Hypotension and resistance to lipopolysaccharide-induced shock in transgenic mice overexpressing adrenomedullin in their vasculature

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 overp roduction affects circulatory physiology under normal and pathological cond itions, we used a preproendothelin-l 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 pre ssure (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 gre ater degree in AM transgenic mice, offsetting the BP difference between the 2 groups. Despite their lower basal BP, administration of bacterial lipopo lysaccharide elicited smaller declines in BP and less severe organ damage i n AM transgenic mice than in wild-type mice. Furthermore, the 24-hour survi val rate after induction of lipopolysaccharide shock was significantly high er in the transgenic mice. Conclusions - A chronic increase in vascular AM production reduces BP at le ast in part via an NO-dependent pathway. In addition, smaller responses to LPS in transgenic mice suggest that AM is protective against the circulator y collapse, organ damage, and mortality characteristic of endotoxic shock.