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(Circulation Research. 2002;90:657.)
© 2002 American Heart Association, Inc.

Integrative Physiology

Role of Endogenous Adrenomedullin in the Regulation of Vascular Tone and Ischemic Renal Injury

Studies on Transgenic/Knockout Mice of Adrenomedullin Gene

Hiroaki Nishimatsu, Yasunobu Hirata, Takayuki Shindo, Hiroki Kurihara, Masao Kakoki, Daisuke Nagata, Hiroshi Hayakawa, Hiroshi Satonaka, Masataka Sata, Akihiro Tojo, Etsu Suzuki, Kenji Kangawa, Hisayuki Matsuo, Tadaichi Kitamura, Ryozo Nagai

From the Departments of Urology (H.N., T.K.) and Internal Medicine (Y.H., T.S., H.K., M.K., D.N., H.H., H.S., M.S., A.T., E.S., R.N.), Faculty of Medicine, The University of Tokyo; and the Research Institute (K.K., H.M.), National Center of Cardiovascular Medicine, Japan.

Correspondence to Yasunobu Hirata, MD, Dept of Cardiovascular Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail hirata-2im{at}h.u-tokyo.ac.jp

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 (%RPP 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 (%RPP 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 (%RPP 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.

Key Words: adrenomedullin • nitric oxide • cGMP • endothelium • ischemia

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