Abstract 327: Attenuated Beta-Adrenergic Response in the Tric-a Knock Out Mice

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_2) ◽  
Author(s):  
Yuichi Toyama ◽  
Manabu Yonekura ◽  
Chong Han ◽  
Hirofumi Tomita ◽  
Hiroshi Takeshima ◽  
...  
Keyword(s):  
Heart Rate ◽  
Action Potential ◽  
Sympathetic Nerve ◽  
Calcium Release ◽  
Calcium Influx ◽  
Ryanodine Receptors ◽  
Low Frequency ◽  
Beta Adrenergic ◽  
Knock Out ◽  
Nerve Regulation

Trimeric intracellular cation (TRIC) channels are expressed on the surface of sarcoplasmic reticulum (SR) and regulate calcium release from ryanodine receptors (RyRs). In a previous study, Tric-a knock out (KO) mice showed diminished calcium release from RyRs following increased calcium-influx via L-type calcium channels, which results in enhanced vascular resistance and non-dipper type hypertension. Decreased activation of RyR1 by PKA in skeletal myocytes in Tric-a KO mice is also known. However, physiological importance of TRIC channels on cardiac rhythm formation and its importance on the sympathetic nerve regulation are still obscure. Therefore, we aimed to clarify the effects of Tric-a ablation on cardiac pace making using Tric-a KO mice. We measured systolic blood pressure (SBP) with tail-cuff method, ECG and spontaneous action potential with microelectrode in the Tric-a KO and wild type (WT) mice. Isoproterenol or propranolol was used for sympathetic nerve manipulation. Furthermore, we evaluated heart rate variability (HRV). Tric-a KO mice tended to show limited responses to isoproterenol (0.3 mg/kg) than the WT mice (-27 ± 6 and -32 ± 6 mmHg, n = 10, p =0.70), and to propranolol (4 ± 6 and 13 ± 7 mmHg, n = 5~6, p =0.48). In ECG analysis, ablation of Tric-a gene resulted in significantly decreased heart rate changes to isoproterenol (23 ± 6 and 99 ± 15 bpm, Tric-a KO and WT mice, respectively, n = 9~10, p <0.001). Response to propranolol was also significantly decreased in the Tric-a KO mice (-28 ± 20 and -122 ± 14 bpm, Tric-a KO and WT mice, respectively, n = 9~10, p <0.001). In the action potential recordings, Tric-a KO mice showed significantly decreased sinus rate changes to 1 microM isoproterenol (35 ± 9 and 71 ± 10 bpm, Tric-a KO and WT mice, respectively, n = 6~8, p <0.05). In HRV analysis, low-frequency/high-frequency (LF/HF) ratio tended to be lower in the Tric-a KO mice than the WT mice under the administration of isoproterenol (0.22 ± 0.31 and 0.65 ± 0.16 bpm, Tric-a KO and WT mice, respectively, n = 9~11, p =0.16), suggesting lower sympathetic nerve tonus in the Tric-a KO mice. In conclusion, our data indicates that Tric-a KO mice showed attenuated responses to beta-adrenergic stimulus, which indicates involvement of TRIC-A channels in sympathetic nerve regulation.

P2565Decreased cardiac pacemaking and attenuated beta-adrenergic response in tric-a knock-out mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y Toyama ◽  
M Yonekura ◽  
H Tomita ◽  
M Murakami
Keyword(s):  
Heart Rate ◽  
Intracellular Calcium ◽  
Calcium Release ◽  
Sinus Node ◽  
Ryanodine Receptors ◽  
Contractile Force ◽  
Knock Out ◽  
Isolated Hearts ◽  
Sinus Rate ◽  
Cardiac Pacemaking

