Regional differences in the role of the Ca2+ and Na+ currents in pacemaker activity in the sinoatrial node

1997 ◽  
Vol 272 (6) ◽  
pp. H2793-H2806 ◽  
Author(s):  
I. Kodama ◽  
M. R. Nikmaram ◽  
M. R. Boyett ◽  
R. Suzuki ◽  
H. Honjo ◽  
...  
Keyword(s):  
Action Potentials ◽  
Regional Differences ◽  
Sinoatrial Node ◽  
Pacemaker Activity ◽  
Na Current ◽  
Na Currents ◽  
Spontaneous Action ◽  
Spontaneous Action Potentials ◽  
Rabbit Sinoatrial Node

The effect of block of the L-type Ca2+ current by 2 microM nifedipine and of the Na+ current by 20 microM tetrodotoxin on the center (normally the leading pacemaker site) and periphery (latent pacemaker tissue) of the rabbit sinoatrial node was investigated. Spontaneous action potentials were recorded with microelectrodes from either an isolated right atrium containing the whole node or small balls of tissue (approximately 0.3-0.4 mm in diameter) from different regions of the node. Nifedipine abolished the action potential in the center, but not usually in the periphery, in both the intact sinoatrial node and the small balls. Tetrodotoxin had no effect, on electrical activity in small balls from the center, but it decreased the takeoff potential and upstroke velocity and slowed the spontaneous activity (by 49 +/- 10%; n = 11) in small balls from the periphery. It is concluded that whereas the L-type Ca2- current plays an obligatory role in pacemaking in the center, the Na+ current plays a major role in pacemaking in the periphery.

scholarly journals Ranolazine inhibits shear sensitivity of endogenous Na+current and spontaneous action potentials in HL-1 cells

Channels ◽  
2012 ◽  
Vol 6 (6) ◽  
pp. 457-462 ◽  
Author(s):  
Peter Strege ◽  
Arthur Beyder ◽  
Cheryl Bernard ◽  
Ruben Crespo-Diaz ◽  
Atta Behfar ◽  
...  
Keyword(s):  
Action Potentials ◽  
Na Current ◽  
Shear Sensitivity ◽  
Spontaneous Action ◽  
Spontaneous Action Potentials

scholarly journals SK Current, Expressed During the Development and Regeneration of Chick Hair Cells, Contributes to the Patterning of Spontaneous Action Potentials

2022 ◽  
Vol 15 ◽  
Author(s):  
Snezana Levic
Keyword(s):  
Electrical Activity ◽  
Hair Cells ◽  
Action Potentials ◽  
Functional Expression ◽  
Basilar Papilla ◽  
Spontaneous Electrical Activity ◽  
Intracellular Ca ◽  
Spontaneous Action ◽  
Spontaneous Action Potentials

Chick hair cells display calcium (Ca2+)-sensitive spontaneous action potentials during development and regeneration. The role of this activity is unclear but thought to be involved in establishing proper synaptic connections and tonotopic maps, both of which are instrumental to normal hearing. Using an electrophysiological approach, this work investigated the functional expression of Ca2+-sensitive potassium [IK(Ca)] currents and their role in spontaneous electrical activity in the developing and regenerating hair cells (HCs) in the chick basilar papilla. The main IK(Ca) in developing and regenerating chick HCs is an SK current, based on its sensitivity to apamin. Analysis of the functional expression of SK current showed that most dramatic changes occurred between E8 and E16. Specifically, there is a developmental downregulation of the SK current after E16. The SK current gating was very sensitive to the availability of intracellular Ca2+ but showed very little sensitivity to T-type voltage-gated Ca2+ channels, which are one of the hallmarks of developing and regenerating hair cells. Additionally, apamin reduced the frequency of spontaneous electrical activity in HCs, suggesting that SK current participates in patterning the spontaneous electrical activity of HCs.

