Effects of tonicity on the pacemaker activity of guinea-pig sino-atrial node.

Ohba, Masahiro

doi:10.2170/jjphysiol.36.1027

Cited by 5 publications

(5 citation statements)

References 28 publications

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“…This may suggest that the contribution of the I Cl,ir to the repolarization at positive potentials is rather small because of its inward rectification property. These data may provide new mechanistic insight into the tonicity regulation of spontaneous beating rate in guinea-pig SAN reported by Ohba in 1986 (125). In that study, it was found that decreasing the osmolarity by 30% increased the heart rate by 6% and increasing the osmolarity to 130%, 150%, and 170% decreased the heart rate to 94%, 89%, and 73%, respectively (125).…”

Section: Phenotypic Study Of Cardiac Channelssupporting

confidence: 53%

Phenomics of Cardiac Chloride Channels

Duan

2013

Comprehensive Physiology

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Forward genetic studies have identified several chloride (Cl−) channel genes, including CFTR, ClC-2, ClC-3, CLCA, Bestrophin, and Ano1, in the heart. Recent reverse genetic studies using gene targeting and transgenic techniques to delineate the functional role of cardiac Cl− channels have shown that Cl− channels may contribute to cardiac arrhythmogenesis, myocardial hypertrophy and heart failure, and cardioprotection against ischemia reperfusion. The study of physiological or pathophysiological phenotypes of cardiac Cl− channels, however, is complicated by the compensatory changes in the animals in response to the targeted genetic manipulation. Alternatively, tissue-specific conditional or inducible knockout or knockin animal models may be more valuable in the phenotypic studies of specific Cl− channels by limiting the effect of compensation on the phenotype. The integrated function of Cl− channels may involve multiprotein complexes of the Cl− channel subproteome. Similar phenotypes can be attained from alternative protein pathways within cellular networks, which are influenced by genetic and environmental factors. The phenomics approach, which characterizes phenotypes as a whole phenome and systematically studies the molecular changes that give rise to particular phenotypes achieved by modifying the genotype under the scope of genome/proteome/phenome, may provide more complete understanding of the integrated function of each cardiac Cl− channel in the context of health and disease.

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Section: Phenotypic Study Of Cardiac Channelssupporting

confidence: 53%

Phenomics of Cardiac Chloride Channels

Duan

2013

Comprehensive Physiology

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“…This may suggest that the contribution of the I Cl,ir to the repolarization at positive potentials is rather small because of its inward rectification property. These data may provide new mechanistic insight into the tonicity regulation of spontaneous beating rate in guinea–pig SAN reported by Ohba in 1986 [49]. In that study it was found that decreasing the osmolarity by 30% increased the heart rate by 6% and increasing the osmolarity to 130, 150, and 170% decreased the heart rate to 94, 89, and 73%, respectively [49].…”

Section: Discussionmentioning

confidence: 70%

Functional role of CLC-2 chloride inward rectifier channels in cardiac sinoatrial nodal pacemaker cells

Huang

Prasad

Britton

et al. 2009

Journal of Molecular and Cellular Cardiology

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A novel Cl − inward rectifier channel (Cl,ir) encoded by ClC-2, a member of the ClC voltage-gated Cl − channel gene superfamily, has been recently discovered in cardiac myocytes of several species. However, the physiological role of Cl,ir channels in the heart remains unknown. In this study we tested the hypothesis that Cl,ir channels may play an important role in cardiac pacemaker activity. In isolated guinea-pig sinoatrial node (SAN) cells, Cl,ir current was activated by hyperpolarization and hypotonic cell swelling. RT-PCR and immunohistological analyses confirmed the molecular expression of ClC-2 in guinea-pig SAN cells. Hypotonic stress increased the diastolic depolarization slope and decreased the maximum diastolic potential, action potential amplitude, APD 50 , APD 90 , and the cycle-length of the SAN cells. These effects were largely reversed by intracellular dialysis of anti-ClC-2 antibody, which significantly inhibited Cl,ir current but not other pacemaker currents, including the hyperpolarization-activated non-selective cationic "funny" current (I f ), the L-type Ca 2+ currents (I Ca,L ), the slowly-activating delayed rectifier I Ks and the volume-regulated outwardlyrectifying Cl − current (I Cl,vol ). Telemetry electrocardiograph studies in conscious ClC-2 knockout (Clcn2 −/− ) mice revealed a decreased chronotropic response to acute exercise stress when compared to their age-matched Clcn2 +/+ and Clcn2 +/− littermates. Targeted inactivation of ClC-2 does not alter intrinsic heart rate but prevented the positive chronotropic effect of acute exercise stress through a sympathetic regulation of ClC-2 channels. These results provide compelling evidence that ClC-2-encoded endogenous Cl,ir channels may play an important role in the regulation of cardiac pacemaker activity, which may become more prominent under stressed or pathological conditions.

