Innervation of sinoatrial nodal cells in the rabbit

Inokaitis, Hermanas; Paužienė, Neringa; Rysevaitė-Kyguolienė, Kristina; Pauža, Dainius Haroldas

doi:10.1016/j.aanat.2016.03.007

Cited by 20 publications

(23 citation statements)

References 41 publications

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“…In the SAN region of multiple species, a dense meshwork of neurons has been characterized by immunohistochemical methods as predominantly cholinergic, although adrenergic-, nitrergic-and peptidergic-positive fibers have also been identified in the rabbit and human (19,25,28,36,37). Protein expression profiling indicates predominantly cholinergic neurons in the RAGP, but we describe the potential for expanded phenotypic diversity of RAGP neurons based on RNA analysis.…”

Section: Discussionmentioning

confidence: 96%

Innervation and Neuronal Control of the Mammalian Sinoatrial Node: A Comprehensive Atlas

Hanna

Dacey

Brennan

et al. 2020

Preprint

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Cardiac function is under exquisite intrinsic cardiac neural control. Neuroablative techniques to modulate control of cardiac function are currently being studied in patients, albeit with variable and sometimes deleterious results. Recognizing the major gaps in our understanding of cardiac neural control, we sought to evaluate neural regulation of impulse initiation in the sinoatrial node as an initial discovery step. Here, we report an in-depth, multi-scale structural and functional characterization of the innervation of the sinoatrial node (SAN) by the right atrial ganglionated plexus (RAGP) in porcine and human hearts. Combining intersectional strategies including tissue clearing, immunohistochemical and ultrastructural techniques, we have delineated a comprehensive neuroanatomic atlas of the RAGP-SAN complex. The RAGP shows significant phenotypic diversity of neurons while maintaining predominant cholinergic innervation. Cellular and tissue-level electrophysiologic mapping and ablation studies demonstrate interconnected ganglia with synaptic convergence within the RAGP to modulate SAN automaticity, atrioventricular (AV) conduction and left ventricular (LV) contractility. For the first time, we demonstrate that intrinsic cardiac neurons influence the pacemaking site in the heart. This provides an experimental demonstration of a discrete neuronal population controlling a specific geographic region of the heart (SAN) that can serve as a framework for further exploration of other parts of the intrinsic cardiac nervous system (ICNS) in mammalian hearts and for developing targeted therapies.

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Section: Discussionmentioning

confidence: 96%

Innervation and Neuronal Control of the Mammalian Sinoatrial Node: A Comprehensive Atlas

Hanna

Dacey

Brennan

et al. 2020

Preprint

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“…For example, intertwined with SANC are fibroblasts that express either Connexin40 or Connexin45 depending on whether they are surrounded by other fibroblasts or myocytes [27]. Also, a dense and complex ganglionated neural network has been reported in the SA node [28]. …”

Section: Discussionmentioning

confidence: 99%

Heterogeneity of calcium clock functions in dormant, dysrhythmically and rhythmically firing single pacemaker cells isolated from SA node

et al. 2018

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Current understanding of how cardiac pacemaker cells operate is based mainly on studies in isolated single sinoatrial node cells (SANC), specifically those that rhythmically fire action potentials similar to the in vivo behavior of the intact sinoatrial node. However, only a small fraction of SANC exhibit rhythmic firing after isolation. Other SANC behaviors have not been studied. Here, for the first time, we studied all single cells isolated from the sinoatrial node of the guinea pig, including traditionally studied rhythmically firing cells ('rhythmic SANC'), dysrhythmically firing cells ('dysrhythmic SANC') and cells without any apparent spontaneous firing activity ('dormant SANC'). Action potential-induced cytosolic Ca transients and spontaneous local Ca releases (LCRs) were measured with a 2D camera. LCRs were present not only in rhythmically firing SANC, but also in dormant and dysrhythmic SANC. While rhythmic SANC were characterized by large LCRs synchronized in space and time towards late diastole, dysrhythmic and dormant SANC exhibited smaller LCRs that appeared stochastically and were widely distributed in time. β-adrenergic receptor (βAR) stimulation increased LCR size and synchronized LCR occurrences in all dysrhythmic and a third of dormant cells (25 of 75 cells tested). In response to βAR stimulation, these dormant SANC developed automaticity, and LCRs became coupled to spontaneous action potential-induced cytosolic Ca transients. Conversely, dormant SANC that did not develop automaticity showed no significant change in average LCR characteristics. The majority of dysrhythmic cells became rhythmic in response to βAR stimulation, with the rate of action potential-induced cytosolic Ca transients substantially increasing. In summary, isolated SANC can be broadly categorized into three major populations: dormant, dysrhythmic, and rhythmic. We interpret our results based on simulations of a numerical model of SANC operating as a coupled-clock system. On this basis, the two previously unstudied dysrhythmic and dormant cell populations have intrinsically partially or completely uncoupled clocks. Such cells can be recruited to fire rhythmically in response to βAR stimulation via increased rhythmic LCR activity and ameliorated coupling between the Ca and membrane clocks.

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“…Following the discovery of the SAN in 1906 by Keith and Flack [2] numerous SAN cell characteristics have been described including a diversity of: cell shapes and protein expression; arrangement of cells within SAN tissue (e.g. gradient vs. mosaic [3]); autonomic neuronal input [4]; cell to cell electrical and mechanical interactions [5]; and intranodal impulse initiation, spread within, and exit from, the SAN [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Synchronized cardiac impulses emerge from multi-scale, heterogeneous local calcium signals within and among cells of heart pacemaker tissue

Bychkov

Juhaszova

Tsutsui

et al. 2020

Preprint

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The current functional paradigm of sinoatrial node (SAN), the heart's natural pacemaker, postulates the entrainment of full-scale action potentials (APs) at one common frequency and does not involve any subcellular events or subthreshold signals. SAN cells studied in isolation, however, generate subcellular, spontaneous, rhythmic, local Ca 2+ releases (LCRs) and, while each LCR is a small, subthreshold signal, the emergent LCR ensemble signal critically contributes to generation of spontaneous APs and accounts for the heterogeneity of AP firing rates of these cells.We hypothesized that cells embedded in SAN tissue also generate heterogeneous subthreshold LCR signals of different rates and amplitudes and that self-organization of the LCRs within and among cells critically contributes to the ignition of APs that emerge from the SAN to excite the heart. To this end we combined immunolabeling with a novel technique to image microscopic Ca 2+ dynamics, including both LCRs and AP-induced Ca 2+ transients (APCTs) within and among individual pacemaker cells across the entire mouse SAN.Immunolabeling identified a meshwork of HCN4(+)/CX43(-) non-striated cells of different morphologies that extended along the crista terminalis from the superior vena cava to the inferior vena cava, becoming intertwined with a network of striated cells, rich in F-actin and CX43, but devoid of HCN4 immunolabeling. The earliest APCTs within a given pacemaker cycle occurred within a small area of HCN4 meshwork below the superior vena cava, just medial to the crista terminalis. Although subsequent APCT appearance throughout the SAN at low magnification resembled a continuous propagation pattern, higher magnification imaging revealed that APCT appearance at different sites within the SAN was patchy and discontinuous. Both LCR dynamics and APCTs were markedly heterogeneous 3 in amplitudes and frequencies among SAN cells: in some cells, APCT occurrence was preceded by diastolic LCRs occurring in the same cell; other cells did not generate spontaneous APCTs, but had subthreshold LCRs only, which preceded APCT generation by adjacent cells; APCTs of various frequencies were generated steadily or in bursts.In summary, we discovered a novel, microscopic Ca 2+ signalling paradigm of SAN operation that could not be detected with low-resolution, macroscopic tissue methods employed in prior studies: synchronized macroscopic signals within the SA node, including full-scale APs, emerge from heterogeneous microscopic subthreshold Ca 2+ signals. This multiscale, complex process of impulse generation within the SAN resembles the emergence of organized signals from heterogeneous local signals generated within clusters of neurons within neuronal networks.

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Innervation of sinoatrial nodal cells in the rabbit

Cited by 20 publications

References 41 publications

Innervation and Neuronal Control of the Mammalian Sinoatrial Node: A Comprehensive Atlas

Innervation and Neuronal Control of the Mammalian Sinoatrial Node: A Comprehensive Atlas

Heterogeneity of calcium clock functions in dormant, dysrhythmically and rhythmically firing single pacemaker cells isolated from SA node

Synchronized cardiac impulses emerge from multi-scale, heterogeneous local calcium signals within and among cells of heart pacemaker tissue

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