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The role of purinergic P2Y12 and P2Y13 receptors in ADPβS-induced inhibition of the cardioaccelerator sympathetic drive in pithed rats

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  • Belinda Villanueva-Castillo
  • Eduardo Rivera-Mancilla
  • Kristian Agmund Haanes
  • Antoinette MaassenVanDenBrink
  • Carlos M Villalón
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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.

OriginalsprogEngelsk
TidsskriftPurinergic Signalling
Vol/bind16
Udgave nummer1
Sider (fra-til)73-84
Antal sider12
ISSN1573-9538
DOI
StatusUdgivet - mar. 2020

ID: 60887568