Adenosine A2a receptors offset cholinergic control of blood pressure, autonomic neuropathy, and brainstem neuroinflammation in sepsis.

The cholinergic antiinflammatory pathway functions to counterbalance the innate immune response to inflammatory disorders including sepsis. Considering the reported contradictory role of adenosine in inflammation, the present study investigated whether central adenosine A2a receptors (A2aARs) arbitrate the cholinergic modulation of cardiovascular and autonomic dysfunction induced by sepsis. Rats were instrumented with femoral and intracisternal (i.c.) catheters for hemodynamic monitoring and central drug administration, respectively, and sepsis was induced by cecal ligation and puncture (CLP). The intravenous treatment with nicotine (100 μg/kg) 24-h post-CLP reversed the hypotension, depression of time- and frequency-domain indices of heart rate variability (HRV) and sympathovagal imbalance induced by sepsis. Intracisternal (i.c.) administration of CGS21680 (A2aAR agonist, 2 μg/rat) accentuated the hypotensive response to sepsis on its own and blunted the rises in blood pressure caused by subsequently administered nicotine. Additionally, CGS21680 suppressed the nicotine-evoked increments in HRV index of cardiac vagal control. The ameliorating action of CGS21680 on cardiovascular protection conferred by nicotine was paralleled with the abolition of nicotine counteraction of the sepsis-evoked augmentation of the protein expression of tumor necrosis factor α (TNFα) and A2aARs in brainstem nuclei of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM). On the other hand, the interrelated cardiovascular and molecular effects of nicotine were maintained following central blockade of A2aARs by 8-(3-chlorosteryl) caffeine (CSC, 40 μg/rat i.c.). The data suggest that medullary A2aARs restrain the machinery by which the cholinergic antiinflammatory pathway acts defensively to rectify cardiovascular and autonomic consequences of sepsis.