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The effects of vasopressin, norepinephrine, and l-arginine alone or combined on intestinal microcirculation were evaluated in the septic mouse by intravital microscopy, with which we measured the erythrocyte flux and velocity in villus tip arterioles and the density of perfused villi.Controlled animal study.University research laboratory.Female BALB/c mice weighing between 18 and 21 g.Anesthetized and ventilated mice received at t0 an intravenous injection of Escherichia coli endotoxin (2 mg/kg bolus intravenously), inducing after 1 hr (t60) a decrease in mean arterial blood pressure to 40–50 mm Hg associated with a significant decrease in erythrocyte flux and velocity in villus tip arterioles and in the density of perfused villi. The mice then received a randomly different treatment for endotoxin-induced shock. Treatments consisted in continuous intravenous infusion for 1 hr with either saline (control group), norepinephrine, vasopressin, l-arginine, vasopressin+ l-arginine, or norepinephrine+l-arginine. The doses of vasopressors (used alone or combined with l-arginine) were titrated to restore mean arterial pressure to the baseline level.At the end of the treatment (t120), we observed in the control group further decreases in arteriolar flux and velocity and in the density of perfused villi. In the groups treated by a vasopressor alone, mean arterial pressure returned to baseline and there were no additional decreases in arteriolar flux and velocity or in the density of perfused villi. However, these latter three variables did not return to their preshock baseline values. Even though l-arginine did not restore mean arterial pressure, the infusion of l-arginine alone prevented the decrease in flux or erythrocyte velocity occurring between t60 and t120 and conserved to some extent the density of perfused villi compared with that in the control groups. In addition, we found that simultaneous administration of norepinephrine or vasopressin with l-arginine improved all microcirculation variables more efficiently than either vasopressor alone.From these data, we conclude that a) restoring mean arterial pressure after 1 hr of endotoxemia was not sufficient to restore ad integrum intestinal mucosa microvascular perfusion; b) l-arginine could have a beneficial effect at the microcirculatory level, which was independent of mean arterial pressure; and c) administration of l-arginine combined with the maintenance of perfusion pressure by vasopressive drugs allowed a better preservation of intestinal microcirculation at an early stage of endotoxemia.