Published Online
on May 2, 2005

A more recent version of this article appeared on June 1, 2005

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Submitted on February 25, 2005
Revised on March 21, 2005

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

Megumi Fujita; Tomoyuki Kuwaki; Katsuyuki Ando; and 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.

^* To whom correspondence should be addressed. E-mail: fujita-dis{at}h.u-tokyo.ac.jp.

Abstract--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

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