Effect of adrenomedullin receptor and calcitonin gene-related peptide receptor antagonists on centrally mediated adrenomedullin renal action

Abstract

To determine pharmacological specificity of intracerebroventricular (IVT) administration of adrenomedullin (AM) on water and sodium excretion, studies were performed in rats pretreated with AM (22-52), a putative AM-receptor antagonist or CGRP(8-37), a ligand that preferentially antagonizes the CGRP 1-receptor subtype. In addition, the effects of IVT injection of calcitonin-gene-related peptide (CGRP) on urinary water and electrolyte excretion was assessed. Intracerebroventricular administration of rat adrenomedullin to conscious hydrated rats resulted in a significant increase in urinary volume and sodium excretion during the 6-h period of urine collection and was most effective at 3 and 6 h. Although less effective than AM, central administration of CGRP induced diuresis and natriuresis. Pretreatment with AM (22-52) or CGRP(8-37) significantly suppressed the diuretic and natriuretic effect of IVT-AM. These data suggest that both CGRP 1 and AM receptors are involved in the centrally mediated diuretic and natriuretic action of the AM. Our results provide evidence supporting the hypothesis that endogenous AM plays a role in the central nervous control of fluid and electrolyte homeostasis.