title: Hypotension and resistance to lipopolysaccharide-induced shock in transgenic mice overexpressing adrenomedullin in their vasculature.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shindo
authors.forename: H
authors.initials: H
authors.lastname: Kurihara
authors.forename: K
authors.initials: K
authors.lastname: Maemura
authors.forename: Y
authors.initials: Y
authors.lastname: Kurihara
authors.forename: T
authors.initials: T
authors.lastname: Kuwaki
authors.forename: T
authors.initials: T
authors.lastname: Izumida
authors.forename: N
authors.initials: N
authors.lastname: Minamino
authors.forename: K H
authors.initials: KH
authors.lastname: Ju
authors.forename: H
authors.initials: H
authors.lastname: Morita
authors.forename: Y
authors.initials: Y
authors.lastname: Oh-hashi
authors.forename: M
authors.initials: M
authors.lastname: Kumada
authors.forename: K
authors.initials: K
authors.lastname: Kangawa
authors.forename: R
authors.initials: R
authors.lastname: Nagai
authors.forename: Y
authors.initials: Y
authors.lastname: Yazaki
mesh_terms: D053607:Adrenomedullin; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000378:metabolism*; D004198:Disease Susceptibility; D019332:Endothelin-1; D016232:Endothelins / Q000235:genetics; D007022:Hypotension / Q000209:etiology* / Q000503:physiopathology; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D010455:Peptides / Q000378:metabolism / Q000502:physiology*; D011498:Protein Precursors / Q000235:genetics; D012769:Shock / Q000139:chemically induced*
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D008070:Lipopolysaccharides; D010455:Peptides; D011498:Protein Precursors; D053607:Adrenomedullin