Dynamic vagal control of pacemaker activity in the mammalian sinoatrial node.

Jalife, José; Slenter, V. A.J.; Salata, Joseph J.; Michaels, D C

doi:10.1161/01.res.52.6.642

Cited by 85 publications

(57 citation statements)

References 42 publications

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“…The PRC ( Figure 5B) resembled the equivalent experimentally generated PRC. 14 The simulation results that were obtained by decreasing the number of pulses per burst ( Figure 5A) were matched qualitatively by decreasing [ACh] directly ( Figure 5B). First, decreasing [ACh] from 18.6 /xM to 4.6 fiM decreased the difference between the amplitudes of the PRC (674-303=371 msec vs. 616-298=318 msec).…”

Section: Phase Response Curvessupporting

confidence: 52%

“…The simulated (Equations 1, 2, and 4) latency between vagal stimulation and hyperpolarization of pacemaker cells equals 30 msec. 7 The latency between stimulation and hyperpolarization equals 80 msec in the rabbit 14 ; we do not know the value in the dog. We incorporated a delay of 50 msec in our model ( Figure 1) to adjust for the difference between the measured and simulated latencies.…”

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confidence: 99%

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Mathematical model of the changes in heart rate elicited by vagal stimulation.

Dexter

Levy

Rudy

1989

Circulation Research

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We developed a mathematical model of the underlying cellular mechanisms responsible for the changes in sinus cycle length (SCL) elicited by vagal stimulation in intact animals. The model incorporated a stimulation-mediated depletion of the releasable pool of acetylcholine (ACh) in the nerve endings, the in vitro reaction kinetics of acetylcholinesterase, and the electrical activity of a pacemaker cell with six membrane ionic currents. SCL increased linearly with the frequency of simulated vagal stimulation, as it does in animal experiments, because the concentration of ACh in the neuroeffector junction ([ACh]) saturated as the frequency of stimulation was increased and because SCL increased geometrically in response to increases in [ACh]. The dependence of SCL on the timing of vagal stimulation in the cardiac cycle resulted, in part, from the dependence of [ACh] on SCL. Simulated vagal stimulation entrained the sinus node because the rate of activation and inactivation of ACh-activated K + channels depended only weakly on membrane potential during diastolic depolarization. SCL increased geometrically with [ACh], because 1) during diastolic depolarization, the amplitude of the ACh-activated K + current was approximately equal to the amplitude of the sum of the other ionic currents, 2) [ACh] was low enough to saturate neither acetylcholinesterase nor the cellular system that activates the ACh-activated K + channels, 3) the pacemaker cell membrane behaved electrotonically like a capacitor, and 4) the sum of all the ionic currents increased linearly with the amplitude of the ACh-activated K + current. (Circulation Research 1989;65:133O-1339) O ur goal is to explain the cellular basis for the changes in sinus cycle length (SCL) elicited by vagal stimulation by using mathematical models of the underlying cellular physiology. In recent papers, we have presented mathematical models of the release of acetylcholine (ACh) from vagal nerve endings, the degradation of ACh in the neuroeffector junctions of the sinus node, and the changes in SCL elicited by ACh.1 . 2 By combining these mathematical models of the underlying cellular physiology, we create a more complete mathematical model that predicts the changes in SCL elicited by vagal stimulation in the intact animal. Our principal goal is to determine how the underlying cellular physiology, which we represented mathematically in our computer model, causes changes in SCL. Methods Mathematical ModelsACh release. Figure 1); the letter v was chosen because the releasable pool of ACh may be stored in intracellular vesicles.3 Let r equal the fastest rate of renewal of the releasable pool of ACh. Let p equal the fraction of the releasable pool of ACh, v, that is released by each vagal stimulus. Let u represent the vagal firing pattern. The change in the quantity of ACh that is available for release is represented by the equation: dv/dt=r(l-v)-pvu(t) (1) where u(t)=l if the vagus nerve is stimulated at time t, and u(t)=0 otherwise (t=0 msec at the start of the stimulation). AC...

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Section: Phase Response Curvessupporting

confidence: 52%

mentioning

confidence: 99%

Mathematical model of the changes in heart rate elicited by vagal stimulation.

Dexter

Levy

Rudy

1989

Circulation Research

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“…1A. These were used to stimulate the postganglionic nerve terminals (Vincenzi & West, 1963;Jalife, Slenter, Salata & Michaels, 1983 (Glick & Braunwald, 1965;Katona, Mclean, Dighton & Guz, 1982) (Kentish & Boyett, 1983 Fig. 1A.…”

Section: Methods Preparationmentioning

confidence: 99%

Regional differences in the response of the isolated sino‐atrial node of the rabbit to vagal stimulation.

