scholarly journals Global Disturbances in Autonomic Function Yield Cardiovascular Instability and Hypertension in the Chromogranin A Null Mouse

Endocrinology ◽  
2009 ◽  
Vol 150 (11) ◽  
pp. 5027-5035 ◽  
Author(s):  
Jiaur R. Gayen ◽  
Yusu Gu ◽  
Daniel T. O'Connor ◽  
Sushil K. Mahata
Keyword(s):  
Chromogranin A ◽  
Baroreflex Sensitivity ◽  
Autonomic Function ◽  
Plasma Catecholamines ◽  
Conscious State ◽  
Null Mouse ◽  
Wild Type ◽  
Cholinergic Antagonist ◽  
Adrenergic Antagonist ◽  
Muscarinic Cholinergic

We reported previously that chromogranin A (Chga) knockout (KO) mice are hypertensive and hyperadrenergic. Here we sought to determine the basis of such alterations by probing physiological, biochemical, and pharmacological responses to perturbations of the autonomic nervous system. In the conscious state, KO mice had substantially elevated basal high blood pressure (BP) and heart rate (HR); immobilization stress caused increments in systolic BP and HR in both wild-type (WT) and KO mice, with higher maxima but blunted increments in the KO state. Catestatin (CST; CHGA352–372) selectively diminished stress-induced increments in BP and HR in KO mice, implicating CST as an antihypertensive peptide, even in stressful conditions. Heightened plasma catecholamines in KO mice returned to WT level after CST. Stress caused further increments in catecholamines in WT mice but no change in KO mice. KO mice displayed diminished baroreflex sensitivity in response to either phenylephrine or sodium nitroprusside, accounting for exaggerated pressor and depressor responses to these compounds; baroreceptor function was normalized by CST. To probe the relative roles of endogenous/basal sympathetic vs. parasympathetic tone in control of BP and HR, we used the muscarinic-cholinergic antagonist atropine or the β-adrenergic antagonist propranolol; HR and BP responses to each antagonist were exaggerated in KO animals. We conclude that ablation of Chga expression results in global disturbances in autonomic function, both sympathetic and parasympathetic, that can be abrogated (or rescued), at least in part, by replacement of CST. The results point to mechanisms whereby CHGA and its CST fragment act to control cardiovascular homeostasis.

Abstract 302: Negative Effects of Fludrocortisone Treatment in Adolescents with POTS and Syncope

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Hossam A Shaltout ◽  
John E Fortunato ◽  
Debra I Diz
Keyword(s):  
Baroreflex Sensitivity ◽  
Autonomic Function ◽  
Tilt Test ◽  
Postural Orthostatic Tachycardia Syndrome ◽  
Mean Square ◽  
Negative Effects ◽  
Time Points ◽  
Treatment Support ◽  
Pharmacologic Agents ◽  
Upright Tilt

Fludrocortisone (Florinef) is commonly used to treat symptoms associated with postural orthostatic tachycardia syndrome (POTS). We have previously shown that Florinef treatment in children with POTS improved the changes in baroreflex sensitivity (BRS) and heart rate variability (HRV) measured as the root of mean square of successive differences (rMSSD) during upright tilt compared to untreated children with POTS. We noticed that a subgroup of our patients experienced POTS symptoms followed by syncope at later time points during the 45 min tilt test in both Florinef treated and untreated groups. We stratified based on syncope and compared the effect of Florinef treatment on both groups. Of the 32 POTS patients studied (15.0 ± 0.6 yrs old), 14 were treated with Florinef of whom 5 had syncope, and 18 were untreated of whom 5 had syncope. In the non-syncopal group, subjects treated with Florinef for a minimum of 4 wks compared with untreated POTS without syncope had similar baseline supine measures of MAP, HR, BRS and HRV before tilt, and less reduction in BRS during tilt measured as Seq UP (-7.1 ± 2.5 vs -15.1 ± 3.5 ms/mmHg; p<0.03), a trend for less attenuation in HRV (-22.4 ± 6.4 vs -35.3 ± 6.3 ms; p<0.07) and reduced tachycardia with tilt (25 ± 6 vs 38 ± 4 beats/min; p<0.02) compared with the untreated group. Meanwhile, in the syncopal group, Florinef-treated patients at baseline in the supine position before tilt had worse BRS function measured as Seq UP compared to untreated (11.9 ± 2.2 vs 26.0 ± 6.7 ms/mm Hg; p<0.04), a tendency for lower HRV (40.8 ± 7 vs 61.2 ± 12 ms; p<0.08) and higher HR (82 ± 3 vs 65 ± 7 beats/min; p<0.02) than untreated POTS patients with syncope. In contrast to non-syncopal POTS, the HR increase during tilt in syncopal POTS subjects was not reduced by the Florinef. The impairments in baseline supine autonomic function in POTS with syncope patients treated with Florinef relative to untreated patients and lack of improvement in the performance upon upright tilt suggests that POTS patients should be stratified by syncope status during the tilt test prior to assigning this treatment regimen. Additional studies are needed to better define these patients and to determine if other pharmacologic agents would provide a more optimal treatment. Support: AHA12CRP9420029

Abstract 422: Cardiovascular Regulation in Mice with Overexpression of the Gene of Vesicular Acetylcholine Transporter (VAChT)

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Geisa C Tezini ◽  
Silvia Guatimosim ◽  
Diogo A Guimarães ◽  
Mauro Oliveira ◽  
Rubens Fazan ◽  
...  
Keyword(s):  
Baroreflex Sensitivity ◽  
Fold Increase ◽  
Cardiovascular Regulation ◽  
Transgenic Animal ◽  
Vesicular Acetylcholine Transporter ◽  
Wild Type ◽  
Autonomic Blockade ◽  
Release Of Acetylcholine ◽  
Cardiovascular Autonomic Regulation ◽  
Spontaneous Baroreflex

It was recently developed a transgenic animal model with overexpression of cholinergic neurotransmission. This mouse, named ChAT-ChR2-EYFP, has several extra copies of the vesicular acetylcholine transporter (VAChT) gene and exhibits three-fold increase in the release of acetylcholine. However, the consequences of overexpression of VAChT protein to the cardiovascular system have not yet been characterized. Therefore, we have investigated the effects of the overexpression of the gene of VAChT on arterial pressure (AP) and heart rate (HR) as well as the autonomic cardiovascular regulation. Mice were assigned into two groups: Wild-type (WT, n=7) and ChAT-ChR2-EYFP (n=7). These animals were anesthetized (isoflurane) and implanted with probes to record AP by telemetry. After 10 days, the mice had basal AP and HR recorded continuously. Assessment of the autonomic function was conducted throughout the following approaches: 1) cardiac sympathovagal balance evaluated by HR responses to methylatropine and propranolol; 2) overall HR variability; 3) spontaneous baroreflex sensitivity by the sequence analysis. ChAT-ChR2-EYFP mice showed lower basal HR (461±8 vs. 502±14 bpm, p<0.01) but similar AP as compared to WT mice. ChAT-ChR2-EYFP mice exhibited higher vagal tone (Δbpm, 169±14 vs. 117±6, p=0.03) and lower HR after double autonomic blockade (IHR, 456±8 vs. 509±11 bpm, p<0.001). HR variability was similar between groups (SDNN: 88±16 vs. 65±7 ms; RMSSD: 11.4±1 vs. 9.7±0.5 ms). However, the baroreflex sensitivity (7.5±1.5 vs. 4.1±0.5 ms/mmHg, p=0.05) was higher in ChAT-ChR2-EYFP mice. Altogether, the results show that the cardiovascular autonomic regulation of ChAT-ChR2-EYFP mice is characterized by higher parasympathetic tone, combined with a lower basal HR and IHR. Moreover, these mice present greater baroreflex sensitivity.

Evidence for increased myofibrillar mobility in desmin-null mouse skeletal muscle

2002 ◽  
Vol 205 (3) ◽  
pp. 321-325
Author(s):  
Sameer B. Shah ◽  
Fong-Chin Su ◽  
Kimberly Jordan ◽  
Derek J. Milner ◽  
Jan Fridén ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Quantitative Estimation ◽  
Horizontal Displacement ◽  
Radial Force ◽  
Null Mouse ◽  
Force Transmission ◽  
Wild Type ◽  
Functional Roles ◽  
Fifth Toe ◽  
Knockout Animals

SUMMARY Quantitative electron microscopy was used to characterize the longitudinal mobility of myofibrils during muscle extension to investigate the functional roles of skeletal muscle intermediate filaments. Extensor digitorum longus fifth toe muscles from wild-type (+/+) and desmin-null (des –/–) animals were passively stretched to varying lengths, and the horizontal displacement of adjacent Z-disks in neighboring myofibrils (Δxmyo) and average sarcomere length (SL) were calculated. At short SL (&lt;2.20 μm), wild-type and desmin-null Δxmyo were not significantly different, although there was a trend towards greater Z-disk misalignment in muscles from knockout animals (Δxmyo 0.34±0.04 μm versus 0.22±0.09 μm; P&gt;0.2; means ± s.e.m.). However, at higher SL (&gt;2.90 μm), muscles from knockout animals displayed a dramatically increased Δxmyo relative to wild-type muscles (0.49±0.10 μm versus 0.25±0.07 μm; P&lt;0.05). The results, which establish a maximum extension of the desmin network surrounding the Z-disk, provide what we believe to be the first quantitative estimation of the functional limits of the desmin intermediate filament system in the presence of an intact myofibrillar lattice. The existence of a limit on the extension of desmin suggests a mechanism for the recruitment of desmin into a network of force transmission, whether as a longitudinal load bearer or as a component in a radial force-transmission system.

