title: Endothelial responses of the aorta from adrenomedullin transgenic mice and knockout mice.
abstract: Adrenomedullin (AM) is a potent vascular wall-derived vasorelaxing peptide which induces the release of nitric oxide (NO). To explore the role of endogenous AM in vascular function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists [AM (22-52), and calcitonin gene-related peptide (CGRP) (8-37)] on the isometric tension of aortic rings isolated from AM transgenic (TG) and knockout (KO) mice and wild type littermates (WT). ACh and AM caused a dose-dependent reduction of the isometric tension of aortic rings, but the degree of vasodilatation was smaller in TG than in KO or WT (% delta tension [10(-6) mol/l ACh]: KO -69 +/- 10%, WT -39 +/- 8%, TG -29 +/- 1%, p < 0.01). On the other hand, N(G)-nitro-L-arginine methyl ester, an NO synthase inhibitor, induced greater vasoconstriction in TG (% delta tension 10(-5)mol/l: KO +78 +/- 16%, WT +99 +/- 27%, TG +184 +/- 20%, p < 0.01), whereas E-4021, a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase inhibitor, caused greater vasodilation in TG mice. Both AM antagonists increased tension in TG to a greater extent than in KO or WT mice (% delta tension [10(-6) mol/l CGRP (8-37)]: KO +24 +/- 5%, WT +51 +/- 6%, TG +75 +/- 7%, p < 0.01). Endothelial denudation of the aorta diminished the vasoconstriction caused by the AM antagonists. In conclusion, the amounts of AM expressed in the aortic endothelium influenced baseline NO release. AM antagonists increased vascular tone in WT as well as in TG, suggesting that endogenous AM plays a physiological role in the regulation of aortic tone.
authors.affiliation: Department of Urology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishimatsu
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Hirata
authors.forename: Takayuki
authors.initials: T
authors.lastname: Shindo
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Etsu
authors.initials: E
authors.lastname: Suzuki
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Satonaka
authors.forename: Ryo
authors.initials: R
authors.lastname: Takeda
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nagata
authors.forename: Masao
authors.initials: M
authors.lastname: Kakoki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hayakawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Matsuo
authors.forename: Tadaichi
authors.initials: T
authors.lastname: Kitamura
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D053607:Adrenomedullin; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology*; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008916:Miotics / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C091517:E 4021; D004791:Enzyme Inhibitors; D008916:Miotics; D010446:Peptide Fragments; D010455:Peptides; D010726:Phosphodiesterase Inhibitors; D010880:Piperidines; D011799:Quinazolines; D014665:Vasodilator Agents; C104782:adrenomedullin (22-52); C058636:calcitonin gene-related peptide (8-37); D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester