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α1-Adrenergic Receptors Control the Activity of Sinoatrial Node by Modulating Transmembrane Transport of Chloride Anions

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Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology Aims and scope

Abstract

Norepinephrine (NE), which is released by sympathetic nerve endings, causes an increase in the frequency of spontaneous action potentials in the pacemaker cardiomyocytes of the sinoatrial node (SAN) of the heart. This results in an increase in heart rate (HR). Two types of postsynaptic adrenoreceptors (ARs), α1-AR and β-AR, mediate the effects of NE. The role of α1-AR in the sympathetic control of heart rate and SAN automaticity, as well as the membrane mechanisms involved in α1-AR-mediated pacemaker control, have not yet been elucidated. In this study, we utilized immunofluorescence confocal microscopy to examine the distribution of α1A-AR in the SAN of rats. Additionally, we assessed the expression of α1A-AR mRNA in the SAN tissue using RT-PCR. Furthermore, we investigated the impact of α1-AR stimulation on key functional parameters of the pacemaker, including the corrected sinus node recovery time (SNRT/cSNRT) and the SAN accommodation, using the Langendorff perfused heart technique. We also used optical mapping of the electrical activity of perfused, isolated tissue preparations to study the effect of α1-AR stimulation on the spatiotemporal characteristics of SAN excitation. We tested the effects of chloride transmembrane conductance blockade on alteration of functional parameters and pattern of SAN excitation caused by α1-AR. Fluorescent signals corresponding to α1A-AR have been identified in SAN cardiomyocytes, indicating the presence of α1A-AR at protein level. The expression of α1A-AR in SAN has been also confirmed at the mRNA level. The stimulation of α1-AR affects SAN functioning. Phenylephrine (PHE) utilized as α1A-AR agonist caused a decrease in SNRT/cSNRT, as well as an acceleration of SAN accommodation. These effects were rate dependent and were observed in a high frequency range of pacemaker tissue stimulation. PHE induces changes in the excitation pattern of the SAN. The effects of PHE on functional parameters and SAN excitation pattern are attenuated by Ca2+-dependent chloride channel blocker NPPB but remains unaffected by the protein kinase C inhibitor BIM. Our results suggest that cardiac α1-ARs are important for maintaining function of SAN pacemaker at high heart rates and that α1-AR signalling cascades in the SAN by targeting Ca2+-dependent chloride channels are involved in the α1-adrenergic modulation of the electrophysiological properties of the heart pacemaker.

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Funding

The work was supported by the Russian Science Foundation (project no. 22-15-00189).

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Authors and Affiliations

  1. Lomonosov Moscow State University, Faculty of Biology, 119234, Moscow, Russia

    Y. A. Voronina, A. V. Fedorov, U. E. Piunova & V. S. Kuzmin

  2. National Medical Research Centre of Cardiology named after academician E.I. Chazov, 121552, Moscow, Russia

    Y. A. Voronina & V. S. Kuzmin

  3. Belozersky Institute of Physico-Chemical Biology, Moscow Lomonosov State University, 119992, Moscow, Russia

    M. A. Chelombitko

Authors
  1. Y. A. Voronina
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  2. A. V. Fedorov
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  3. M. A. Chelombitko
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  4. U. E. Piunova
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  5. V. S. Kuzmin
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Correspondence to Y. A. Voronina.

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ETHICS APPROVAL AND CONSENT TO PARTICIPATE

All experimental procedures were carried out in accordance with European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Council of Europe No. 123, Strasbourg 1985) and approved by the Ethics Committee of the NMRCC Institute of Experimental Cardiology.

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Translated by E. Puchkov

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Voronina, Y.A., Fedorov, A.V., Chelombitko, M.A. et al. α1-Adrenergic Receptors Control the Activity of Sinoatrial Node by Modulating Transmembrane Transport of Chloride Anions. Biochem. Moscow Suppl. Ser. A 17 (Suppl 1), S39–S50 (2023). https://doi.org/10.1134/S1990747823070061

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