Role of endogenous adrenomedullin in the regulation of vascular tone and ischemic renal injury: studies on transgenic/knockout mice of adrenomedullin gene.
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.
Nishimatsu
Hiroaki
H
Department of Urology, Faculty of Medicine, The University of Tokyo, Japan.
Hirata
Yasunobu
Y
Shindo
Takayuki
T
Kurihara
Hiroki
H
Kakoki
Masao
M
Nagata
Daisuke
D
Hayakawa
Hiroshi
H
Satonaka
Hiroshi
H
Sata
Masataka
M
Tojo
Akihiro
A
Suzuki
Etsu
E
Kangawa
Kenji
K
Matsuo
Hisayuki
H
Kitamura
Tadaichi
T
Nagai
Ryozo
R
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
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