Adenosine A3 Receptors Offset the Nicotine Amelioration of Sepsis-Induced Brainstem Inflammation and Depressed Reflex Bradycardia

Abstract ID 87640 Poster Board 074 We have previously reported that the central cholinergic pathway improves arterial baroreflex dysfunction induced by sepsis. Given the role of central adenosinergic neurotransmission in baroreflex control, we tested the hypothesis that central adenosine A3 receptors (A3ARs) alter the nicotine/baroreflex interaction in sepsis via the modulation of mitogen activated protein kinases (MAPKs) and related inflammatory signals. Sepsis was induced by cecal ligation and puncture (CLP) and baroreflex sensitivity (BRS) was measured in awake rats by the vasoactive method, which correlates the increases and decreases in blood pressure caused by phenylephrine (PE) and sodium nitroprusside (SNP), respectively, with corresponding reciprocal changes in heart rate. The upward shift in PE baroreflex curves and reductions in BRS-PE value caused by CLP were dose-dependently reversed by nicotine (25 and 100 μg/kg, i.v.) whereas the CLP-evoked falls in BRS-SNP remained unaffected. The favorable BRS-PE effect of nicotine was abrogated following intracisternal (i.c.) administration of IB-MECA (A3AR agonist, 4 μg/rat) and remained unaltered after A3AR blockade by i.c. VUF5574 (2 μg/rat). The alleviation by A3ARs of cholinergically-mediated BRS facilitation was blunted following pharmacological inhibition of central MAPK-JNK (SP600125), PI3K (wortmannin) and TNF α (infliximab), but persisted after MAP-ERK inhibition (PD98059). Immunohistochemically, IB-MECA blocked the nicotine suppression of the sepsis-evoked upregulation of NFκB and NOX2 expression in neurons of the brainstem solitary tract. The molecular NFκB effect of IB-MECA disappeared upon i.c. treatment with PD98059, SP600125, wortmannin or infliximab while the IB-MECA-NOX2 effect was inhibited by wortmannin only. Collectively, the data highlight that central PI3K/MAPK/TNF α pathway contributes to the restraining action of A3ARs on the nicotine amelioration of sepsis-induced neuroinflammation and consequent baroreflex dysfunction.