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 (%ΔRPP 10−7 mol/L ACh: KO −48.1±3.9%, WT −57.5±5.6%, TG −22.8±4.8%, P<0.01), whereas NG-nitro-l-arginine methyl ester (L-NAME) caused greater vasoconstriction in TG (%ΔRPP 10−4 mo...