ATP is a cotransmitter released with other neurotransmitters from sympathetic nerves, where it stimulates purinergic receptors. Purinergic adenosine P₁ receptors (coupled to G_i/o proteins) produce sympatho-inhibition in several autonomic effectors by prejunctional inhibition of neurotransmitter release. Similarly, signalling through P2Y₁₂ and P2Y₁₃ receptors coupled to G_i/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.

中文翻译：

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嘌呤能的P2Y12和P2Y13受体在ADPβS诱导的抑制成年大鼠的心脏促进剂交感神经驱动中的作用。

ATP是与其他神经递质从交感神经中释放的一种共递质，可刺激嘌呤能受体。嘌呤能腺苷P ₁受体（与G _{i / o}蛋白偶联）通过神经递质释放的结节抑制作用，在几种自主效应中产生交感抑制作用。类似地，通过ATP分解产物ADP引发通过与G _{i / o}蛋白偶联的P2Y ₁₂和P2Y ₁₃受体发出的信号。因此，本研究使用稳定的ADP类似物（ADPβS）和嘌呤能性P2Y ₁，P2Y的选择性拮抗剂，在药理学上研究了ADP诱导的对成年大鼠心脏促进剂交感驱动的抑制作用₁₂和P2Y ₁₃受体。因此，将雄性Wistar大鼠拔髓，并：（i）用没食子胺（25 mg / kg）和地昔帕明（50μg/ kg）iv预处理，以刺激神经节前性脊髓（C ₇ -T ₁）刺激心脏加速剂交感神经驱动（n  = 78） ）; 或（ii）准备接受静脉注射外源性去甲肾上腺素（n  = 12）。静脉内连续输注ADPβS（10和30μg/ kg / min）剂量依赖性地抑制了对电交感刺激的心动过速反应，但对外源性去甲肾上腺素没有抑制作用。30μg/ kg / minADPβS产生的心脏交感神经抑制作用（静脉内施用化合物后）（i）1-ml / kg蒸馏水或300μg/ kg MRS 2500（P2Y）不变₁受体拮抗剂），（ii）被300-μg/ kg PSB 0739（P2Y ₁₂受体拮抗剂）废除，和（iii）被3000-μg/ kg MRS 2211（P2Y ₁₃受体拮抗剂）部分阻断。我们的结果表明，ADPβS诱导心脏交感神经抑制，其主要涉及P2Y ₁₂受体亚型，并且可能在较小程度上涉及P2Y ₁₃受体亚型。这些受体可以代表用于治疗心血管疾病包括中风和心肌梗塞的治疗靶标。