Dopamine D 4 receptor subtype activation reduces the rat cardiac parasympathetic discharge
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INTEGRATIVE PHYSIOLOGY
Dopamine D4 receptor subtype activation reduces the rat cardiac parasympathetic discharge José Ángel García-Pedraza 1 & Asunción Morán 1 & María Luisa Martín 1 & Claudia Ollauri-Ibáñez 2 & Alicia Rodríguez-Barbero 2 & Carlos M. Villalón 3 & Mónica García-Domingo 1 Received: 3 July 2020 / Revised: 31 July 2020 / Accepted: 14 August 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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), dosedependently 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. Keywords Bradycardia . Cardiac parasympathetic neurotransmission . D4 receptor . Dopamine . Heart rate . Rat atria
Introduction Dopamine is a catecholamine that plays an important role as a neurotransmitter in the central and peripheral nervous systems, and that exerts complex peripheral actions at * Mónica García-Domingo [email protected] 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
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
3
Departamento de Farmacobiología, Cinvestav-Coapa, Czda. Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, 14330 Mexico City, Mexico
cardiovascular level [3, 20]. Indeed, dopamine
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