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The sinoatrial node (SAN), the primary pacemaker of the heart, consists of a heterogeneous population of specialized cardiac myocytes that can spontaneously produce action potentials, generating the rhythm of the heart and coordinating heart contractions. Spontaneous beating can be observed from very early embryonic stage and under a series of genetic programing, the complex heterogeneous SAN cells are formed with specific biomarker proteins and generate robust automaticity. The SAN is capable to adjust its pacemaking rate in response to environmental and autonomic changes to regulate the heart’s performance and maintain physiological needs of the body. Importantly, the origin of the action potential in the SAN is not static, but rather dynamically changes according to the prevailing conditions. Changes in the heart rate are associated with a shift of the leading pacemaker location within the SAN and accompanied by alterations in P wave morphology and PQ interval on ECG. Pacemaker shift occurs in response to different interventions: neurohormonal modulation, cardiac glycosides, pharmacological agents, mechanical stretch, a change in temperature, and a change in extracellular electrolyte concentrations. It was linked with the presence of distinct anatomically and functionally defined intranodal pacemaker clusters that are responsible for the generation of the heart rhythm at different rates. Recent studies indicate that on the cellular level, different pacemaker clusters rely on a complex interplay between the calcium (referred to local subsarcolemmal Ca2+ releases generated by the sarcoplasmic reticulum via ryanodine receptors) and voltage (referred to sarcolemmal electrogenic proteins) components of so-called “coupled clock pacemaker system” that is used to describe a complex mechanism of SAN pacemaking. In this review, we examine the structural, functional, and molecular evidence for hierarchical pacemaker clustering within the SAN. We also demonstrate the unique molecular signatures of intranodal pacemaker clusters, highlighting their importance for physiological rhythm regulation as well as their role in the development of SAN dysfunction, also known as sick sinus syndrome.

Aims: Changes in the rabbit sinoatrial node (SAN) activation sequence with the cholinergic and adrenergic factors were studied. The correlation between the sinus rhythm rate and the leading pacemaker site shift was determined. The hypothesis concerning the cholinergic suppression of nodal cell excitability as one of the mechanisms associated with pacemaker shift was tested. Methods: A high-resolution optical mapping technique was used to register beat-to-beat changes in the SAN activation pattern under the influence of the cholinergic and adrenergic factors. Results: Acetylcholine (10 μm) and strong intramural parasympathetic nerve stimulation caused a pacemaker shift as well as rhythmic slowing and the formation of an inexcitable region in the central part of SAN. In this region the generation of action potentials was suppressed. The slowing of the sinus rhythm (which exceeded 12.8 ± 3.1% of the rhythm control rate) always accompanied the pacemaker shift. Isoproterenol (10, 100 nm, 1 μm) and sympathetic postganglionic nerve stimulation also evoked a pacemaker shift but without formation of an inexcitable zone. The acceleration of the sinus rhythm, which exceeded 10.5 ± 1.3% of the control rate of the rhythm, always accompanied the shift. Conclusions: Both cholinergic and adrenergic factors cause pacemaker shifts in the rabbit SAN. While modest changes in the sinus rhythm do not coincide with the pacemaker shift, greater changes always accompany the shift and may be caused by it, according to one hypothesis. The formation of an inexcitable zone at the place where the leading pacemaker is situated is one of the mechanisms associated with pacemaker shift. [ABSTRACT FROM AUTHOR]