Kodama

Boyett

Suzuki

et al. 1996

The Journal of Physiology

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1. The effects of brief postganglionic vagal nerve stimulation on electrical activity in different regions of the rabbit sino-atrial node and surrounding atrial muscle were recorded. 2. At the centre of the node (the leading pacemaker site), the brief stimulation resulted in a large hyperpolarization followed by a depolarization and a shortening of the action potential. All effects were short lasting (time to 90% recovery of membrane potential, 0 8 s). 3. At other sites within the node and in the surrounding atrial muscle, although there was still a substantial action potential shortening, the hyperpolarization was smaller and the depolarization was small or absent. All effects were longer lasting (time to 90 % recovery in atrial muscle, 11 4 s). 4. The depolarization in the centre of the node was abolished by block of the hyperpolarizationactivated current (if) by Cs+ or zatebradine (UL-FS 49). It could, therefore, result from the activation of if during the preceding hyperpolarization. 5. Block of acetylcholinesterase by eserine greatly slowed recovery from vagal stimulation at all sites, demonstrating that recovery is dependent on acetylcholinesterase. The longer lasting effects of vagal stimulation in atrial muscle, therefore, result from lower acetylcholinesterase activity. 6. Vagal stimulation resulted in a short-lasting initial slowing of spontaneous action potentials followed by a long-lasting secondary slowing. Whereas the initial slowing coincided with the effects of vagal stimulation on the centre of the node, the secondary slowing coincided with the slower effects of vagal stimulation on the surrounding atrial muscle. The secondary slowing was reduced by 68 + 11 % (n = 5) by cutting the atrial muscle away from the node. 7. It is concluded that the short-lasting initial slowing of spontaneous action potentials is the direct effect of vagal stimulation on the centre of the sino-atrial node, whereas the secondary slowing is the result of the longer lasting effects of vagal stimulation on the surrounding atrial muscle and the electrotonic suppression of the node by the muscle.

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“…Based on the phase resetting patterns of various periodic oscillators such as cardiac pacemakers (20,21,(41)(42)(43)(44), Winfree has developed a topological model demonstrating the unavoidable existence of a critical point which he calls a "phase singularity." At a phase singularity, the interaction of a specific stimulus within the natural cycle of the oscillator causes the response of the oscillator to become undefined.…”

Section: Critical Points and Reentrymentioning

confidence: 99%

Stimulus-induced critical point. Mechanism for electrical initiation of reentry in normal canine myocardium.

Frazier

Wolf²,

Wharton³

et al. 1989

J. Clin. Invest.

368

190

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The hypothesis was tested that the field of a premature (S2) stimulus, interacting with relatively refractory tissue, can create unidirectional block and reentry in the absence of nonuniform dispersion of recovery. Simultaneous recordings from a small region of normal right ventricular (RV) myocardium were made from 117 to 120 transmural or epicardial electrodes in 14 dogs. SI pacing from a row of electrodes on one side of the mapped area generated parallel activation isochrones followed by uniform parallel isorecovery lines. Cathodal S2 shocks of 25 to 250 V lasting 3 ms were delivered from a mesh electrode along one side of the mapped area to scan the recovery period, creating isogradient electric field lines perpendicular to the isorecovery lines. Circus reentry was created following S2 stimulation; initial conduction was distant from the S2 site and spread towards more refractory tissue. Reentry was clockwise for right S1 (near the septum) with top S2 (near the pulmonary valve) and for left SI with bottom S2; and counterclockwise for right S1 with bottom S2 and left SI with top S2. The center of the reentrant circuit for all S2 voltages and coupling intervals occurred at potential gradients of 5.1±0.6 V/cm (mean±standard deviation) and at preshock intervals 1±3 ms longer than refractory periods determined locally for a 2 mA stimulus. Thus, when S2 field strengths and tissue refractoriness are uniformally dispersed at an angle to each other, circus reentry occurs around a "critical point" where an S2 field of -

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Dynamic vagal control of pacemaker activity in the mammalian sinoatrial node.

Cited by 85 publications

References 42 publications

Mathematical model of the changes in heart rate elicited by vagal stimulation.

Mathematical model of the changes in heart rate elicited by vagal stimulation.

Regional differences in the response of the isolated sino‐atrial node of the rabbit to vagal stimulation.

Stimulus-induced critical point. Mechanism for electrical initiation of reentry in normal canine myocardium.

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