Regional differences in effects of 4-aminopyridine within the sinoatrial node

1998 ◽  
Vol 275 (4) ◽  
pp. H1158-H1168 ◽  
Author(s):  
M. R. Boyett ◽  
H. Honjo ◽  
M. Yamamoto ◽  
M. R. Nikmaram ◽  
R. Niwa ◽  
...  
Keyword(s):  
Action Potential ◽  
Regional Differences ◽  
Sinoatrial Node ◽  
Outward Current ◽  
Peripheral Tissue ◽  
Transient Outward Current ◽  
Pacemaker Activity ◽  
Small Ball ◽  
Tissue Differences ◽  
Rabbit Sinoatrial Node

4-Aminopyridine (4-AP)-sensitive transient outward current ( I to) has been observed in the sinoatrial node, but its role is unknown. The effect of block of I to by 5 mM 4-AP on small ball-like tissue preparations (diameter ∼0.3–0.4 mm) from different regions of the rabbit sinoatrial node has been investigated. 4-AP elevated the plateau, prolonged the action potential, and decreased the maximum diastolic potential. Effects were greater in tissue from the periphery of the node than from the center. In peripheral tissue, 4-AP abolished the action potential notch, if present. 4-AP slowed pacemaker activity of peripheral tissue but accelerated that of central tissue. Differences in the response to 4-AP were also observed between tissue from more superior and inferior regions of the node. In the intact sinoatrial node, 4-AP resulted in a shift of the leading pacemaker site consistent with the regional differences in the response to 4-AP. It is concluded that 4-AP-sensitive outward current plays a major role in action potential repolarization and pacemaker activity in the sinoatrial node and that its role varies regionally.

The increase of extracellular Ca2+ from physiological concentrations to hypercalcemia impairs sino-atrial automaticity

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
AG Torrente ◽  
L Fossier ◽  
M Baudot ◽  
E Torre ◽  
I Bidaud ◽  
...  
Keyword(s):  
Action Potentials ◽  
Ex Vivo ◽  
Pacemaker Activity ◽  
Funding Source ◽  
Cell Contractility ◽  
Funding Sources ◽  
Spontaneous Action ◽  
Spontaneous Action Potentials ◽  
Ca2 Channels ◽  
Funding Acknowledgements

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): ESC FRM Lefoulon Delalande Aims To investigate whether extracellular hypercalcemia alters the conduction through L-type Ca2+ channels (LTCCs), impairing the pacemaker activity of the heart. Introduction In the sino-atrial node (SAN), membrane currents and the dynamics of intracellular Ca2+ ([Ca2+]i) generate the pacemaker activity of the heart. SAN dysfunctions (SNDs) harm heart automaticity and have been associated with abnormal dynamics of [Ca2+]i. The LTCCs, Cav1.2 and Cav1.3 carry the main Ca2+ influx of SAN cells, which is necessary to sustain [Ca2+]i dynamics. Modified extracellular Ca2+ ([Ca2+]o) could alter Ca2+ influx through these channels. For example, cancer and hyperparathyroidism can raise [Ca2+]o, causing an extracellular hypercalcemia that could alter [Ca2+]i dynamics and impair SAN activity and heart automaticity. Methods and results To test this hypothesis, we measured contractions, [Ca2+]i release and L-type Ca2+ current (ICa,L) in spontaneous cells of the murine SAN. Then, we recorded rate and propagation of the spontaneous action potentials (APs) generated by the SAN tissue ex-vivo. In spontaneously beating SAN cells, we observed that the modification of [Ca2+]o affected [Ca2+]i and cell contractility through changes of ICa,L. In particular, the increase of [Ca2+]o dysregulated pacemaker activity, likely through excessive Ca2+ influx mediated by Cav1.2. [Ca2+]o increase to hypercalcemia induced arrhythmia also in the intact SAN tissues, activating ectopic leading regions of pacemaking and impairing conduction towards the atria. Conclusions Hypercalcemia causes excessive Cav1.2-mediated Ca2+ influx, which alters [Ca2+]I leading to pacemaker impairment. Modulation of LTCC may reduce pacemaker dysfunctions, preventing SND progression.