Abstract Background Trimeric intracellular cation (TRIC) channels are expressed on the surface of the sarcoplasmic reticulum and compensate for calcium release from ryanodine receptors. Tric-a knock-out (KO) mice showed diminished calcium release from ryanodine receptors in vascular smooth muscle cells. The cardiac pacemaker is controlled by the surface membrane and intracellular calcium clocks. In spontaneously firing sinus node action potentials, the membrane and calcium clocks work together via numerous interactions modulated by membrane voltage, intracellular calcium release, and protein phosphorylation. Intracellular calcium changes modulate cardiac pacemaking in the sinus node, but the physiological importance of TRIC channels in cardiac rhythm formation is still obscure. Purpose In this study, we aimed to clarify the importance of TRIC channels on cardiac pacemaking using Tric-a KO mice. Methods The expression level of mRNA and proteins in the sinus node was examined by RT-PCR and immunoblotting. Systolic blood pressure was measured with tail-cuff method. Heart rate was measured by ECG, and heart rate variability was examined. The atrial contractile force from isolated hearts was measured with a force transducer. Cardiac action potential and spontaneous sinus rate from isolated hearts were measured with a microelectrode. Isoproterenol was used for sympathetic nerve manipulation. Results Tric-a KO heart showed increased adrenergic β1-receptor expression in immunoblotting. Although there was no significant difference in basal systolic blood pressure between Tric-a KO and wild type (WT) mice, basal heart rate in Tric-a KO mice was significantly lower than that in WT mice (660±10 and 698±10 bpm, n=15 and 19, Tric-a KO mice and WT mice, respectively, p=0.017). Tric-a KO mice showed limited heart rate changes to isoproterenol (24±6 and 99±15 bpm, n=9 and 10, Tric-a KO mice and WT mice, respectively, p<0.001). In the action potential recordings, Tric-a KO atria showed only limited sinus rate changes to isoproterenol (35±9 and 71±10 bpm, n=8 and 6, Tric-a KO mice and WT mice, respectively, p=0.038). WT mice and Tric-a KO mice atrial contractile force showed dose-dependent changes in response to isoproterenol (10–100 nM), but Tric-a KO mice atria showed limited contractile force changes to isoproterenol (116 and 169%, n=7 and 6, Tric-a KO mice and WT mice, respectively, p<0.01). In heart rate variability, Tric-a KO mice showed unstable RR intervals and longer standard deviation of RR intervals than WT mice. Conclusion Tric-a KO mice showed decreased cardiac pacemaking in the sinus node and attenuated responses to beta-adrenergic stimulus, which indicates the involvement of TRIC channels in cardiac rhythm formation and sympathetic nerve regulation.

Discharge Pattern of Renal Sympathetic Nerve Activity in the Conscious Rat: Spectral Analysis of Integrated Activity

2000 ◽  
Vol 84 (6) ◽  
pp. 2859-2867 ◽  
Author(s):  
Takato Kunitake ◽  
Hiroshi Kannan
Keyword(s):  
Heart Rate ◽  
Power Spectrum ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Low Frequency ◽  
Heart Beat ◽  
Nerve Activity ◽  
Renal Sympathetic Nerve Activity ◽  
Conscious Rats ◽  
Renal Sympathetic

We investigated the periodic characteristics of bursting discharge in renal sympathetic nerve activity (RSNA) in conscious rats. Employing a discrete fast Fourier transform algorithm, a power spectrum analysis was used to quantify periodicities present in rectified and integrated RSNA whose signal-to-noise ratio in the recordings was greater than six. In conscious rats with intact baroreceptors, RSNA was characterized by four frequency components occurring at about 0.5, 1.5, 6, and 12 Hz, which corresponded to the low-frequency fluctuation of heart rate, respiration, and frequency of heart beat, and its harmonics, respectively. After intravenous infusion of sodium nitroprusside (SNP) to elicit reflex increases in RSNA and heart rate, the power for the component at 6 Hz followed the changes in heart beat frequency and was significantly increased, while those for the three other components were attenuated or experienced no change. In sino-aortic denervated (SAD) conscious rats, all four components were abolished, and the power spectrum was well fitted by a flat or Lorentzian curve, suggesting an almost random pattern. Only a respiratory-related component, which suggested common central modulation, appeared sporadically for short periods but was absent for the most part. Therefore most of this component together with the low-frequency component was also likely due to the baroreceptor-dependent peripheral modulation. The activity was sorted in 15 subgroups on the basis of spike amplitudes in the RSNA. Each subgroup showed frequency characteristics similar to the whole nerve activity. These results suggest that all periodicity in the RSNA of conscious rats with intact baroreceptors is caused by the baroreceptor input.

