Cellular and subcellular mechanisms of cardiac pacemaker oscillations

1979 ◽  
Vol 81 (1) ◽  
pp. 205-215
Author(s):  
R. W. Tsien ◽  
R. S. Kass ◽  
R. Weingart
Keyword(s):  
Membrane Potential ◽  
Voltage Clamp ◽  
Surface Membrane ◽  
Cardiac Pacemaker ◽  
Oscillatory Activity ◽  
Purkinje Fibre ◽  
Pacemaker Activity ◽  
Heart Cells ◽  
Control Loop ◽  
Internal Oscillation

Rhythmic oscillations in the membrane potential of heart cells are important in normal cardiac pacemaker activity as well as cardiac arrhythmias. Two fundamentally different mechanisms of oscillatory activity can be distinguished at the cellular and subcellular level. The first mechanism, referred to as a surface membrane oscillator, can be represented by a control loop in which membrane potential changes evoke delayed conductance changes and vice versa. Since the surface membrane potential is a key variable within the control loop, the oscillation can be interrupted at any time by holding the membrane potential constant with a voltage clamp. This mode of oscillation seems to describe spontaneous pacemaker activity in the primary cardiac pacemaker (sinoatrial node) as well as other regions (Purkinje fibre, atrial or ventricular muscle). In all tissues studied so far, the pacemaker depolarization is dominated by the slow shutting-off of an outward current, largely carried by potassium ions. The second mechanism can be called an internal oscillator since it depends upon a subcellular rhythm generator which is largely independent from the surface membrane. Under voltage clamp, the existence of the internal oscillation is revealed by the presence of oscillations in membrane conductance or contractile force which occur even though the membrane potential is held fixed. The two oscillatory mechanisms are not mutually exclusive; the subcellular mechanism can be preferentially enhanced in any given cardiac cell by conditions which elevate intracellular calcium. Such conditions include digitalis intoxication, high Cao, low Nao, low or high Ko, cooling, or rapid stimulation. Several lines of evidence suggest that the subcellular mechanism involves oscillatory variations in myoplasmic calcium, probably due to cycles of Ca uptake and release by the sarcoplasmic reticulum. The detailed nature of the Cai oscillator and its interaction with the surface membrane await further investigation.

scholarly journals Phase resetting properties of cardiac pacemaker cells.

1984 ◽  
Vol 83 (4) ◽  
pp. 613-629 ◽  
Author(s):  
W P Van Meerwijk ◽  
G deBruin ◽  
C G Van Ginneken ◽  
J VanHartevelt ◽  
H J Jongsma ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Cardiac Electrophysiology ◽  
Phase Response Curve ◽  
Cardiac Pacemaker ◽  
Internal Noise ◽  
Resting Membrane Potential ◽  
Heart Cells ◽  
Phase Resetting ◽  
Intracellular Microelectrodes ◽  
Random Responses

Aggregates of heart cells from chicken embryos beat spontaneously. We used intracellular microelectrodes to record the periodic behavior of the membrane potential that triggers the contractions. Every 5-12 beats, a short current pulse was applied at various points in the cycle to study the phase-dependent resetting of the rhythm. Pulses stronger than 2.5 nA caused the final rhythm to be reset to almost the same point in the cycle regardless of the phase at which the pulse was applied (type zero resetting). Pulses of less than or equal to 1 nA only caused a slight change of the phase. Increasing current intensities to between 1 and 2.5 nA gave rise to an increasing steepness in a small part of the phase-response curve. The observation of type zero resetting implies the existence of a critical stimulation that might annihilate the rhythm. Although we did find a phase at which more or less random responses occurred, the longest pause in the rhythm was 758 ms, 2.4 times the spontaneous interval. This suggests that the resting membrane potential was unstable, at least against the internal noise of the system. The conclusions are discussed in terms of the concepts of classical cardiac electrophysiology.

scholarly journals Extracellular Hco3− Dependence of Electrogenic Na/Hco3 Cotransporters Cloned from Salamander and Rat Kidney

2000 ◽  
Vol 115 (5) ◽  
pp. 533-546 ◽  
Author(s):  
Irina I. Grichtchenko ◽  
Michael F. Romero ◽  
Walter F. Boron
Keyword(s):  
Membrane Potential ◽  
Voltage Clamp ◽  
Xenopus Oocytes ◽  
Rat Kidney ◽  
Outward Current ◽  
Membrane Vesicles ◽  
Disulfonic Acid ◽  
Ambystoma Tigrinum ◽  
Ph Titration ◽  
Electrode Voltage

