Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock

Abstract

Current therapies of sepsis and septic shock require administration of a large volume of fluid to maintain hemodynamic stability. The vasoregulatory peptide adrenomedullin has been shown to prevent the transition to the fatal hypocirculatory septic state by poorly understood mechanisms. We tested the hypothesis that therapeutic administration of adrenomedullin would reduce vascular hyperpermeability, thereby contributing to improved hemodynamics and survival. Prospective randomized controlled animal study. Male Sprague-Dawley rats (270 g). We used 4.8 x 10(3) U/kg of Staphylococcus aureus alpha-toxin, a pore-forming exotoxin, to induce vascular leakage and circulatory shock in rats. The infusion rate was 24 microg/kg per hour. Adrenomedullin was started 1 h after alpha-toxin administration. Infusion of alpha-toxin in rats induced cardiocirculatory failure resulting in a 6-h mortality of 53%. alpha-Toxin provoked massive vascular hyperpermeability, which was indicated by an enrichment of Evans blue dye albumin in the tissues of lung, liver, ileum and kidney. Plasma fluid loss led to a significant hemoconcentration. Hemodynamic impairment observed after alpha-toxin infusion was closely correlated to vascular hyperpermeability. Therapeutic administration of 24 microg/kg per hour adrenomedullin reduced 6-h mortality from 53% to 7%. Stabilization of the endothelial barrier by adrenomedullin was indicated by reduced extravasation of albumin and plasma fluid and may have contributed to hemodynamic improvement. These data suggest that adrenomedullin-related reduction of vascular hyperpermeability might represent a novel and important mechanism contributing to the beneficial effects of this endogenous vasoregulatory peptide in sepsis and septic shock.