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Dopamine D4 receptor subtype activation reduces the rat cardiac parasympathetic discharge

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Abstract

The dopaminergic system influences the heart rhythm by inhibiting the rat cardiac sympathetic and parasympathetic neurotransmissions through activation of D2-like receptors (encompassing the D2, D3, and D4 subtypes). Whereas D2 receptor subtype activation results in cardiac sympatho-inhibition, the dopamine receptor subtypes involved in rat cardiac vago-inhibition remain unknown. Hence, this study investigated the specific functional role of the D2-like receptor subtypes (D2, D3, and/or D4) inhibiting the rat heart cholinergic drive. For this purpose, male Wistar rats were pithed and prepared for cardiac vagal stimulation. Bradycardic responses were obtained by electrical stimulation of vagal fibres (3, 6, 9 Hz; n = 100) or i.v. acetylcholine (ACh; 1, 5, 10 μg/kg; n = 15). Expression of D2, D3, and D4 receptors was studied in left and right atrium samples by PCR (n = 4). Intravenous injections of quinpirole (D2-like agonist; 1–30 μg/kg), but not of SFK-38393 (D1-like agonist; 1–30 μg/kg), dose-dependently inhibited the vagally induced bradycardia. The vago-inhibition induced by quinpirole (which failed to affect the bradycardia to i.v. ACh) was unchanged after i.v. injections of the antagonists L-741,626 (D2; 100 μg/kg) or SB-277011-A (D3; 100 μg/kg), but it was abolished by L-745,870 (D4; 100 μg/kg). mRNA levels of D2, D3, and D4 receptor subtype were detected in the left and right rat atria. Our results suggest that the quinpirole-induced vagolytic effect involves prejunctional D4 receptor subtypes, located in the left and right atria. This provides new evidence on the relevance of D4 receptor modulating the heart parasympathetic control.

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All material and data obtained and processed in this manuscript is available for further query to the authors in the Laboratory of Pharmacology of the University of Salamanca.

Funding

This work received financial support from the University of Salamanca (project KB7N/463AC01) and SEP-Cinvestav (grant no. 50, Mexico City).

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Authors and Affiliations

  1. Laboratorio de Farmacología, Dep. de Fisiología y Farmacología, Facultad de Farmacia, Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, 37007, Salamanca, Spain

    José Ángel García-Pedraza, Asunción Morán, María Luisa Martín & Mónica García-Domingo

  2. Unidad de Fisiopatología Renal y Cardiovascular, Instituto Reina Sofía de Investigación Nefrológica, Dep. de Fisiología y Farmacología, Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca, 37007, Salamanca, Spain

    Claudia Ollauri-Ibáñez & Alicia Rodríguez-Barbero

  3. Departamento de Farmacobiología, Cinvestav-Coapa, Czda. Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, 14330, Mexico City, Mexico

    Carlos M. Villalón

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  1. José Ángel García-Pedraza
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  2. Asunción Morán
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Contributions

Conceived and designed experiments: AM, CMV, MGD. Performed experiments: AM, ARB, COI, JAGP, MGD. Analysed data: AM, CMV, JAGP, MGD, MLM. Wrote and revised the manuscript: AM, CMV, JAGP, MGD.

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Correspondence to Mónica García-Domingo.

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The authors declare that they have no conflict of interest.

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This study was approved by the University of Salamanca Institutional Bioethics committee (permit number 006N°201400037737). Maintenance and manipulation protocols were performed following European guidelines (Directive 2010/63/EU) and Spanish legislation (R.D. 53/2013) for the use and care of animals in Biomedical Research, in full compliance with (i) the guide for the Care and Use of Laboratory Animals in USA and (ii) the ARRIVE guidelines for reporting experiments involving animals [21].

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García-Pedraza, J.Á., Morán, A., Martín, M.L. et al. Dopamine D4 receptor subtype activation reduces the rat cardiac parasympathetic discharge. Pflugers Arch - Eur J Physiol 472, 1693–1703 (2020). https://doi.org/10.1007/s00424-020-02452-8

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