Abstract P206: Improvement Of Autonomic Function, Sleep, Depression, Anxiety, And Stress In Military Personnel With Traumatic Stress After Use Of A Closed Loop Neurotechnology

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Catherine Tegeler ◽  
Lindsay Howard ◽  
Kenzie L Brown ◽  
Faiza Asif-Fraz ◽  
Dawn C Kellar ◽  
...  
Keyword(s):  
Heart Rate ◽  
Traumatic Stress ◽  
Baroreflex Sensitivity ◽  
Primary Outcome ◽  
Closed Loop ◽  
Autonomic Function ◽  
Brain Activity ◽  
Acoustic Stimulation ◽  
Beneficial Effects ◽  
Symptom Scores

Introduction: Symptoms associated with military-related traumatic stress (MTS) include insomnia, depression, anxiety, and impaired autonomic control. High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®) is a noninvasive, closed-loop acoustic stimulation technology that identifies dominant brain frequencies and translates them in real time into audible tones of variable pitch and timing, to support self-optimization of brain activity. Objective: Evaluate changes in autonomic and symptoms scores after use of HIRREM in subjects enrolled in a pilot study for MTS. Methods: Thirty-two service members or Veterans (1 female), mean (SD) age 40.8 (6.4), with MTS symptoms for 7.3 years (3.9), received 19.2 (1.0) HIRREM sessions over 12 days. Continuous recordings of blood pressure and heart rate, for analysis of baroreflex sensitivity (BRS) and heart rate variability (HRV), were done at V1 and V2. Symptom inventories collected before (Visit 1, V1), immediately after (primary outcome, V2, n = 32), and at 1, 3, and 6 months after completion of HIRREM included traumatic stress (PCL-M), insomnia (ISI), depression (CES-D), and anxiety (GAD-7). Paired t-tests were performed. Results: HIRREM improved BRS measured as HF alpha (10.8 ms/mmHg, 2.5, p<0.001), Sequence Down (7.3 ms/mmHg, 2.1, p<0.001), Sequence Up (7.6 ms/mmHg, 2.4, p=0.001), and Sequence All (7.3 ms/mmHg, 1.8, p<0.001), as well as HRV; SDNN (14.1 ms, 3.6, p=0.005), rMSSD (12.8 ms, 2.6, p<0.05). MAP dropped 2.7 mmHg, 1.2, p<0.05 and SAP dropped 5.9 mmHg, 1.8, p=0.007. Mean symptom scores were reduced at V2; PCL-M [-12.9 (± 9.1), p<0.001], ISI [-6.3 (± 5.0), p<0.001], CES-D [-13.7 (±9.2), p<0.001], and GAD-7 [-6.7. (± 4.7), p<0.001]. Symptom scores improved 1-month post-HIRREM for all measures, and clinically relevant and significant benefits persist at 3 and 6 months. Conclusions: These results suggest improved autonomic cardiovascular regulation and statistically significant reduction in scales associated with the use of HIRREM for symptoms of MTS. Controlled trials could provide important insights regarding both the mechanisms associated with the beneficial effects of HIRREM, and the functional disturbances underlying MTS.

Evaluation of Adrenergic Function

2016 ◽  
pp. 635-642
Author(s):  
Phillip A. Low
Keyword(s):  
Blood Pressure ◽  
Recovery Time ◽  
Baroreflex Sensitivity ◽  
Autonomic Function ◽  
Pressure Change ◽  
Pressure Recovery ◽  
Blood Pressure Change ◽  
Noninvasive Evaluation ◽  
Peripheral Neuropathies ◽  
Heart Period

Peripheral adrenergic function is important in the maintenance of postural normotension. It may be impaired in peripheral neuropathies, and this may be manifested as alterations in acral temperature, color, or sweating. Simple, accurate, and reproducible tests of peripheral adrenergic function are now routinely used in clinical autonomic laboratories. For noninvasive evaluation of autonomic function, tests of peripheral adrenergic function can be used to separately evaluate the vagal and adrenergic components of baroreflex sensitivity. The vagal component is derived from the heart period response to blood pressure change and the adrenergic component by the blood pressure recovery time in response to the preceding fall in blood pressure, induced by the Valsalva maneuver.This chapter describes methods used to determine peripheral adrenergic function and their value and shortcomings.

