Cerebellar adrenomedullinergic system. Role in cardiovascular regulation

Abstract

Adrenomedullin (AM) is a multifunctional peptide which exerts numerous biological activities through the activation of AM1 (CRLR + RAMP2) and AM2 (CRLR + RAMP3) receptors. AM immunoreactivity, AM binding sites and CRLR, RAMP1, RAMP2 and RAMP3 are expressed in rat cerebellar vermis. AM binding sites are discretely and differentially distributed in the rat cerebellar cortex with higher levels detected in SHR when compared with WKY rats. In addition, there is an up-regulation of cerebellar CGRP1 (CRLR + RAMP1) and AM2 (CRLR + RAMP3) receptors and a down-regulation of AM1 (CRLR + RAMP2) receptor during hypertension associated with a decreased AM expression. These changes may constitute a mechanism which contributes to the development of hypertension, and supports the notion that cerebellar AM is involved in the regulation of blood pressure. Cerebellar AM activates ERK, increases cAMP, cGMP and nitric oxide, and decreases antioxidant enzyme activity. These effects are mediated through AM1 receptor since they are blunted by AM(22-52). AM-stimulated cAMP production is mediated through AM2 and CGRP receptors. In vivo administration of AM into the cerebellar vermis caused a profound, specific and dose-dependent hypotensive effect in SHR, but not in normotensive WKY rats. This effect was mediated through AM1 receptor since it was abolished by AM(22-52). In addition, AM injected into the cerebellar vermis reduced vasopressor response to footshock stress. These findings demonstrate dysregulation of cerebellar AM system during hypertension, and suggest that cerebellar AM plays an important role in the regulation of blood pressure. Likewise, they constitute a novel mechanism of blood pressure control which has not been described so far.