We studied the extracellular [HCOabstract 3 −] dependence of two renal clones of the electrogenic Na/HCO3 cotransporter (NBC) heterologously expressed in Xenopus oocytes. We used microelectrodes to measure the change in membrane potential (ΔVm) elicited by the NBC cloned from the kidney of the salamander Ambystoma tigrinum (akNBC) and by the NBC cloned from the kidney of rat (rkNBC). We used a two-electrode voltage clamp to measure the change in current (ΔI) elicited by rkNBC. Briefly exposing an NBC-expressing oocyte to HCOabstract 3 −/CO2 (0.33–99 mM HCOabstract 3−, pHo 7.5) elicited an immediate, DIDS (4,4-diisothiocyanatostilbene-2,2-disulfonic acid)-sensitive and Na+-dependent hyperpolarization (or outward current). In ΔVm experiments, the apparent Km for HCOabstract 3− of akNBC (10.6 mM) and rkNBC (10.8 mM) were similar. However, under voltage-clamp conditions, the apparent Km for HCOabstract 3− of rkNBC was less (6.5 mM). Because it has been reported that SOabstract 3=/HSO abstract 3− stimulates Na/HCO3 cotransport in renal membrane vesicles (a result that supports the existence of a COabstract 3= binding site with which SOabstract 3= interacts), we examined the effect of SOabstract 3=/HSO abstract 3− on rkNBC. In voltage-clamp studies, we found that neither 33 mM SOabstract 4= nor 33 mM SOabstract 3 =/HSOabstract 3− substantially affects the apparent Km for HCO abstract 3−. We also used microelectrodes to monitor intracellular pH (pHi) while exposing rkNBC-expressing oocytes to 3.3 mM HCOabstract 3 −/0.5% CO2. We found that SO abstract 3=/HSOabstract 3 − did not significantly affect the DIDS-sensitive component of the pHi recovery from the initial CO2 -induced acidification. We also monitored the rkNBC current while simultaneously varying [CO2]o, pHo, and [COabstract 3=]o at a fixed [HCOabstract 3−]o of 33 mM. A Michaelis-Menten equation poorly fitted the data expressed as current versus [COabstract 3=]o . However, a pH titration curve nicely fitted the data expressed as current versus pHo. Thus, rkNBC expressed in Xenopus oocytes does not appear to interact with SOabstract 3 =, HSOabstract 3−, or COabstract 3=.

Developmental change in fast Na channel properties in embryonic chick ventricular heart cells

1995 ◽  
Vol 73 (10) ◽  
pp. 1475-1484 ◽  
Author(s):  
Hideaki Sada ◽  
Takashi Ban ◽  
Takeshi Fujita ◽  
Yoshio Ebina ◽  
Nicholas Sperelakis
Keyword(s):  
Steady State ◽  
Voltage Clamp ◽  
Time Constant ◽  
Voltage Dependence ◽  
Cell Voltage ◽  
Developmental Changes ◽  
Heart Cells ◽  
Embryonic Chick ◽  
Whole Cell ◽  
Whole Cell Voltage Clamp

To assess developmental changes in kinetic properties of the cardiac sodium current, whole-cell voltage-clamp experiments were conducted using 3-, 10-, and 17-day-old embryonic chick ventricular heart cells. Experimental data were quantified according to the Hodgkin–Huxley model. While the Na current density, as examined by the maximal conductance, drastically increased (six- to seven-fold) with development, other current–voltage parameters remained unchanged. Whereas the activation time constant and the steady-state activation characteristics were comparable among the three age groups, the voltage dependence of the inactivation time constant and the steady-state inactivation underwent a shift in the voltage dependence toward negative potentials during embryonic development. Consequently, the steady-state (window current) conductance, which was sufficient to induce automatic activity in the young embryos, was progressively reduced with age.Key words: cardiac electrophysiology, whole-cell voltage-clamp experiments, fast Na currents, heart, development, developmental changes.

scholarly journals Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking

2020 ◽  
Vol 472 (12) ◽  
pp. 1733-1742
Author(s):  
Nadine Erlenhardt ◽  
Olaf Kletke ◽  
Franziska Wohlfarth ◽  
Marlene A. Komadowski ◽  
Lukas Clasen ◽  
...  
Keyword(s):  
Family History ◽  
Sick Sinus Syndrome ◽  
Cardiac Pacemaker ◽  
Cell Surface Expression ◽  
Pacemaker Activity ◽  
Hcn Channel ◽  
Functional Interpretation ◽  
Rat Cardiomyocytes ◽  
Cardiac Pacemaking ◽  
History Of

