Central Adenosine A1 Receptors Arbitrate the Nicotine Counteraction of Cardiovascular and Autonomic Dysfunctions in Septic Rats.

The cholinergic anti-inflammatory pathway plays a crucial role in improving end-organ damage provoked by inflammatory disorders. Given the interplay between cholinergic and adenosinergic neuronal circuits in the central nervous system, we tested the hypothesis that central adenosine A1 receptors (A1Rs) modulate the offsetting action of nicotine on cardiovascular and inflammatory insults induced by sepsis. Pharmacologic agonistic and antagonistic studies were conducted in conscious rats, pre-instrumented with femoral vessel and intracisternal (i.c.) catheters. Sepsis was induced by cecal ligation and puncture (CLP) 24 hr before cardiovascular measurements. Nicotine (25 or 100 µg/kg i.v.) dose-dependently reversed septic manifestations of hypotension and concomitant reductions in time and spectral measures of heart rate variability (HRV) and cardiac sympathovagal balance (low-frequency/high-frequency ratio). Like nicotine, the i.c. administration of N(6)-cyclopentyladenosine (CPA, AR1 agonist) to CLP rats caused significant increases in indices of HRV and sympathovagal balance and greater surges in these parameters were noted upon simultaneous administration of CPA plus nicotine. We also show that the favorable influences of nicotine on blood pressure and HRV in septic rats were significantly inhibited after central blockade of A1Rs by i.c. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX). Immunohistochemically, the alleviation by nicotine of the upregulated myocardial expression of NFκB in septic rats disappeared upon prior exposure to DPCPX. The data suggest that central adenosine A1Rs act tonically to facilitate the ameliorative effect of nicotine against the inflammatory response of sepsis and interrelated cardiomyopathic and neuropathic hitches.