Affiliation:
1. Lomonosov Moscow State University
2. National Medical Research Centre of Cardiology named after academician E.I. Chazov
3. Belozersky Research Institute of Physico-Chemical Biology, Moscow Lomonosov State University
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), also known as the “pacemaker” of the heart. This results in an increase in heart rate (HR). It is known that two types of postsynaptic adrenoreceptors (ARs), α1-AR and β-AR, can 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 mediation the effects of α1-AR on the pacemaker, 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 causes a decrease in SNRT/cSNRT, as well as an acceleration of SAN accommodation. These effects were rate dependent and were observed at a high frequency 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 target Ca2+-dependent chloride channels are involved in the α1-adrenergic modulation of the electrophysiological properties of the heart pacemaker.
Publisher
The Russian Academy of Sciences
Reference49 articles.
1. Chandler N., Greener I., Tellez J., Inada S., Musa H., Molenaar P., DiFrancesco D., Baruscotti M., Longhi R., Anderson R., Billeter R., Sharma V., Sigg D., Boyett M., Dobrzynski H. 2009. Molecular architecture of the human sinus node insights into the function of the cardiac pacemaker. Circulation. 119 (12), 1562–1575.
2. Lakatta E., Maltsev V., Vinogradova T. 2010. A Coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart’s pacemaker. Circ. Res. 106 (4), 659–673.
3. Keith A., Flack M. 1907. The form and nature of the muscular connections between the primary divisions of the vertebrate heart. J. Anat. Physiol. 41 (3), 172–189.
4. James T. 1961. Anatomy of the human sinus node. Anat. Rec. 141 (2), 109–139.
5. Dobrzynski H., Li J., Tellez J., Greener I., Nikolski V., Wright S., Parson S., Jones S., Lancaster M., Yamamoto M., Honjo H., Takagishi Y., Kodama I., Efimov I., Billeter R., Boyett M. 2005. Computer three-dimensional reconstruction of the sinoatrial node. Circulation. 111 (7), 846–854.