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(Circulation Research. 2006;98:262.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Enhanced Vascular Responses to Adrenomedullin in Mice Overexpressing Receptor-Activity–Modifying Protein 2

C.W. Tam^*, K. Husmann^*, N.C. Clark^*, J.E. Clark, Z. Lazar, L.M. Ittner, J. Götz, G. Douglas, A.D. Grant, D. Sugden, L. Poston, R. Poston, I. McFadzean, M.S. Marber, J.A. Fischer, W. Born, S.D. Brain

From the Cardiovascular Division (C.W.T., N.C.C., J.E.C., Z.L., A.D.G., R.P., I.Mc.F., M.S.M., S.D.B.) and Division of Reproduction, Endocrinology and Diabetes (G.D., D.S., I.P.), King’s College London, United Kingdom; Research Laboratory for Calcium Metabolism (K.H., L.M.I., J.A.F., W.B.), Department of Orthopedic Surgery, University of Zurich, Balgrist University Hospital, Switzerland; and Division of Psychiatry Research (J.G.), University of Zürich, Switzerland.

Correspondence to Prof S.D. Brain, Cardiovascular Division, King’s College London, New Hunt’s House, Guy’s Campus, London SE1 1UL, United Kingdom. E-mail sue.brain{at}kcl.ac.uk

Adrenomedullin (AM) levels are elevated in cardiovascular disease, but little is known of the role of specific receptor components. AM acts via the calcitonin receptor-like receptor (CLR) interacting with a receptor-activity–modifying protein (RAMP). The AM₁ receptor is composed of CLR and RAMP2, and the calcitonin gene–related peptide (CGRP) receptor of CLR and RAMP1, as determined by molecular and cell-based analysis. This study examines the relevance of RAMP2 in vivo. Transgenic (TG) mice that overexpress RAMP2 in smooth muscle were generated. The role of RAMP2 in the regulation of blood pressure and in vascular function was investigated. Basal blood pressure, acute angiotensin II–raised blood pressure, and cardiovascular properties were similar in wild-type (WT) and TG mice. However, the hypotensive effect of IV AM, unlike CGRP, was enhanced in TG mice (P<0.05), whereas a negative inotropic action was excluded by left-ventricular pressure–volume analysis. In aorta relaxation studies, TG vessels responded in a more sensitive manner to AM (EC₅₀, 8.0±1.5 nmol/L) than WT (EC₅₀, 17.9±3.6 nmol/L). These responses were attenuated by the AM receptor antagonist, AM_22-52, such that residual responses were identical in all mice. Remaining relaxations were further inhibited by CGRP receptor antagonists, although neither affected AM responses when given alone. Mesenteric and cutaneous resistance vessels were also more sensitive to AM in TG than WT mice. Thus RAMP2 plays a key role in the sensitivity and potency of AM-induced hypotensive responses via the AM₁ receptor, providing evidence that this receptor is a selective target for novel therapeutic approaches.

Key Words: adrenomedullin • blood pressure • CGRP • receptor-activity–modifying protein • RAMP2 • transgenic mouse

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