Dysfunction of the cholinergic anti-inflammatory pathway mediates organ damage in hypertension

Inflammatory responses are associated with the genesis and progression of end-organ damage (EOD) in hypertension. A role for the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) in inflammation has recently been identified. We tested the hypothesis that alpha7nAChR dysfunction contributes to hypertensive EOD. In both spontaneously hypertensive rats (SHRs) and rats with abdominal aorta coarctation-induced hypertension, atropine-induced tachycardia was blunted compared with normotensive controls. Both models of hypertension were associated with deficits in expression of the vesicular acetylcholine transporter and the alpha7nAChR in cardiovascular tissues. In hypertension induced by abdominal aorta coarctation, deficits in aortic vesicular acetylcholine transporter and alpha7nAChR were present both above and below the coarctation site, indicating that they were independent of the level of arterial pressure itself. Hypertension in 40-week-old SHRs was associated with cardiac and aortic hypertrophy. Morphological abnormalities consistent with EOD, along with elevated tissue levels of proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6) were observed in the heart, kidney, and aorta. Chronic treatment of SHRs with the alpha7nAChR agonist PNU-282987 relieved EOD and inhibited tissue levels of proinflammatory cytokines and activation of nuclear factor kappaB. Greater serum levels of proinflammatory cytokines and more severe damage in the heart, aorta, and kidney were seen in alpha7nAChR(-/-) mice subjected to 2-kidney-1-clip surgery than in wild-type mice. A deficit in the cholinergic anti-inflammatory pathway appears to contribute to the pathogenesis of EOD in models of hypertension of varying etiology. This pathway may provide a new target for preventing cardiovascular disease resulting from hypertension.