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Cerebellar adrenomedullin: A new target for blood pressure regulation

Adrenomedullin (AM) and their receptor components, CRLR, RAMP1, RAMP2 and RAMP3 are widely expressed in the central nervous system, including cerebellum. Recent evidence suggests a role for cerebellar adrenomedullinergic system in blood pressure (BP) regulation. We assessed AM, RAMP1, RAMP2, RAMP3 and CRLR expression; and AM receptor signaling pathway in the cerebellar vermis of WKY and SHR rats.  Our findings demonstrated that CRLR, RAMP1 and RAMP3  expression was higher in cerebellum of SHR rats, while AM and RAMP2 expression was lower than those of WKY rats, both in 8 and 16 week old rats. In regard of AM signaling pathways, we show that AM activates ERK, increases cAMP production, increases cGMP production and NO accumulation. These effects are mediated through the activation of AM 1 receptor, since AM 22-52 blunted AM action, meanwhile AM increase of cAMP production is also mediated through stimulation of AM2 and CGRP receptors.  Furthermore, AM decreased TBARS production and antioxidant enzymes basal activity:  catalase (CAT), gluthation peroxidase (GPx) and superoxide dismutase (SOD).   During hypertension, AM signaling pathways in the cerebellar vermis are altered.  Effectively, in WKY rats AM decreased the activity of three antioxidant enzymes and TBARS production, while in SHR rats AM was unable to affect these signaling pathways; AM-induced ERK1/2 activation in cerebellum of the SHR was smaller in magnitude than in WKY; and AM increased cGMP/NO production in cerebellar vermis of the WKY rats, while in SHR rats AM was unable to stimulate this signaling pathway.  We anticipated a possible functional role of cerebellar AM on BP regulation. Indeed, in vivo microinjection of AM into the cerebellar vermis caused a profound, dose dependent, hypotensive effect in SHR but not in normotensive WKY rats. Co-injections of a putative AM receptor antagonist, AM 22–52 abolished the decreases in MAP evoked by AM, showing that AM acts through its AM1 receptor to reduce blood pressure.  These findings demonstrate dysregulation of cerebellar AM system during hypertension, and suggest that cerebellar AM plays an important role in the regulation of BP.  Likewise, they constitute a novel mechanism of BP control which has not been described so far.