AbstractThe hyperpolarization-activated cation current If is a key determinant for cardiac pacemaker activity. It is conducted by subunits of the hyperpolarization-activated cyclic nucleotide–gated (HCN) channel family, of which HCN4 is predominant in mammalian heart. Both loss-of-function and gain-of-function mutations of the HCN4 gene are associated with sinus node dysfunction in humans; however, their functional impact is not fully understood yet. Here, we sought to characterize a HCN4 V759I variant detected in a patient with a family history of sick sinus syndrome. The genomic analysis yielded a mono-allelic HCN4 V759I variant in a 49-year-old woman presenting with a family history of sick sinus syndrome. This HCN4 variant was previously classified as putatively pathogenic because genetically linked to sudden infant death syndrome and malignant epilepsy. However, detailed electrophysiological and cell biological characterization of HCN4 V759I in Xenopus laevis oocytes and embryonic rat cardiomyocytes, respectively, did not reveal any obvious abnormality. Voltage dependence and kinetics of mutant channel activation, modulation of cAMP-gating by the neuronal HCN channel auxiliary subunit PEX5R, and cell surface expression were indistinguishable from wild-type HCN4. In good agreement, the clinically likewise affected mother of the patient does not exhibit the reported HCN4 variance. HCN4 V759I resembles an innocuous genetic HCN channel variant, which is not sufficient to disturb cardiac pacemaking. Once more, our work emphasizes the importance of careful functional interpretation of genetic findings not only in the context of hereditary cardiac arrhythmias.

Influence of anomalous rectifier activation on afterhyperpolarizations of neurons from cat sensorimotor cortex in vitro

1988 ◽  
Vol 59 (2) ◽  
pp. 468-481 ◽  
Author(s):  
P. C. Schwindt ◽  
W. J. Spain ◽  
W. E. Crill
Keyword(s):  
Membrane Potential ◽  
Voltage Clamp ◽  
Sensorimotor Cortex ◽  
Model Parameters ◽  
Fast Decay ◽  
Time Constants ◽  
Anomalous Rectifier ◽  
Betz Cells ◽  
K Currents

1. Large neurons from layer V of cat sensorimotor cortex (Betz cells) were studied to determine the influence of the anomalous rectifier current (IAR) on slow afterhyperpolarizations (AHPs). The neurons were examined using intracellular recording and single-microelectrode voltage clamp in an in vitro brain slice preparation. 2. A faster medium-duration AHP (mAHP) and slower AHP (sAHP) followed repetitive firing (22, 23). The amplitude of the mAHP often increased or remained constant during membrane potential hyperpolarization. The membrane potential trajectory resulting solely from IAR activation was similar to the mAHP. 3. Postrepetitive firing voltage clamp was used to measure directly slowly decaying K+ currents (IK) and IAR at different membrane potentials. IK exhibited both a fast and slow decay. The time constants of the fast decay of IK and IAR activation were similar. IAR increased with hyperpolarization or raised extracellular K+ concentration [( K+]o), whereas both the fast and slow components of IK reversed or nulled near -100 mV and behaved as pure K+ currents in response to raised [K+]o. 4. To determine the precise contribution of IK and IAR to the AHP waveform, theoretical AHPs were computed using a quantitative model based on voltage-clamp measurements. The calculated AHPs were qualitatively similar to measured AHPs. The amplitude of the mAHP showed little change with hyperpolarization because of the increasing dominance of IAR at more negative membrane potentials. The sAHP was little affected by IAR activation. 5. Several model parameters subject to biological variation among Betz cells were varied in the calculations to determine their importance in the AHP waveform. With IK parameters held constant, the amplitude and time course of the mAHP depended on resting potential, membrane time constant, the kinetics of the anomalous rectifier conductance (GAR), and the maximum value of GAR. IAR activation could result in a biphasic AHP even when the fast decay of IK was omitted from the calculations. 6. A wider variation of model parameters revealed behavior that may be relevant to other neurons. Certain values of membrane or IAR activation time constants resulted in a monophasic AHP even when the fast decay of IK was present. The decay of a biphasic AHP could reflect either the onset of IAR or the fast decay of IK, depending on the relative value of their time constants. Procedures are outlined to discriminate between these possibilities using current clamp methods.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals The effect of temperature on spontaneous action potential discharge of the isolated sinus venosus from winter and summer plaice (Pleuronectes platessa)

1995 ◽  
Vol 198 (1) ◽  
pp. 137-140 ◽  
Author(s):  
A A Harper ◽  
I P Newton ◽  
P W Watt
Keyword(s):  
Action Potential ◽  
Discharge Rate ◽  
Cardiac Pacemaker ◽  
Intrinsic Rate ◽  
Effect Of Temperature ◽  
Pacemaker Activity ◽  
Duration Of Action ◽  
Diastolic Depolarization ◽  
Significant Difference

