attenuated the resulting vagal bradycardia. The specificity of these inhibitions was verified by an equally gradual reversal of the inhibition with an excess of the NOS substrate l-arginine. Introduction of MEAP into the nodal interstitium produced a quickly developing but quantitatively similar interruption of vagal bradycardia that was also slowly reversed by the addition of l-arginine and not by d-arginine. Additional support for convergence of opioid and NO pathways was provided when the vagolytic effects of MEAP were also reversed by the addition of the NO donor S-nitroso- N-acetyl-penicillamine, the protein kinase G activator 8-bromo-cGMP, or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. MEAP and 7-nitroindazole were individually combined with the direct acting muscarinic agonist methacholine to evaluate potential interactions with muscarinic receptors within the SA node. MEAP and 7-nitroindazole were unable to overcome the bradycardia produced by methacholine. These data suggest that NO and enkephalins moderate the vagal control of heart rate via interaction with converging systems that involve the regulation of cAMP within nodal parasympathetic nerve terminals.

scholarly journals PKCδ Mediates Mineralocorticoid Receptor Activation by Angiotensin II to Modulate Smooth Muscle Cell Function

Endocrinology ◽  
2019 ◽  
Vol 160 (9) ◽  
pp. 2101-2114 ◽  
Author(s):  
Qing Lu ◽  
Ana P Davel ◽  
Adam P McGraw ◽  
Sitara P Rao ◽  
Brenna G Newfell ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Mineralocorticoid Receptor ◽  
Target Gene ◽  
Cell Function ◽  
Receptor Activation ◽  
Serine Phosphorylation ◽  
Dependent Manner ◽  
Responsive Element ◽  
The Impact

Abstract Angiotensin II (AngII) and the mineralocorticoid receptor (MR) ligand aldosterone both contribute to cardiovascular disorders, including hypertension and adverse vascular remodeling. We previously demonstrated that AngII activates MR-mediated gene transcription in human vascular smooth muscle cells (SMCs), yet the mechanism and the impact on SMC function are unknown. Using an MR-responsive element-driven transcriptional reporter assay, we confirm that AngII induces MR transcriptional activity in vascular SMCs and endothelial cells, but not in Cos1 or human embryonic kidney-293 cells. AngII activation of MR was blocked by the MR antagonist spironolactone or eplerenone and the protein kinase C-δ (PKCδ) inhibitor rottlerin, implicating both in the mechanism. Similarly, small interfering RNA knockdown of PKCδ in SMCs prevented AngII-mediated MR activation, whereas knocking down of MR blocked both aldosterone- and AngII-induced MR function. Coimmunoprecipitation studies reveal that endogenous MR and PKCδ form a complex in SMCs that is enhanced by AngII treatment in association with increased serine phosphorylation of the MR N terminus. AngII increased mRNA expression of the SMC-MR target gene, FKBP51, via an MR-responsive element in intron 5 of the FKBP51 gene. The impact of AngII on FKBP51 reporter activity and gene expression in SMCs was inhibited by spironolactone and rottlerin. Finally, the AngII-induced increase in SMC number was also blocked by the MR antagonist spironolactone and the PKCδ inhibitor rottlerin. These data demonstrate that AngII activates MR transcriptional regulatory activity, target gene regulation, and SMC proliferation in a PKCδ-dependent manner. This new mechanism may contribute to synergy between MR and AngII in driving SMC dysfunction and to the cardiovascular benefits of MR and AngII receptor blockade in humans.

scholarly journals Transcriptional regulation of structural and functional adaptations in a developing adulthood myocardium

2020 ◽  
Author(s):  
Sini Sunny ◽  
Anil Kumar Challa ◽  
Joseph Barchue ◽  
Muralidharan T. Ramamurthy ◽  
David K Crossman ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Signaling Pathways ◽  
Redox Homeostasis ◽  
Progressive Decline ◽  
Functional Changes ◽  
Adult Mice ◽  
Cycle Growth ◽  
Myocardial Development ◽  
Transcriptional Changes ◽  
Structural Adaptations

AbstractThe development of the heart follows a synergic action of several signaling pathways during gestational, pre- & postnatal stages. The current study aimed to investigate whether the myocardium experiences transcriptional changes during the transition from post-natal to adult hood stages. Herein, we used C57/Bl6/J mice at 4 (28-days; post-natal/PN) and 20 weeks (adulthood/AH) of ages and employed the next generation RNAseq (NGS) to profile the transcriptome and echocardiography analysis to monitor the structural/functional changes in the heart. NGS-based RNA-seq revealed that 1215 genes were significantly upregulated and 2549 were down regulated in the AH versus PN hearts, indicating a significant transcriptional change during this transition. A synchronized cardiac transcriptional regulation through cell cycle, growth hormones, redox homeostasis and metabolic pathways was noticed in both PN and AH hearts. Echocardiography reveals significant structural and functional (i.e. systolic/diastolic) changes during the transition of PN to adult stage. Particularly, a progressive decline in ejection fraction (EF) and cardiac output was observed in AH hearts. These structural adaptations are in line with critical signaling pathways that drive the maturation of heart during AH. Overall, we have presented a comprehensive transcriptomic analysis along with structural-functional relationship during the myocardial development in adult mice.

scholarly journals Circadian modulation of neurons and astrocytes controls synaptic plasticity in hippocampal area CA1

