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(Circulation. 2000;101:2309.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Hypotension and Resistance to Lipopolysaccharide-Induced Shock in Transgenic Mice Overexpressing Adrenomedullin in Their Vasculature

Takayuki Shindo, MD, PhD; Hiroki Kurihara, MD, PhD; Koji Maemura, MD, PhD; Yukiko Kurihara, MD, PhD; Tomoyuki Kuwaki, PhD; Taro Izumida, MD, PhD; Naoto Minamino, PhD; Ki-Hwan Ju, PhD; Hiroyuki Morita, MD, PhD; Yoshio Oh-hashi, MD; Mamoru Kumada, MD, PhD; Kenji Kangawa, PhD; Ryozo Nagai, MD, PhD; Yoshio Yazaki, MD, PhD

From the Department of Cardiovascular Medicine (T.S., H.K., K.M., Y.K., T.I., H.M., Y.O., R.N.) and Department of Physiology (K.-H.J.), Graduate School of Medicine, University of Tokyo; CREST (Core Research for Evolutional Science and Technology), Japan Science and Technology Corp, Tokyo (H.K.); the Department of Physiology, School of Medicine, Chiba University (T.K.); the National Cardiovascular Center Research Institute, Suita (N.M., K.K.); St Luke’s College of Nursing, Tokyo (M.K.); and the International Medical Center of Japan, Tokyo (Y.Y.), Japan.

Correspondence to Hiroki Kurihara, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail kuri-tky{at}umin.ac.jp

Background—Adrenomedullin (AM) is a vasodilating peptide involved in the regulation of circulatory homeostasis and in the pathophysiology of certain cardiovascular diseases. To determine the extent to which chronic AM overproduction affects circulatory physiology under normal and pathological conditions, we used a preproendothelin-1 promoter to establish transgenic mouse lines overexpressing AM in their vasculature.

Methods and Results—Transgenic mice overexpressing AM mainly in vascular endothelial and smooth muscle cells exhibited significantly lower blood pressure (BP) and higher plasma cGMP levels than their wild-type littermates. Blockade of NO synthase with N^G-monomethyl-L-arginine elevated BP to a greater degree in AM transgenic mice, offsetting the BP difference between the 2 groups. Despite their lower basal BP, administration of bacterial lipopolysaccharide elicited smaller declines in BP and less severe organ damage in AM transgenic mice than in wild-type mice. Furthermore, the 24-hour survival rate after induction of lipopolysaccharide shock was significantly higher in the transgenic mice.

Conclusions—A chronic increase in vascular AM production reduces BP at least in part via an NO-dependent pathway. In addition, smaller responses to LPS in transgenic mice suggest that AM is protective against the circulatory collapse, organ damage, and mortality characteristic of endotoxic shock.

Key Words: adrenomedullin • genes • vasculature • blood pressure • shock

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