Effect of intravenous administration of adrenomedullin on blood pressure in wild-type and RAMP2 overexpressing mice

Gabor Pozsgai, Susan D. Brain

Cardiovascular Division, King’s College London, London, UK

CGRP and adrenomedullin (AM) are members of CGRP peptide family. They show marked hypotensive effects, the former having higher potency. They exert their actions via the G-protein-linked calcitonin receptor-like receptor (CL). However, their specificity is determined by receptor activity-modifying proteins (RAMP) attached to CL. CL/RAMP1 compose CGRP1 receptor with the highest affinity to CGRP, but also binding AM. CL/RAMP2 make up AM1 receptor which is selective to AM (see Brain et al., 2004).

Here we investigate responses to i.v. CGRP and AM with a view to learning more about desensitisation processes. These have been suggested to occur for AM, but not CGRP after i.v. administration (Tam et al., 2003). In the present study we use genetically modified RAMP2 overexpressing mice to analyse the participation of AM1 receptors in the desensitising action of AM. RAMP2 overexpressing animals have an increased number of functional AM1 receptors (Tam et al., 2006).

C57BL/6 wild type (WT) or RAMP2 overexpressing (TG) mice (both sexes, 25-35 g) were anaesthetised with urethane (2.5g/kg) and a tracheal tube was inserted. The left carotid artery was cannulated and connected to a pressure transducer. Arterial pressure was monitored by PowerLab data acquisition system. Two injections of a submaximal dose of AM (5.2 nmol/kg) were given into the right jugular vein (2 ml/kg) with an interval of 60 min.

RAMP2 WT mice had a baseline arterial pressure of 64.47±2.39 mmHg (n=6), whereas TG animals showed 62.91±4.53 mmHg (n=5). In WT animals the second injection induced significantly smaller decrease of arterial pressure (22.26±1.25% vs. 15.92±2.18%, p<0.01, paired t-test). By comparison, there was no significant difference in TG mice (21.25±0.91% vs. 18.94±1.67%).

The mechanism underlying the lack of desensitisation in TG mice is unknown, but may be related to the increased number of functional AM1 receptors in these animals.

We thank the British Heart Foundation for funding.

Brain, S et al. (2004) Physiol Rev 507:273-280.

Tam, CW et al. (2003) BPS Winter Meeting, 085P GKT, www.pa2online.org/Vol1Issue4abst085P.html

Tam, CW et al. (2006) Circ Res 98:262-270.