The sino-atrial node (SAN) is the natural pacemaker of the heart. Mechanisms of the leading pacemaker site generation and dynamic pacemaker shifts in the SAN have been so far studied with an electrophysiological technique, but the detailed spatial distribution of action potential characteristics in the SAN has not been analyzed due to the limited number of simultaneously recorded sites in microelectrode recording. To elucidate the mechanism of leading pacemaker site generation in the SAN, we applied a voltage imaging technique and analyzed the spatial distribution of action potential characteristics in the rabbit SAN. Action potential parameters, i.e., action potential duration at 50% repolarization level, the slope of upstroke, and the slope of the linearly depolarizing early phase of pacemaker activity (phase-4), were calculated from optical signals. Action potential parameter values derived from intracellular recording with a microelectrode and those from optical recording were significantly correlated. The leading pacemaker site occurred in the region of either globally or locally maximum phase-4 slope in 7 of 12 preparations, however, it did not coincide with the region of the early maximum phase-4 slope in the other 5 preparations. Carbenoxolone, a gap junction blocker, changed action potential properties and caused pacemaker shifts. Model simulation, assuming an inhomogeneous distribution of intrinsic properties of SAN cells, reproduced the experimental results. We conclude that the functional structure of the SAN is more inhomogeneous than that dictated by previous models. Besides intrinsic cellular properties, cell-to-cell interaction through gap junctions influences action potential characteristics and leading pacemaker site generation. [ABSTRACT FROM AUTHOR]

SUMMARY 1. The pacemaker site is known to shift away from the sinoatrial (SA) node in response to autonomic stimuli. 2. To test whether the shifting of the impulse-initiation site that occurs during autonomic nerve stimulation can be explained by the spatial distributions of β -adrenoceptor and muscarinic receptors, we obtained densities (Bmax ) and dissociation constants (Kd ) for these receptors in three regions along the sulcus terminalis (the SA node itself and regions superior and inferior to it) and a region of the right atrial appendage in the dog. 3. The Bmax values for [125 I]-iodocyanopindolol binding to β -adrenoceptors were not different among the four regions. The Bmax value for [3 H]-quinuclidinyl benzilate binding to muscarinic receptors was significantly higher in the SA node area than in any other region (P < 0.01), although there was no difference among the other three regions. 4. For each receptor, Kd values were similar among the four regions. 5. These results suggest that spatial variations in the densities of β -adrenoceptors and muscarinic receptors are not important for shifting the impulse-initiation site and that other factors, such as non-uniform innervation by autonomic nerve fibres, may be mainly responsible for the pacemaker shift induced by autonomic nerve stimulation. [ABSTRACT FROM AUTHOR]

Introduction: The ionic basis underlying the negative chronotropic effect of acetylcholine (ACh) on sinoatrial (SA) node cells is unresolved and controversial. In the present study, mathematical modeling was used to address this issue. Methods and Results: The known concentration-dependent effects of ACh on iK,ACh, iCa,L and if were introduced into models of rabbit central and peripheral SA node cells. In the central and peripheral models, 9 x 10-8 and 14 x 10-8M ACh, respectively, caused a 50% decrease in pacemaking rate, whereas in rabbit SA node ∼7.4 x 10-8 M ACh caused such a decrease. In the models, ik,ACh as primarily responsible for the decrease and actions of ACh on iCa,L or if alone caused a negligible effect. Although the inhibition of if did not directly contribute to the chronotropic effect, it was indirectly important, because it minimized the opposition by if to the decrease of rate caused by activation of is iK,ACh. The central model was more sensitive to ACh than the peripheral model. Conclusion: The chronotropic effect of ACh is principally the result of activation of iK,ACh, and inhibition of iCa,L plays little or no role. Inhibition of if and possible inhibition of ib,Na play an important facilitative role by reducing the ability of if and ib,Na to curtail the chronotropic effect caused by activation of iK,ACh. [ABSTRACT FROM AUTHOR]

