title: Role of endogenous adrenomedullin in the regulation of vascular tone and ischemic renal injury: studies on transgenic/knockout mice of adrenomedullin gene.
abstract: Adrenomedullin (AM) is a potent depressor peptide whose vascular action is suggested to involve nitric oxide (NO) release. To explore the role of endogenous AM in vascular and renal function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists AM(22-52) and CGRP(8-37) on the renal perfusion pressure (RPP) of kidneys isolated from AM transgenic (TG)/heterozygote knockout (KO) mice and wild-type littermates (WT). Furthermore, we evaluated the renal function and histology 24 hours after bilateral renal artery clamp for 45 minutes in TG, KO, and WT mice. Baseline RPP was significantly lower in TG than in KO and WT mice (KO 93.4+/-4.6, WT 85.8+/-4.2, TG 72.4+/-2.4 mm Hg [mean+/-SE], P<0.01). ACh and AM caused a dose-related reduction in RPP, but the degree of vasodilatation was smaller in TG than that in KO and WT (%DeltaRPP 10(-7) mol/L ACh: KO -48.1+/-3.9%, WT -57.5+/-5.6%, TG -22.8+/-4.8%, P<0.01), whereas N(G)-nitro-L-arginine methyl ester (L-NAME) caused greater vasoconstriction in TG (%DeltaRPP 10(-4) mol/L: KO 33.1+/-3.3%, WT 55.5+/-7.2%, TG 152.6+/-21.2%, P<0.01). Both AM antagonists increased RPP in TG to a greater extent compared with KO and WT mice (%DeltaRPP 10(-6) mol/L CGRP(8-37): KO 12.8+/-2.6%, WT 19.4+/-3.6%, TG 41.8+/-8.7%, P<0.01). In mice with ischemic kidneys, serum levels of urea nitrogen and renal damage scores showed smaller values in TG and greater values in KO mice (urea nitrogen: KO 104+/-5>WT 98+/-15>TG 38+/-7 mg/dL, P<0.05 each). Renal NO synthase activity was also greater in TG mice. However, the differences in serum urea nitrogen and renal damage scores among the 3 groups of mice were not observed in mice pretreated with L-NAME. In conclusion, AM antagonists increased renal vascular tone in WT as well as in TG, suggesting that endogenous AM plays a role in the physiological regulation of the vascular tone. AM is likely to protect renal tissues from ischemia/reperfusion injury through its NO releasing activity.
authors.affiliation: Department of Urology, Faculty of Medicine, The University of 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: Masao
authors.initials: M
authors.lastname: Kakoki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nagata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hayakawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Satonaka
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tojo
authors.forename: Etsu
authors.initials: E
authors.lastname: Suzuki
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; D018678:Cholinergic Agents / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000097:blood; D010455:Peptides / Q000235:genetics / Q000502:physiology*; D015427:Reperfusion Injury / Q000097:blood / Q000503:physiopathology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D018678:Cholinergic Agents; D004791:Enzyme Inhibitors; D010455:Peptides; D053607:Adrenomedullin; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester