This Article Full Text Full Text (PDF) All Versions of this Article: 45/6/1165    most recent 01.HYP.0000165690.85505.37v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fujita, M. Articles by Fujita, T. Search for Related Content PubMed PubMed Citation Articles by Fujita, M. Articles by Fujita, T. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Hazardous Substances DB SODIUM CHLORIDE Related Collections Genetically altered mice Autonomic, reflex, and neurohumoral control of circulation

(Hypertension. 2005;45:1165.)
© 2005 American Heart Association, Inc.

Original Articles

Sympatho-Inhibitory Action of Endogenous Adrenomedullin Through Inhibition of Oxidative Stress in the Brain

Megumi Fujita; Tomoyuki Kuwaki; Katsuyuki Ando; Toshiro Fujita

From the Department of Nephrology and Endocrinology (M.F., K.A., T.F.), Faculty of Medicine, The University of Tokyo, Japan; and the Department of Molecular & Integrative Physiology and Autonomic Physiology (T.K.), Chiba University Graduate School of Medicine, Chiba-city, Japan.

Correspondence to Toshiro Fujita, MD, PhD, Department of Nephrology and Endocrinology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. E-mail fujita-dis{at}h.u-tokyo.ac.jp

Central sympathetic activation is one of the possible mechanisms underlying hypertension, in which reactive oxygen species may play a role. Thus, we examined whether adrenomedullin, an antioxidant peptide, is involved in the central regulation of arterial pressure through sympatho-modulatory action. Adrenomedullin knockout mice were fed with high-salt diet for 4 weeks to stimulate adrenomedullin production. In the wild-type littermates, brain adrenomedullin content was significantly increased with salt loading, but not in the knockout mice. Intracerebroventricular hyperosmotic saline increased arterial pressure and sympathetic nerve activity in a dose-dependent fashion. With the normal salt diet, the hyperosmotic saline-induced response did not significantly differ between the knockout and wild-type mice; with the high-salt diet, however, the response was significantly greater in the knockout mice than in wild-type littermates (arterial pressure: 35.3±5.7% versus 20.1±2.1%, P<0.05; sympathetic nerve activity: 30.3±4.8% versus 15.9±1.5%, P<0.05; respectively). Moreover, pretreatment with 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol), a membrane-permeable superoxide dismutase mimetic, inhibited the augmented response to central hyperosmotic saline in salt-loaded knockout mice. Consistently, the hyperosmotic saline-induced production of reactive oxygen species, measured by the lucigenin chemiluminescence method, was significantly greater in the isolated hypothalamus of salt-loaded knockout mice than in that of salt-loaded wild-type ones. In conclusion, endogenous adrenomedullin in the brain may inhibit sympathetic activation through its antioxidant action.

Key Words: central nervous system • free radicals • hypertension, arterial • mice • sodium, dietary • sympathetic nervous system

This article has been cited by other articles:

				A. Nagae, M. Fujita, H. Kawarazaki, H. Matsui, K. Ando, and T. Fujita Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Obesity-Induced Hypertension Circulation, February 24, 2009; 119(7): 978 - 986. [Abstract] [Full Text] [PDF]

				C. S. Wilcox and A. Pearlman Chemistry and Antihypertensive Effects of Tempol and Other Nitroxides Pharmacol. Rev., December 1, 2008; 60(4): 418 - 469. [Abstract] [Full Text] [PDF]

				S. Oba, M. Hino, and T. Fujita Adrenomedullin protects against oxidative stress-induced podocyte injury as an endogenous antioxidant Nephrol. Dial. Transplant., February 1, 2008; 23(2): 510 - 517. [Abstract] [Full Text] [PDF]

				B.-S. Deng, A. Nakamura, W. Zhang, M. Yanagisawa, Y. Fukuda, and T. Kuwaki Contribution of orexin in hypercapnic chemoreflex: evidence from genetic and pharmacological disruption and supplementation studies in mice J Appl Physiol, November 1, 2007; 103(5): 1772 - 1779. [Abstract] [Full Text] [PDF]

				M. Fujita, K. Ando, A. Nagae, and T. Fujita Sympathoexcitation by Oxidative Stress in the Brain Mediates Arterial Pressure Elevation in Salt-Sensitive Hypertension Hypertension, August 1, 2007; 50(2): 360 - 367. [Abstract] [Full Text] [PDF]

				D. Li, L. Wang, C.-W. Lee, T. A. Dawson, and D. J. Paterson Noradrenergic Cell Specific Gene Transfer With Neuronal Nitric Oxide Synthase Reduces Cardiac Sympathetic Neurotransmission in Hypertensive Rats Hypertension, July 1, 2007; 50(1): 69 - 74. [Abstract] [Full Text] [PDF]