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“…Our work shows that the mathematical approach provides a convenient way of understanding how individual currents contribute to SA node pacemaking. Further investigations of bifurcation structures of our model may also serve to clarify the mechanisms of abnormal SA node activities such as skipped-beat runs, annihilations, and early afterdepolarizations (11,25,39,41,48).…”

Section: Significance Of Applying Nonlinear Dynamics and Bifurcation mentioning

confidence: 98%

Roles of L-type Ca²⁺ and delayed-rectifier K⁺ currents in sinoatrial node pacemaking: insights from stability and bifurcation analyses of a mathematical model

Kurata¹,

Hisatome²,

Imanishi³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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To elucidate the dynamical mechanisms of the sinoatrial (SA) node pacemaker activity, we investigated the roles of L-type Ca2+ (ICa,L) and delayed-rectifier K+ (IKr) currents in pacemaking by stability and bifurcation analyses of our rabbit SA node model (Kurata Y, Hisatome I, Imanishi S, and Shibamoto T. Am J Physiol Heart Circ Physiol 283: H2074-H2101, 2002). Equilibrium points (EPs), periodic orbits, stability of EPs, and Hopf bifurcation points were calculated as functions of conductance or gating time constants of the currents for constructing bifurcation diagrams. Structural stability (robustness) of the system was also evaluated by computing stability and dynamics during applications of constant bias currents (Ibias). Blocking ICa,L or IKr caused stabilization of an EP and cessation of pacemaking via a Hopf bifurcation. The unstable zero-current potential region determined with Ibias applications, where spontaneous oscillations appear, shrunk and finally disappeared as ICa,L diminished, but shrunk little when IKr was eliminated. The reduced system, including no time-dependent current except ICa,L, exhibited pacemaker activity. These results suggest that ICa,L is responsible for EP instability and pacemaker generation, whereas IKr is not necessarily required for constructing a pacemaker cell system. We further explored the effects of various K+ currents with different kinetics on stability and dynamics of the model cell. The original IKr of delayed activation and inward rectification appeared to be most favorable for generating large-amplitude oscillations with stable frequency, suggesting that IKr acts as an oscillation amplifier and frequency stabilizer. IKr may also play an important role in preventing bifurcation to quiescence of the system.

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Effects of tonicity on the pacemaker activity of guinea-pig sino-atrial node.

Cited by 5 publications

References 28 publications

Phenomics of Cardiac Chloride Channels

Phenomics of Cardiac Chloride Channels

Functional role of CLC-2 chloride inward rectifier channels in cardiac sinoatrial nodal pacemaker cells

Roles of L-type Ca²⁺ and delayed-rectifier K⁺ currents in sinoatrial node pacemaking: insights from stability and bifurcation analyses of a mathematical model

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Effects of tonicity on the pacemaker activity of guinea-pig sino-atrial node.

Cited by 5 publications

References 28 publications

Phenomics of Cardiac Chloride Channels

Phenomics of Cardiac Chloride Channels

Functional role of CLC-2 chloride inward rectifier channels in cardiac sinoatrial nodal pacemaker cells

Roles of L-type Ca2+ and delayed-rectifier K+ currents in sinoatrial node pacemaking: insights from stability and bifurcation analyses of a mathematical model

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Roles of L-type Ca²⁺ and delayed-rectifier K⁺ currents in sinoatrial node pacemaking: insights from stability and bifurcation analyses of a mathematical model