title: Sympatho-inhibitory action of endogenous adrenomedullin through inhibition of oxidative stress in the brain.
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.
authors.affiliation: Department of Nephrology and Endocrinology, Faculty of Medicine, The University of Tokyo, 7-3-1, Hongo, Tokyo, 113-8655, Japan. fujita-dis@h.u-tokyo.ac.jp
authors.forename: Megumi
authors.initials: M
authors.lastname: Fujita
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kuwaki
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Ando
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
mesh_terms: D053607:Adrenomedullin; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology; D006339:Heart Rate; D007031:Hypothalamus / Q000378:metabolism; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000502:physiology*; D009994:Osmolar Concentration; D018384:Oxidative Stress / Q000502:physiology*; D010455:Peptides / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D012965:Sodium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000494:pharmacology; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D010455:Peptides; D017673:Sodium Chloride, Dietary; D013113:Spin Labels; D013481:Superoxides; D053607:Adrenomedullin; D012965:Sodium Chloride; C001803:tempol