Adrenomedullin reduces intestinal epithelial permeability in vivo and in vitro.

Leakage of the gut mucosal barrier in the critically ill patient may allow translocation of bacteria and their virulence factors, thereby perpetuating sepsis and inflammation. Present evidence suggests that adrenomedullin (AM) improves endothelial barrier function and stabilizes circulatory function in systemic inflammation. We tested the hypothesis that exogenously applied AM stabilizes gut epithelial barrier function. Infusion of Staphylococcus aureus alpha-toxin induced septic shock in rats. AM infusion in a therapeutic setting reduced translocation of labeled dextran from the gut into the systemic circulation in this model. AM also reduced alpha-toxin and hydrogen peroxide (H2O2)-related barrier disruption in Caco-2 cells in vitro and reduced H2O2-related rat colon barrier malfunction in Ussing chamber experiments. AM was shown to protect endothelial barrier function via cAMP elevation, but AM failed to induce cAMP accumulation in Caco-2 cells. cAMP is degraded via phosphodiesterases (PDE), and Caco-2 cells showed high activity of cAMP-degrading PDE3 and 4. However, AM failed to induce cAMP accumulation in Caco-2 cells even in the presence of sufficient PDE3/4 inhibition, whereas adenylyl cyclase activator forskolin induced strong cAMP elevation. Furthermore, PDE3/4 inhibition neither amplified AM-induced epithelial barrier stabilization nor affected AM cAMP-related rat colon short-circuit current, furthermore indicating that AM may act independently of cAMP in Caco-2 cells. Finally, experiments using chemical inhibitors indicated that PKC, phosphatidylinositide 3-kinase, p38, and ERK did not contribute to AM-related stabilization of barrier function in Caco-2 cells. In summary, during severe inflammation, elevated AM levels may substantially contribute to the stabilization of gut barrier function.

Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock.

OBJECTIVE: 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. DESIGN: Prospective randomized controlled animal study. SUBJECTS: Male Sprague-Dawley rats (270 g). INTERVENTIONS: 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. MEASUREMENT AND RESULTS: 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. CONCLUSIONS: 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.