Comparison of phenylephrine bolus and infusion methods in baroreflex measurements

1990 ◽  
Vol 69 (3) ◽  
pp. 962-967 ◽  
Author(s):  
J. T. Sullebarger ◽  
C. S. Liang ◽  
P. D. Woolf ◽  
A. E. Willick ◽  
J. F. Richeson
Keyword(s):  
Heart Rate ◽  
Arterial Pressure ◽  
Baroreflex Sensitivity ◽  
Heart Rate Response ◽  
Pressor Response ◽  
Plasma Catecholamines ◽  
Systolic Arterial Pressure ◽  
Normal Subjects ◽  
Vagus Nerves ◽  
Baroreflex Control

Phenylephrine (PE) bolus and infusion methods have both been used to measure baroreflex sensitivity in humans. To determine whether the two methods produce the same values of baroreceptor sensitivity, we administered intravenous PE by both bolus injection and graded infusion methods to 17 normal subjects. Baroreflex sensitivity was determined from the slope of the linear relationship between the cardiac cycle length (R-R interval) and systolic arterial pressure. Both methods produced similar peak increases in arterial pressure and reproducible results of baroreflex sensitivity in the same subjects, but baroreflex slopes measured by the infusion method (9.9 +/- 0.7 ms/mmHg) were significantly lower than those measured by the bolus method (22.5 +/- 1.8 ms/mmHg, P less than 0.0001). Pretreatment with atropine abolished the heart rate response to PE given by both methods, whereas plasma catecholamines were affected by neither method of PE administration. Naloxone pretreatment exaggerated the pressor response to PE and increased plasma beta-endorphin response to PE infusion but had no effect on baroreflex sensitivity. Thus our results indicate that 1) activation of the baroreflex by the PE bolus and infusion methods, although reproducible, is not equivalent, 2) baroreflex-induced heart rate response to a gradual increase in pressure is less than that seen with a rapid rise, 3) in both methods, heart rate response is mediated by the vagus nerves, and 4) neither the sympathetic nervous system nor the endogenous opiate system has a significant role in mediating the baroreflex control of heart rate to a hypertensive stimulus in normal subjects.

scholarly journals Induction of long-lasting depolarization in medioventral medulla neurons by cholinergic input from the pedunculopontine nucleus

2005 ◽  
Vol 99 (3) ◽  
pp. 1127-1137 ◽  
Author(s):  
Keiko Mamiya ◽  
Kevin Bay ◽  
R. D. Skinner ◽  
E. Garcia-Rill
Keyword(s):  
Action Potential ◽  
Pedunculopontine Nucleus ◽  
Intracellular Recordings ◽  
Stable States ◽  
Cholinergic Agonist ◽  
Firing Rates ◽  
Cholinergic Antagonist ◽  
Muscarinic Cholinergic ◽  
Stimulation Of

Stimulation of the pedunculopontine nucleus (PPN) is known to induce changes in arousal and postural/locomotor states by activation of such descending targets as the caudal pons and the medioventral medulla (MED). Previously, PPN stimulation was reported to induce prolonged responses (PRs) in intracellularly recorded caudal pontine neurons in vitro. The present study used intracellular recordings in semihorizontal slices from rat brain stem (postnatal days 12–21) to determine responses in MED neurons following PPN stimulation. One-half (40/81) of MED neurons showed PRs after PPN stimulation. MED neurons with PRs had shorter duration action potential, longer duration afterhyperpolarization, and higher amplitude afterhyperpolarization than non-PR MED neurons. PR MED neurons were significantly larger (568 ± 44 μm2) than non-PR MED neurons (387 ± 32 μm2). The longest mean duration PRs and maximal firing rates during PRs were induced by PPN stimulation at 60 Hz compared with 10, 30, or 90 Hz. The muscarinic cholinergic agonist carbachol induced depolarization in all PR neurons tested, and the muscarinic cholinergic antagonist scopolamine reduced or blocked carbachol- and PPN stimulation-induced PRs in all MED neurons tested. These findings suggest that PPN stimulation-induced PRs may be due to activation of muscarinic receptor-sensitive channels, allowing MED neurons to respond to a transient, frequency-dependent depolarization with long-lasting stable states. PPN stimulation appears to induce PRs in large MED neurons using parameters known best to induce locomotion.

