title: Glycine-extended adrenomedullin exerts vasodilator effect through amidation in the rat aorta.
abstract: Human adrenomedullin (hAM) is an endogenous peptide that has potent vasodilator activity. Mature AM is biosynthesized from its intermediate form, glycine-extended AM (AM-gly), by carboxy-terminal amidation. AM-gly is generally considered to be biologically inactive but is a major molecular form in human and rat plasma. The present study demonstrated that recombinant human AM-gly (hAM-gly) elicits potent vasodilator effect on isolated rat aorta. In aortic rings, hAM-gly produced dose-dependent (0.1-100 nM) relaxation in phenylephrine-precontracted strips (pD(2) 8.4+/-0.5). The vasorelaxant potency of hAM-gly was comparable to that of hAM (pD(2) 8.6+/-0.2) but hAM-gly took a significantly (P<0.01) longer time to reach the maximal relaxation compared with hAM (T(max) 23+/-4 vs. 5+/-2 min). Vasorelaxant responses to hAM-gly were abolished by endothelial removal. N(omega)-nitro-L-arginine (L-NNA) and AM(22-52) significantly (P<0.01) reduced the vasodilator effect of hAM-gly. Furthermore, 4-phenyl-3-butenoic acid (PBA), an alpha-amidation enzyme inhibitor, significantly (P<0.05) inhibited the vasorelaxant responses to hAM-gly without any effect on the hAM-induced relaxation, suggesting the possible process of amidation in the rat aorta. We further clarified that the aorta has the ability to convert exogenous hAM-gly to mature hAM and the conversion is inhibited by PBA. These results suggest that the circulating AM-gly may play a role in regulating vascular tone and increased plasma AM-gly may be involved in the pathophysiology of cardiovascular diseases.
authors.affiliation: First Department of Internal Medicine, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
authors.forename: Yuan-Ning
authors.initials: YN
authors.lastname: Cao
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitamura
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ito
authors.forename: Johji
authors.initials: J
authors.lastname: Kato
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hashida
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Morishita
authors.forename: Tanenao
authors.initials: T
authors.lastname: Eto
mesh_terms: D053607:Adrenomedullin; D000577:Amides / Q000737:chemistry; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D005998:Glycine / Q000737:chemistry*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D019335:Nitroarginine / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D010455:Peptides; D011994:Recombinant Proteins; D014665:Vasodilator Agents; D053607:Adrenomedullin; D019335:Nitroarginine; C064180:4-phenyl-3-butenoic acid; D005998:Glycine