The spontaneous cardiac pacemaker activity and conformation were recorded in vitro, using intracellular recording methods, from heart tissue of summer- and winter-caught plaice. The effects of changing temperature on the pacemaker rate, duration of action potential and diastolic depolarization were investigated by altering the temperature of the superfusing medium. The resting intrinsic rate of discharge was significantly greater in pacemaker cells from winter plaice (P=0.05), but there was no significant difference between winter and summer fish in the apparent Arrhenius activation energies for this process. However, there was a significant difference in the estimated intercept, indicating a thermal shift in the processes underlying the spontaneous pacemaker rhythm. There was no significant difference in the diastolic depolarization duration recorded from winter and summer fish over the temperature range 4­22 °C. The major effect of previous environmental temperature was on the duration of the action potential (P<0.02), indicating that the observed changes in pacemaker discharge rate were not influenced by the processes that determine the duration of the pacemaker diastolic depolarisation but were modulated by the channel events that give rise to the action potential.

Conductance changes underlying a late synaptic hyperpolarization in hippocampal CA3 neurons

1987 ◽  
Vol 58 (1) ◽  
pp. 160-179 ◽  
Author(s):  
J. J. Hablitz ◽  
R. H. Thalmann
Keyword(s):  
Membrane Potential ◽  
Voltage Clamp ◽  
Time Course ◽  
Membrane Potentials ◽  
Resting Membrane Potential ◽  
Extracellular Potassium ◽  
Voltage Sensitivity ◽  
Base Line ◽  
Membrane Hyperpolarization ◽  
Ca3 Neurons

1. Single-electrode current- and voltage-clamp techniques were employed to study properties of the conductance underlying an orthodromically evoked late synaptic hyperpolarization or late inhibitory postsynaptic potential (IPSP) in CA3 pyramidal neurons in the rat hippocampal slice preparation. 2. Late IPSPs could occur without preceding excitatory postsynaptic potentials at the resting membrane potential and were graded according to the strength of the orthodromic stimulus. The membrane hyperpolarization associated with the late IPSP peaked within 140-200 ms after orthodromic stimulation of mossy fiber afferents. The late IPSP returned to base line with a half-decay time of approximately 200 ms. 3. As determined from constant-amplitude hyperpolarizing-current pulses, the membrane conductance increase during the late IPSP, and the time course of its decay, were similar whether measurements were made near the resting membrane potential or when the cell was hyperpolarized by approximately 35 mV. 4. When 1 mM cesium was added to the extracellular medium to reduce inward rectification, late IPSPs could be examined over a range of membrane potentials from -60 to -140 mV. For any given neuron, the late IPSP amplitude-membrane potential relationship was linear over the same range of membrane potentials for which the slope input resistance was constant. The late IPSP reversed symmetrically near -95 mV. 5. Intracellular injection of ethyleneglycol-bis-(beta-aminoethylether)-N,N'-tetraacetic acid or extracellular application of forskolin, procedures known to reduce or block certain calcium-dependent potassium conductances in CA3 neurons, had no significant effect on the late IPSP. 6. Single-electrode voltage-clamp techniques were used to analyze the time course and voltage sensitivity of the current underlying the late IPSP. This current [the late inhibitory postsynaptic current (IPSC)] began as early as 25 ms after orthodromic stimulation and reached a peak 120-150 ms following stimulation. 7. The late IPSC decayed with a single exponential time course (tau = 185 ms). 8. A clear reversal of the late IPSC at approximately -99 mV was observed in a physiological concentration of extracellular potassium (3.5 mM).(ABSTRACT TRUNCATED AT 400 WORDS)

Coupling mechanisms in airway smooth muscle

1990 ◽  
Vol 258 (4) ◽  
pp. L119-L133 ◽  
Author(s):  
R. F. Coburn ◽  
C. B. Baron
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Airway Smooth Muscle ◽  
Electromechanical Coupling ◽  
Cell Function ◽  
Surface Membrane ◽  
Smooth Muscles ◽  
Membrane Receptors ◽  
Airway Smooth Muscle Cells ◽  
Coupling Mechanisms

This review documents available information about coupling mechanisms involved in airway smooth muscle force development and maintenance and relaxation of force. Basic concepts, obtained from experiments performed on many different mammalian cell types, are in place regarding coupling between surface membrane receptors and cell function; these concepts are considered as a framework for understanding coupling between receptors and contractile proteins in smooth muscles and in airway smooth muscles. We have divided various components of coupling mechanisms into those dependent on changes in the surface membrane potential (electromechanical coupling) and those independent of the surface membrane potential (pharmacomechanical coupling). We have, to some degree, emphasized modulation of coupling mechanisms by intrasurface membrane microprocessing or by second messengers. A challenge for the future is to obtain a better understanding of how coupling mechanisms are altered or modulated during different phases of contractions evoked by a single agonist and under conditions of multiple agonist exposure to airway smooth muscle cells.

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