Adenosine has a negative chronotropic effect in a number of species. The studies reported here were undertaken to characterize further the effects of adenosine using isolated perfused rabbit hearts and isolated SA node tissue. In the isolated perfused hearts ( n=9) the threshold doses for slowing by adenosine and 2-chloroadenosine, an adenosine analog, were 1×10 M and 1×10 M, respectively. In the isolated hearts adenosine, in addition to slowing sinus rate, also caused a change in the activation pattern of the right atrium. During adenosine infusion the earliest site of activation shifted from the SA node region to the right atria near the crista terminalis. The pacemaker shift was reversible upon washout of adenosine. The adenosine-induced shift in pacemaker could also be demonstrated using microelectrode recordings in the isolated SA node preparation that included the crista terminalis and some of the surrounding tissue. During control the activation of SA node preceded that of the crista terminalis (CT) by 44±4.1 ms ( n=11). Adenosine infusion caused an increase in cycle length and, in addition shifted the earliest site of activation from the SA node region to CT, i.e., in the presence of adenosine CT preceded SA node activation by 26.68±3.2 ms. All the effects were reversible after washout of adenosine. Adenosine also caused conduction block within the sinus node. No effect on the action potentials or on conduction in the CT was observed. In small preparations (250×250 μm) which precludes pacemaker shift ( n=18), adenosine and 2-chloroadenosine slowed the rate and caused a decrease in rate of phase four depolarization. The threshold for adenosine and 2-chloro-adenosine was 1×10 M and 3×10, respectively. Associated with pacemaker slowing was an increase in the maximum diastolic potential with a concomitant increase in the maximum rate of rise of the action potential. Adenosine had no effect on the SA node action potential duration or amplitude. The results were similar to those observed for acetylcholine, however, the adenosine effects were blocked by aminophylline but not by atropine. Adenosine-induced sinus slowing and pacemaker shift may be of importance during periods of metabolically compromised myocardium such as hypoxia and ischemia where there is increased production of adenosine. [ABSTRACT FROM AUTHOR]

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We describe unusual responses of the sinus node to programmed atrial stimulation in two asymptomatic cardiac transplant recipients. In one patient the sinoatrial conduction time, calculated using the revised method of Strauss, is extremely short (5 ms), and in the other it is extremely long (460 ms). The various mechanisms that might be involved in these atypical responses to atrial extrastimulation are discussed. These include sinus node suppression, shift o/pacemaker, direct stimulation of the sinus node and shortening of the sinus node action potential duration. [ABSTRACT FROM AUTHOR]

Copyright of Pflügers Archiv: European Journal of Physiology is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The sinoatrial node (SAN), the primary pacemaker of the heart, consists of a heterogeneous population of specialized cardiac myocytes that can spontaneously produce action potentials, generating the rhythm of the heart and coordinating heart contractions. Spontaneous beating can be observed from very early embryonic stage and under a series of genetic programing, the complex heterogeneous SAN cells are formed with specific biomarker proteins and generate robust automaticity. The SAN is capable to adjust its pacemaking rate in response to environmental and autonomic changes to regulate the heart's performance and maintain physiological needs of the body. Importantly, the origin of the action potential in the SAN is not static, but rather dynamically changes according to the prevailing conditions. Changes in the heart rate are associated with a shift of the leading pacemaker location within the SAN and accompanied by alterations in P wave morphology and PQ interval on ECG. Pacemaker shift occurs in response to different interventions: neurohormonal modulation, cardiac glycosides, pharmacological agents, mechanical stretch, a change in temperature, and a change in extracellular electrolyte concentrations. It was linked with the presence of distinct anatomically and functionally defined intranodal pacemaker clusters that are responsible for the generation of the heart rhythm at different rates. Recent studies indicate that on the cellular level, different pacemaker clusters rely on a complex interplay between the calcium (referred to local subsarcolemmal Ca 2+ releases generated by the sarcoplasmic reticulum via ryanodine receptors) and voltage (referred to sarcolemmal electrogenic proteins) components of so-called "coupled clock pacemaker system" that is used to describe a complex mechanism of SAN pacemaking. In this review, we examine the structural, functional, and molecular evidence for hierarchical pacemaker clustering within the SAN. We also demonstrate the unique molecular signatures of intranodal pacemaker clusters, highlighting their importance for physiological rhythm regulation as well as their role in the development of SAN dysfunction, also known as sick sinus syndrome.