ATP is a cotransmitter released with other neurotransmitters from sympathetic nerves, where it stimulates purinergic receptors. Purinergic adenosine P1 receptors (coupled to Gi/o proteins) produce sympatho-inhibition in several autonomic effectors by prejunctional inhibition of neurotransmitter release. Similarly, signalling through P2Y12 and P2Y13 receptors coupled to Gi/o proteins is initiated by the ATP breakdown product ADP. Hence, this study has pharmacologically investigated a possible role of ADP-induced inhibition of the cardioaccelerator sympathetic drive in pithed rats, using a stable ADP analogue (ADPβS) and selective antagonists for the purinergic P2Y1, P2Y12 and P2Y13 receptors. Accordingly, male Wistar rats were pithed and: (i) pretreated i.v. with gallamine (25 mg/kg) and desipramine (50 μg/kg) for preganglionic spinal (C7-T1) stimulation of the cardioaccelerator sympathetic drive (n = 78); or (ii) prepared for receiving i.v. injections of exogenous noradrenaline (n = 12). The i.v. continuous infusions of ADPβS (10 and 30 μg/kg/min) dose-dependently inhibited the tachycardic responses to electrical sympathetic stimulation, but not those to exogenous noradrenaline. The cardiac sympatho-inhibition produced by 30 μg/kg/min ADPβS was (after i.v. administration of compounds) (i) unchanged by 1-ml/kg bidistilled water or 300-μg/kg MRS 2500 (P2Y1 receptor antagonist), (ii) abolished by 300-μg/kg PSB 0739 (P2Y12 receptor antagonist) and (iii) partially blocked by 3000-μg/kg MRS 2211 (P2Y13 receptor antagonist). Our results suggest that ADPβS induces a cardiac sympatho-inhibition that mainly involves the P2Y12 receptor subtype and, probably to a lesser extent, the P2Y13 receptor subtype. These receptors may represent therapeutic targets for treating cardiovascular pathologies, including stroke and myocardial infarctions.

Additional Metadata
Keywords Cardioaccelerator sympathetic drive, Pithed rat, Purinergic receptor, Sympatho-inhibition
Persistent URL dx.doi.org/10.1007/s11302-020-09689-z, hdl.handle.net/1765/125026
Journal Purinergic Signalling
Citation
Villanueva-Castillo, B. (Belinda), Rivera-Mancilla, E. (Eduardo), Haanes, K.A, Maassen van den Brink, A, & Villalón, C.M. (2020). The role of purinergic P2Y12 and P2Y13 receptors in ADPβS-induced inhibition of the cardioaccelerator sympathetic drive in pithed rats. Purinergic Signalling. doi:10.1007/s11302-020-09689-z