Low-frequency oscillations in arterial pressure and heart rate: a simple computer model

1989 ◽  
Vol 256 (6) ◽  
pp. H1573-H1579 ◽  
Author(s):  
J. B. Madwed ◽  
P. Albrecht ◽  
R. G. Mark ◽  
R. J. Cohen
Keyword(s):  
Heart Rate ◽  
Nervous System ◽  
Computer Model ◽  
Low Frequency ◽  
Beta Adrenergic ◽  
Simple Computer ◽  
Effector Mechanism ◽  
Arterial Blood ◽  
Low Frequency Oscillations ◽  
Effector Mechanisms

We have previously reported that low-frequency oscillations in arterial blood pressure (ABP) and heart rate (HR) occur when conscious dogs experience severe blood loss. These low-frequency oscillations are generated by enhancement of the sympathetic nervous system and inhibition of the parasympathetic nervous system. We have developed a simple computer model to elucidate those properties critical to the generation of these oscillations. Our model incorporates several important features: 1) arterial baroreceptor feedback loops, which relate ABP to targeted HR and total peripheral resistance (TPR) values; 2) two effector outputs, HR and TPR, which are controlled by the outputs of vagal, beta-adrenergic, and alpha-adrenergic effector mechanisms; 3) a fixed beat-to-beat stroke volume; and 4) a wind-kessel model, which represents the peripheral circulation. Each effector mechanism is modeled as a low-pass filter in series with a delay. The vagal effector mechanism slows the HR after a 100-ms delay and reaches maximal HR at that time. The beta-adrenergic effector mechanism speeds HR after a 2.5-s delay and then increases to maximal HR 7.5 s later. The alpha-adrenergic effector mechanism begins vasoconstriction after a 5-s delay and then reaches maximal contraction 15 s later. Computer simulations of inhibition of the vagal effector mechanism and activation of the adrenergic effector mechanisms elicit low-frequency oscillations in ABP and HR. These oscillations are similar to those observed experimentally in the dog during hemorrhage. We conclude that the slow temporal response of the alpha-adrenergic effector mechanism controlling TPR is the critical element in predicting the observed low-frequency oscillations in ABP and HR.

scholarly journals Large-conductance calcium-activated potassium current modulates excitability in isolated canine intracardiac neurons

2013 ◽  
Vol 304 (3) ◽  
pp. C280-C286 ◽  
Author(s):  
Guillermo J. Pérez ◽  
Mayurika Desai ◽  
Seth Anderson ◽  
Fabiana S. Scornik
Keyword(s):  
Membrane Potential ◽  
Calcium Release ◽  
Single Channel ◽  
Calcium Influx ◽  
Ryanodine Receptors ◽  
Bk Channels ◽  
Release Mechanism ◽  
Dependent Manner ◽  
Whole Cell ◽  
Intracardiac Neurons

We studied principal neurons from canine intracardiac (IC) ganglia to determine whether large-conductance calcium-activated potassium (BK) channels play a role in their excitability. We performed whole cell recordings in voltage- and current-clamp modes to measure ion currents and changes in membrane potential from isolated canine IC neurons. Whole cell currents from these neurons showed fast- and slow-activated outward components. Both current components decreased in the absence of calcium and following 1–2 mM tetraethylammonium (TEA) or paxilline. These results suggest that BK channels underlie these current components. Single-channel analysis showed that BK channels from IC neurons do not inactivate in a time-dependent manner, suggesting that the dynamic of the decay of the fast current component is akin to that of intracellular calcium. Immunohistochemical studies showed that BK channels and type 2 ryanodine receptors are coexpressed in IC principal neurons. We tested whether BK current activation in these neurons occurred via a calcium-induced calcium release mechanism. We found that the outward currents of these neurons were not affected by the calcium depletion of intracellular stores with 10 mM caffeine and 10 μM cyclopiazonic acid. Thus, in canine intracardiac neurons, BK currents are directly activated by calcium influx. Membrane potential changes elicited by long (400 ms) current injections showed a tonic firing response that was decreased by TEA or paxilline. These data strongly suggest that the BK current present in canine intracardiac neurons regulates action potential activity and could increase these neurons excitability.