Role of K+ Channels in Frequency Regulation of Spontaneous Action Potentials in Rat Pituitary GH3 Cells

2003 ◽  
Vol 78 (5) ◽  
pp. 260-269 ◽  
Author(s):  
Suk-Ho Lee ◽  
Eun Hae Lee ◽  
Shin Young Ryu ◽  
Hyewhon Rhim ◽  
Hye-Jung Baek ◽  
...  
Keyword(s):  
Action Potentials ◽  
Frequency Regulation ◽  
Rat Pituitary ◽  
Spontaneous Action ◽  
Spontaneous Action Potentials

Spontaneous electrical rhythmicity and the role of the sarcoplasmic reticulum in the excitability of guinea pig gallbladder smooth muscle cells

2006 ◽  
Vol 290 (4) ◽  
pp. G655-G664 ◽  
Author(s):  
Onesmo B. Balemba ◽  
Matthew J. Salter ◽  
Thomas J. Heppner ◽  
Adrian D. Bonev ◽  
Mark T. Nelson ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Sarcoplasmic Reticulum ◽  
Action Potentials ◽  
Cyclopiazonic Acid ◽  
Cellular Mechanisms ◽  
Voltage Dependent ◽  
Spontaneous Action ◽  
Potential Activity ◽  
Spontaneous Action Potentials

Spontaneous action potentials and Ca2+ transients were investigated in intact gallbladder preparations to determine how electrical events propagate and the cellular mechanisms that modulate these events. Rhythmic phasic contractions were preceded by Ca2+ flashes that were either focal (limited to one or a few bundles), multifocal (occurring asynchronously in several bundles), or global (simultaneous flashes throughout the field). Ca2+ flashes and action potentials were abolished by inhibiting sarcoplasmic reticulum (SR) Ca2+ release via inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] channels with 2-aminoethoxydiphenyl borate and xestospongin C or by inhibiting voltage-dependent Ca2+ channels (VDCCs) with nifedipine or diltiazem or nisoldipine. Inhibiting ryanodine channels with ryanodine caused multiple spikes superimposed upon plateaus of action potentials and extended quiescent periods. Depletion of SR Ca2+ stores with thapsigargin or cyclopiazonic acid increased the frequency and duration of Ca2+ flashes and action potentials. Acetylcholine, carbachol, or cholecystokinin increased synchronized and increased the frequency of Ca2+ flashes and action potentials. The phospholipase C (PLC) inhibitor U-73122 did not affect Ca2+ flash or action potential activity but inhibited the excitatory effects of acetylcholine on these events. These results indicate that Ca2+ flashes correspond to action potentials and that rhythmic excitation in the gallbladder is multifocal among gallbladder smooth muscle bundles and can be synchronized by excitatory agonists. These events do not depend on PLC activation, but agonist stimulation involves activation of PLC. Generation of these events depends on Ca2+ entry via VDCCs and on Ca2+ mobilization from the SR via Ins(1,4,5)P3 channels.

Abstract 17699: Inositol-1,4,5-Trisphosphate-Mediated Pacemaker Activity in NCX KO Mouse Sinoatrial Nodal Cells

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Nidhi Kapoor ◽  
Andrew Tran ◽  
Rui Zhang ◽  
Jeanney Kang ◽  
Joshua I Goldhaber
Keyword(s):  
Action Potentials ◽  
Adrenergic Receptor ◽  
Sinoatrial Node ◽  
Systolic Heart Failure ◽  
Pacemaker Activity ◽  
Ca Channels ◽  
Adult Cardiomyocytes ◽  
Diastolic Depolarization ◽  
Adrenergic Receptor Agonist

Sinoatrial node (SAN) automaticity is due to the interplay of several membrane currents, including the current produced by Na-Ca exchanger (NCX) in response to Ca cycling. Several lines of evidence suggest that inositol-1,4,5-triphosphate receptors (IP 3 Rs) that mobilize [Ca] i are implicated in generation of automaticity in embryonic and adult cardiomyocytes. Increased IP 3 R expression observed in failing heart may predispose to arrhythmias and could contribute to the elevated heart rates associated with systolic heart failure. However, whether IP 3 R signaling influences SAN pacemaking is still controversial, in part due to the confounding influence of periodic Ca flux through the sarcolemma during every beat. To address this concern, we used NCX knockout (KO) SAN cells to study the role of IP 3 signaling on pacemaker activity. In these cells Ca flux across the sarcolemmal membrane is practically eliminated due to NCX ablation and no Ca flux through L-type Ca channels due to lack of action potentials, yet periodic spontaneous waves are still generated by the localized Ca releases (LCRs) of the “Ca clock”. Thus these waves are “uncoupled” from the membrane because there is no NCX to contribute to the diastolic depolarization in response to the release of [Ca] i . We recorded spontaneous Ca oscillations using line scan confocal microscopy in WT and NCX KO SAN cells in the presence of an IP 3 R blocker or during inhibition of phospholipase C (PLC). We found that superfusion with the IP 3 R blocker, 2-APB (2 μm) decreased the frequency of Ca transients in WT SAN cells by 82.6% (n=9, p<0.05) and Ca waves in NCX KO cells by 66% (n=10, p<0.05). Similar results were also obtained on superfusion with the PLC antagonist, U73122 (1 μm). Alternatively, an increase in IP 3 production using the α-1 adrenergic receptor agonist phenylephrine (10 μm) led to an increase in the frequency of Ca transients in WT SAN cells (n=8. P< 0.05) and Ca waves in NCX KO cells (n=9, p <0.05). This effect was blocked on the subsequent additional application of 2-APB. In summary our results indicate that Ca release from IP 3 Rs can modulate Ca oscillation frequency in NCX KO SAN cells and support our hypothesis that IP 3 signaling modulates the Ca cycling processes that regulate pacemaker frequency in the SAN.