2019 ◽  
Author(s):  
John P. McCauley ◽  
Maurice A. Petroccione ◽  
Lianna Y. D’Brant ◽  
Gabrielle C. Todd ◽  
Nurat Affinnih ◽  
...  
Keyword(s):  
Cognitive Processing ◽  
Temporal Dynamics ◽  
Rhythmic Activity ◽  
Surface Expression ◽  
Receptor Activation ◽  
Cellular Mechanisms ◽  
Functional Changes ◽  
Area Ca1 ◽  
Hippocampal Area

SummaryMost animal species operate according to a 24-hour period set by the suprachiasmatic nucleus (SCN) of the hypothalamus. The rhythmic activity of the SCN is known to modulate hippocampal-dependent memory processes, but the molecular and cellular mechanisms that account for this effect remain largely unknown. Here, we show that there are cell-type specific structural and functional changes that occur with circadian rhythmicity in neurons and astrocytes in hippocampal area CA1. Pyramidal neurons change the surface expression of NMDA receptors, whereas astrocytes change their proximity to synapses. Together, these phenomena alter glutamate clearance, receptor activation and integration of temporally clustered excitatory synaptic inputs, ultimately shaping hippocampal-dependent learningin vivo. We identify corticosterone as a key contributor to changes in synaptic strength. These findings identify important mechanisms through which neurons and astrocytes modify the molecular composition and structure of the synaptic environment, contribute to the local storage of information in the hippocampus and alter the temporal dynamics of cognitive processing.

scholarly journals Regulation of murine myocardial energy metabolism during adrenergic stress studied by in vivo 31P NMR spectroscopy

2003 ◽  
Vol 285 (5) ◽  
pp. H1976-H1979 ◽  
Author(s):  
A. V. Naumova ◽  
R. G. Weiss ◽  
V. P. Chacko
Keyword(s):  
Heart Rate ◽  
Cardiac Metabolism ◽  
High Energy ◽  
Dobutamine Stress ◽  
Resonance Spectroscopy ◽  
31P Nmr Spectroscopy ◽  
Adult Mice ◽  
The Mean ◽  
Large Animals

Image-guided, spatially localized 31P magnetic resonance spectroscopy (MRS) was used to study in vivo murine cardiac metabolism under resting and dobutamine-induced stress conditions. Intravenous dobutamine infusion (24 μg · min–1 · kg body wt–1) increased the mean heart rate by ∼39% from 482 ± 46 per min at baseline to 669 ± 77 per min in adult mice. The myocardial phosphocreatine (PCr)-to-ATP (PCr/ATP) ratio remained unchanged at 2.1 ± 0.5 during dobutamine stress, compared with baseline conditions. Therefore, we conclude that a significant increase in heart rate does not result in a decline in the in vivo murine cardiac PCr/ATP ratio. These observations in very small mammals, viz., mice, at extremely high heart rates are consistent with studies in large animals demonstrating that global levels of high-energy phosphate metabolites do not regulate in vivo myocardial metabolism during physiologically relevant increases in cardiac work.

scholarly journals Using Redox Potential as a Feasible Marker for Banked Blood Quality and the State of Oxidative Stress in Stored Red Blood Cells

2020 ◽  
Author(s):  
Rodney C Daniels ◽  
Hyesun Jun ◽  
Robertson D Davenport ◽  
Maryanne M Collinson ◽  
Kevin R Ward
Keyword(s):  
Oxidative Stress ◽  
Redox Potential ◽  
Red Blood Cells ◽  
Healthy Volunteers ◽  
Blood Cells ◽  
Storage Time ◽  
Cell Function ◽  
Venous Blood ◽  
Functional Changes ◽  
Over Time

Abstract Background Stored Red Blood Cells (RBCs) may undergo oxidative stress over time, with functional changes affecting critical tasks such as oxygen delivery. Central to these changes are oxidation-reduction (redox) reactions and the redox potential (RP) that must be maintained for proper cell function. RP imbalance can lead to oxidative stress that may contribute to storage lesions and transfusion-related morbidities. Direct measures of RP may allow for evaluation of erythrocyte quality and enable corrections of RP prior to transfusion. Methods Multiple random RBC segments were tested, ranging in age from 5 to 40 days at 5 day intervals. RP was recorded by measuring open circuit potential of RBCs using novel nanoporous gold electrodes with Ag/AgCl reference. RP measures were also performed on peripheral venous blood samples from 10 healthy volunteers. RP measures were compared between groups of aged RBCs, and with volunteer blood. Results Stored RBCs show time-dependent increases in RP. There were significant differences in Day 5 RP compared to all other groups (p≤0.005), Day 10-15 vs ages ≥ Day 20 (p≤0.025), Day 20-25 vs Day 40 (p=0.039), and all groups compared to healthy volunteers. RP became more positive over time suggesting ongoing oxidation as RBCs age. However, storage time alone does not predict the ultimate RP value measured from a given unit.Conclusions There are significant differences in RP between freshly stored RBCs and all others, with RP becoming more positive over time. However, storage time alone does not predict RP, indicating RP screening may be important independent of storage time and may serve as a marker of RBC quality and state of oxidative stress. RP measurements may also provide a target by which to restore RP balance in aged pRBCs, improving their clinical effectiveness while reducing associated morbidities.

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