Continual recordings of cardiac sympathetic nerve activity in conscious sheep

2002 ◽  
Vol 282 (1) ◽  
pp. H93-H99 ◽  
Author(s):  
David L. Jardine ◽  
Christopher J. Charles ◽  
Ian C. Melton ◽  
Clive N. May ◽  
Melanie D. Forrester ◽  
...  
Keyword(s):  
Heart Rate ◽  
Cardiac Disease ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Low Frequency ◽  
Cardiac Sympathetic Nerve ◽  
Nerve Activity ◽  
Recording Time ◽  
Cardiac Sympathetic Nerve Activity ◽  
Conscious Sheep

Cardiac sympathetic nerve activity (CSNA) is of major importance in the etiology of heart disease but is impossible to measure directly in humans. Ovine and human cardiovascular systems are similar; therefore, we have developed a method for the daily recording of CSNA in conscious sheep. After thoracotomy, electrodes were glued into the left thoracic cardiac nerve and CSNA, blood pressure (BP), and heart rate were recorded daily. Satisfactory recordings ≥7 days of CSNA were obtained in 11 of 28 sheep (40%), mean recording time 10.6 days, range 7-47. During the first week, CSNA decreased gradually from 78 ± 8 at baseline to 60 ± 7 bursts/min on day 5( P = 0.02) or from 76 ± 9 to 57 ± 7 bursts/100 beats on day 7 ( P = 0.04). Similarly, BP decreased from 103 ± 4 to 94 ± 4 mmHg ( P = 0.03). Low-frequency heart rate variability decreased from 0.12 ± 0.02 to 0.06 ± 0.02 ms2on day 6 ( P = 0.004) but was not correlated to CSNA. In conclusion, CSNA that can be continually recorded in conscious sheep decreases during the first week postsurgery and, thereafter, stabilizes. This model should provide valuable insights in future investigations of cardiac disease.

Low-frequency oscillation of sympathetic nerve activity decreases during development of tilt-induced syncope preceding sympathetic withdrawal and bradycardia

2005 ◽  
Vol 289 (4) ◽  
pp. H1758-H1769 ◽  
Author(s):  
Atsunori Kamiya ◽  
Junichiro Hayano ◽  
Toru Kawada ◽  
Daisaku Michikami ◽  
Kenta Yamamoto ◽  
...  
Keyword(s):  
Heart Rate ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Low Frequency ◽  
Vagal Nerve ◽  
Low Frequency Oscillation ◽  
Nerve Activity ◽  
Neurally Mediated Syncope ◽  
Severe Hypotension ◽  
Vagal Nerve Activity

Sympathetic activation during orthostatic stress is accompanied by a marked increase in low-frequency (LF, ∼0.1-Hz) oscillation of sympathetic nerve activity (SNA) when arterial pressure (AP) is well maintained. However, LF oscillation of SNA during development of orthostatic neurally mediated syncope remains unknown. Ten healthy subjects who developed head-up tilt (HUT)-induced syncope and 10 age-matched nonsyncopal controls were studied. Nonstationary time-dependent changes in calf muscle SNA (MSNA, microneurography), R-R interval, and AP (finger photoplethysmography) variability during a 15-min 60° HUT test were assessed using complex demodulation. In both groups, HUT during the first 5 min increased heart rate, magnitude of MSNA, LF and respiratory high-frequency (HF) amplitudes of MSNA variability, and LF and HF amplitudes of AP variability but decreased HF amplitude of R-R interval variability (index of cardiac vagal nerve activity). In the nonsyncopal group, these changes were sustained throughout HUT. In the syncopal group, systolic AP decreased from 100 to 60 s before onset of syncope; LF amplitude of MSNA variability decreased, whereas magnitude of MSNA and LF amplitude of AP variability remained elevated. From 60 s before onset of syncope, MSNA and heart rate decreased, index of cardiac vagal nerve activity increased, and AP further decreased to the level at syncope. LF oscillation of MSNA variability decreased during development of orthostatic neurally mediated syncope, preceding sympathetic withdrawal, bradycardia, and severe hypotension, to the level at syncope.

