title: Biological properties of adrenomedullin conjugated with polyethylene glycol.
abstract: Adrenomedullin (AM) is a vasodilator peptide with pleiotropic effects, including cardiovascular protection and anti-inflammation. Because of these beneficial effects, AM appears to be a promising therapeutic tool for human diseases, while intravenous injection of AM stimulates sympathetic nerve activity due to short-acting potent vasodilation, resulting in increased heart rate and renin secretion. To lessen these acute reactions, we conjugated the N-terminal of human AM peptide with polyethylene glycol (PEG), and examined the biological properties of PEGylated AM in the present study. PEGylated AM stimulated cAMP production, an intracellular second messenger of AM, in cultured human embryonic kidney cells expressing a specific AM receptor in a dose-dependent manner, as did native human AM. The pEC50 value of PEGylated AM was lower than human AM, but no difference was noted in maximum response (Emax) between the PEGylated and native peptides. Intravenous bolus injection of 10nmol/kg PEGylated AM lowered blood pressure in anesthetized rats, but the acute reduction became significantly smaller by PEGylation as compared with native AM. Plasma half-life of PEGylated AM was significantly longer than native AM both in the first and second phases in rats. In summary, N-terminal PEGylated AM stimulated cAMP production in vitro, showing lessened acute hypotensive action and a prolonged plasma half-life in comparison with native AM peptide in vivo.
authors.affiliation: Department of Internal Medicine, University of Miyazaki Faculty of Medicine, Miyazaki 889-1692, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Kubo
authors.affiliation: Department of Internal Medicine, University of Miyazaki Faculty of Medicine, Miyazaki 889-1692, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Tokashiki
authors.affiliation: Frontier Science Research Center, University of Miyazaki Faculty of Medicine, Miyazaki 889-1692, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kuwasako
authors.affiliation: SAITO Research Center, Peptide Institute, Inc., Ibaraki, Osaka 567-0085, Japan.
authors.forename: Masaji
authors.initials: M
authors.lastname: Tamura
authors.affiliation: SAITO Research Center, Peptide Institute, Inc., Ibaraki, Osaka 567-0085, Japan.
authors.forename: Shugo
authors.initials: S
authors.lastname: Tsuda
authors.affiliation: SAITO Research Center, Peptide Institute, Inc., Ibaraki, Osaka 567-0085, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kubo
authors.affiliation: SAITO Research Center, Peptide Institute, Inc., Ibaraki, Osaka 567-0085, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Yoshizawa-Kumagaye
authors.affiliation: Frontier Science Research Center, University of Miyazaki Faculty of Medicine, Miyazaki 889-1692, Japan. Electronic address: jkjpn@med.miyazaki-u.ac.jp.
authors.forename: Johji
authors.initials: J
authors.lastname: Kato
authors.affiliation: Department of Internal Medicine, University of Miyazaki Faculty of Medicine, Miyazaki 889-1692, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitamura
mesh_terms: D053607:Adrenomedullin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis*; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D058265:Receptors, Adrenomedullin / Q000096:biosynthesis
chemical_list: D010455:Peptides; D058265:Receptors, Adrenomedullin; D053607:Adrenomedullin; D011092:Polyethylene Glycols; D000242:Cyclic AMP
keywords: Adrenomedullin; Molecular modification; Polyethylene glycol