scholarly journals Muscles of mice deficient in α-sarcoglycan maintain large masses and near control force values throughout the life span

2005 ◽  
Vol 22 (2) ◽  
pp. 244-256 ◽  
Author(s):  
Christina M. Consolino ◽  
Franck Duclos ◽  
Jane Lee ◽  
Roger A. Williamson ◽  
Kevin P. Campbell ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Life Span ◽  
Structure And Function ◽  
Null Mouse ◽  
Control Force ◽  
Wild Type ◽  
Cross Sectional ◽  
Muscle Structure ◽  
And Function

α-Sarcoglycan-deficient ( Sgca-null) mice provide potential for elucidating the pathogenesis of limb girdle muscular dystrophy type 2D (LGMD 2D) as well as for studying the effectiveness of therapeutic strategies. Skeletal muscles of Sgca-null mice demonstrate an early onset of extensive fiber necrosis, degeneration, and regeneration, but the progression of the pathology and the effects on muscle structure and function throughout the life span are not known. Thus the phenotypic accuracy of the Sgca-null mouse as a model of LGMD 2D has not been fully established. To investigate skeletal muscle structure and function in the absence of α-sarcoglycan throughout the life span, we analyzed extensor digitorum longus and soleus muscles of male and female Sgca-null and wild-type mice at 3, 6, 12, and 18 mo of age. Maximum isometric forces and powers were measured in vitro at 25°C. Also determined were individual myofiber cross-sectional areas and numbers, water content, and the proportion of the cross section occupied by connective tissue. Muscle masses were 40–100% larger for Sgca-null compared with age- and gender-matched wild-type mice, with the majority of the increased muscle mass for Sgca-null mice attributable to greater connective tissue and water contents. Although the greater mass of muscles in Sgca-null mice was primarily noncontractile material, absolute forces and powers were maintained near control levels at all ages, indicating a successful adaptation to the deficiency in α-sarcoglycan not observed at any age in LGMD 2D patients.

scholarly journals Carotid body chemosensory responses in mice deficient of TASK channels

2010 ◽  
Vol 135 (4) ◽  
pp. 379-392 ◽  
Author(s):  
Patricia Ortega-Sáenz ◽  
Konstantin L. Levitsky ◽  
María T. Marcos-Almaraz ◽  
Victoria Bonilla-Henao ◽  
Alberto Pascual ◽  
...  
Keyword(s):  
Carotid Body ◽  
Sensory Transduction ◽  
Resting Potential ◽  
Cell Phenotype ◽  
Null Mouse ◽  
Wild Type ◽  
Glomus Cell ◽  
Secretory Rate ◽  
K Channels ◽  
Glomus Cells

Background K+ channels of the TASK family are believed to participate in sensory transduction by chemoreceptor (glomus) cells of the carotid body (CB). However, studies on the systemic CB-mediated ventilatory response to hypoxia and hypercapnia in TASK1- and/or TASK3-deficient mice have yielded conflicting results. We have characterized the glomus cell phenotype of TASK-null mice and studied the responses of individual cells to hypoxia and other chemical stimuli. CB morphology and glomus cell size were normal in wild-type as well as in TASK1−/− or double TASK1/3−/− mice. Patch-clamped TASK1/3-null glomus cells had significantly higher membrane resistance and less hyperpolarized resting potential than their wild-type counterpart. These electrical parameters were practically normal in TASK1−/− cells. Sensitivity of background currents to changes of extracellular pH was drastically diminished in TASK1/3-null cells. In contrast with these observations, responsiveness to hypoxia or hypercapnia of either TASK1−/− or double TASK1/3−/− cells, as estimated by the amperometric measurement of catecholamine release, was apparently normal. TASK1/3 knockout cells showed an enhanced secretory rate in basal (normoxic) conditions compatible with their increased excitability. Responsiveness to hypoxia of TASK1/3-null cells was maintained after pharmacological blockade of maxi-K+ channels. These data in the TASK-null mouse model indicate that TASK3 channels contribute to the background K+ current in glomus cells and to their sensitivity to external pH. They also suggest that, although TASK1 channels might be dispensable for O2/CO2 sensing in mouse CB cells, TASK3 channels (or TASK1/3 heteromers) could mediate hypoxic depolarization of normal glomus cells. The ability of TASK1/3−/− glomus cells to maintain a powerful response to hypoxia even after blockade of maxi-K+ channels, suggests the existence of multiple sensor and/or effector mechanisms, which could confer upon the cells a high adaptability to maintain their chemosensory function.

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