Abstract 16157: Catheter Ablation Induces an Increase in Heart Rate With Discordant With a Decrease in Sympathetic Nerve Activity in Patients With Paroxysmal Atrial Fibrillation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yusuke Mukai ◽  
Hisayoshi Murai ◽  
Tadayuki Hirai ◽  
Hiroyuki Sugimoto ◽  
Takuto Hamaoka ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Heart Rate ◽  
Catheter Ablation ◽  
Sympathetic Nerve ◽  
High Frequency ◽  
Sympathetic Nerve Activity ◽  
Low Frequency ◽  
Frequency Component ◽  
Nerve Activity ◽  
Parasympathetic Nerve

Background/Introduction: Paroxysmal atrial fibrillation (PAF) is the most common arrhythmia and catheter ablation (CA) is selected with the aim of rhythm control. CA was reported to increase heart rate (HR), which explains the modulation on the cardiac autonomic nervous system. However, little is known about the relationship between heart rate, sympathetic nerve activity and parasympathetic nerve activity in patient with PAF. Purpose: The purpose of this study was to evaluate the effect of CA on direct recording of muscle sympathetic nerve activity (MSNA) and heart rate variability (HRV), and these influences on HR. Methods: This study was conducted as a prospective, observational study. Patients with PAF who were scheduled for CA were enrolled. We measured blood pressure, HR, body weight, brain natriuretic peptide (BNP), echocardiogram parameters, high frequency component as cardiac parasympathetic nerve activity and low frequency component as cardiac sympathetic nerve activity in HRV, and MSNA before and 12 weeks after CA. Results: 21 PAF patients participated in this study. After CA, E/e’ and Ln BNP were significantly reduced(10.6±2.9 to 9.2±2.6, p<0.05. 3.8±1.3 to 3.3±1.6 log/pg/ml, p<0.05, respectively) while no significant changes were observed in EF, SV, left atrial diameter, left ventricular end diastolic and systolic diameters. HR was significantly increased (61.3±7.8 to 71.1±7.6 beats/min, p<0.05, respectively). However, the MSNA burst incidence and frequency were significantly decreased (65.4±12.6 to 41.3±13.4 bursts/100beats, p<0.01, n=21. 39.8±8.8 to 28.1±9.6 bursts/min, p<0.01, n=21. respectively). Also, the reduction in MSNA burst frequency was correlated with the increase in HR (r=0.57, 95%CI 0.183-0.804, p=0.00702). Ln Low frequency component in HRV was significantly decreased (5.72±1.75 to 3.85±2.13 log/ms 2 , p<0.05, n=12), but Ln high frequency (HF) component was not changed . No significant relationship observed between increased HR and HF component. Conclusion: CA induced paradoxical increasing heart rate with the reduction in sympathetic nerve activity in patient with PAF. These findings suggest that CA might modulate autonomic interaction between sinus nodes and in left atrium with denervated in ganglionated plexi.

Governance of arteriolar oscillation by ryanodine receptors

2003 ◽  
Vol 285 (1) ◽  
pp. R125-R131 ◽  
Author(s):  
Tsuneo Takenaka ◽  
Yoichi Ohno ◽  
Koichi Hayashi ◽  
Takao Saruta ◽  
Hiromichi Suzuki
Keyword(s):  
Calcium Channels ◽  
Calcium Release ◽  
Calcium Influx ◽  
Ryanodine Receptors ◽  
Voltage Dependent ◽  
Fourth Series ◽  
Voltage Dependent Calcium Channels ◽  
Afferent Arterioles ◽  
Series Of Experiments ◽  
Bayk 8644

