Dopamine D₄ receptor subtype activation reduces the rat cardiac parasympathetic discharge

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.