Abstract 1522: Local Ca Releases And Spontaneous Beating Rate Of Rabbit Sinoatrial Node Cells Are Controlled By Interaction Of Basal Phosphodiesterase 3 And 4 Activity

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Tatiana M Vinogradova ◽  
Alexey E Lyashkov ◽  
Harold Spurgeon ◽  
Edward G Lakatta
Keyword(s):  
Sinoatrial Node ◽  
Pde4 Inhibitor ◽  
Phosphodiesterase 3 ◽  
Whole Cell Patch Clamp ◽  
Diastolic Depolarization ◽  
Spontaneous Action ◽  
Beating Rate ◽  
Sinoatrial Node Cells ◽  
Spontaneous Action Potentials

A high basal phosphodiesterase (PDE) activity in sinoatrial node cells (SANC) regulates cAMP and modulates cAMP-mediated PKA-dependent phosphorylation of Ca 2+ cycling proteins that determines the characteristics of local subsarcolemmal Ca 2+ releases (LCR). LCRs occur during the terminal diastolic depolarization and activate the inward Na + -Ca 2+ exchange current, thus, regulating the SANC basal spontaneous beating rate. Though both PDE3 and PDE4 are present in rabbit SANC, a role of PDE4 or its interaction with PDE3 is not clear. To determine to what extent PDE4 controls LCRs and the SANC spontaneous beating rate, we used perforated patch to record spontaneous action potentials (APs) in conjunction with confocal linescan images or whole-cell patch clamp to measure L-type Ca 2+ current (I Ca,L ) at 35 o C. A specific PDE3 inhibitor, cilostamide (Cil, 0.3 μmol/L), increased the spontaneous beating rate by 28% (from 154 ± 21 to 191 ± 17 beat/min); in contrast a specific PDE4 inhibitor, rolipram (Rol, 2 μmol/L), had no effect on the firing rate. The substantial role of PDE4 in the control of basal spontaneous SANC firing was unmasked when PDE3 and PDE4 were simultaneously inhibited: the combination of Rol and Cil produced ~57% acceleration of the beating rate (from129 ± 10 to 200 ± 10 beat/min) equivalent to that produced by the broad-spectrum PDE inhibitor, IBMX (100μM), i.e. ~55% (from 145 ± 8 to 221 ± 6 beat/min). The combination of Cil and Rol increased LCR amplitude, size and decreased the LCR period similar to IBMX. Both IBMX and the combination of Cil and Rol produced a substantial increase in I Ca,L ~135% (from 10 ± 2 to 22 ± 3 pA/pF) and ~125% (from 6 ± 1 to 13 ± 3 pA/pF) respectively. The efficiency of PDE3 inhibition alone on spontaneous beating rate might be ascribed to its lower K m for cAMP, than that of PDE4. When PDE3 is suppressed level of cAMP is sufficiently elevated to activate PDE4. Therefore, in the presence of PDE3 inhibition, PDE4 inhibition contributes to the increase in the spontaneous beating rate. Thus, an interaction of basal PDE3 and PDE4 activities in SANC modulates cAMP level and I Ca,L which controls Ca 2+ influx, cell Ca 2+ load, determining LCR characteristics. When both PDE3 and PDE4 are inhibited the maximum spontaneous beating rate of SANC is achieved.

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