To investigate the role of ryanodine receptors in glomerular arterioles, experiments were performed using an isolated perfused hydronephrotic kidney model. In the first series of studies, BAYK-8644 (300 nM), a calcium agonist, constricted afferent (19.6 ± 0.6 to 17.6 ± 0.5 μm, n = 6, P < 0.01) but not efferent arterioles. Furthermore, BAYK-8644 elicited afferent arteriolar oscillatory movements. Subsequent administration of nifedipine (1 μM) inhibited both afferent arteriolar oscillation and constriction by BAYK-8644 (to 19.4 ± 0.5 μm). In the second group, although BAYK-8644 constricted afferent arterioles treated with 1 μM of thapsigargin (19.7 ± 0.6 to 16.8 ± 0.6 μm, n = 5, P < 0.05), it failed to induce rhythmic contraction. Removal of extracellular calcium with EGTA (2 mM) reversed BAYK-8644-induced afferent arteriolar constriction (to 20.0 ± 0.5 μm). In the third series of investigations, ryanodine (10 μM) but not 2-aminoethoxyphenyl borate (100 μM) abolished afferent arteriolar vasomotion by BAYK-8644. In the fourth series of experiments, in the presence of caffeine (1 mM), the stronger activation of voltage-dependent calcium channels by higher potassium media resulted in greater afferent arteriolar constriction and faster oscillation. Our results indicate that L-type calcium channels are rich in preglomerular but not postglomerular microvessels. Furthermore, the present findings suggest that either prolonged calcium influx through voltage-dependent calcium channels (BAYK-8644) or sensitized ryanodine receptors (caffeine) is required to trigger periodic calcium release through ryanodine receptors in afferent arterioles.

Dissociation between microneurographic and heart rate variability estimates of sympathetic tone in normal subjects and patients with heart failure

1999 ◽  
Vol 96 (6) ◽  
pp. 557-565 ◽  
Author(s):  
Catherine F. NOTARIUS ◽  
Gary C. BUTLER ◽  
Shin-ichi ANDO ◽  
Michael J. POLLARD ◽  
Beverley L. SENN ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Low Frequency ◽  
Normal Subjects ◽  
Left Ventricular ◽  
Nerve Activity ◽  
Heart Failure Patients ◽  
Sympathetic Nervous

The concept that spectral analysis of heart rate variability (HRV) can estimate cardiac sympathetic nerve traffic in subjects with both normal and impaired left ventricular systolic function has not been validated against muscle sympathetic nerve activity (MSNA). We used coarse-graining spectral analysis to quantify the harmonic and non-harmonic, or fractal, components of HRV and to determine low-frequency (0.0–0.15 Hz; PL) and high-frequency (0.15–0.5 Hz; PH) harmonic power. To test the hypothesis that MSNA and HRV representations of sympathetic nerve activity (PL and PL/PH) increase in parallel in heart failure, we recorded heart rate and MSNA during supine rest in 35 patients (age 52.4±2 years; mean±S.E.M.), with a mean left ventricular ejection fraction of 22±2%, and in 34 age-matched normal subjects. Power density was log10 transformed. Mean MSNA was 52.9±2.6 bursts/min in heart failure patients and 34.9±1.9 bursts/min in normal subjects (P < 0.0001). In normal subjects, but not in heart failure patients, total power (PT) (r = -0.41; P = 0.02) and fractal power (PF) (r = -0.36; P = 0.04) were inversely related to age. In heart failure patients, total and fractal power were reduced (P < 0.009 for both), and were inversely related to MSNA burst frequency (r = -0.55, P = 0.001 and r = -0.60, P = 0.0003 respectively). In normal subjects, there was no relationship between MSNA and either PL or PH. In heart failure patients, as anticipated, PH was inversely related to MSNA (r = -0.41; P < 0.02). However, PL was also inversely rather than directly related to MSNA (r = 0.44 for 1/log10 PL; P < 0.01). There was no relationship between other sympathetic (PL/PH) or parasympathetic (PH/PT) indices and MSNA in either heart failure patients or normal subjects. The lack of concordance between these direct and indirect estimates of sympathetic nervous system activity indicates that this component of HRV cannot be used for between-subject comparisons of central sympathetic nervous outflow. It is the absence of low-frequency power that relates most closely to sympathetic activation in heart failure.

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