Background and ObjectiveApart from its inotropic property, milrinone has vasodilator, anti-inflammatory and antithrombotic effects that could assist in the reversal of septic microcirculatory changes. This paper investigates the effects of milrinone on endotoxemia-related microcirculatory changes and compares them to those observed with the use of norepinephrine.Materials and MethodsAfter skinfold chamber implantation procedures and endotoxemia induction by intravenous Escherichia coli lipopolysaccharide administration (2 mg.kg-1), male golden Syrian hamsters were treated with two regimens of intravenous milrinone (0.25 or 0.5 μg.kg-1.min-1). Intravital microscopy of skinfold chamber preparations allowed quantitative analysis of microvascular variables. Macro-hemodynamic, biochemical, and hematological parameters and survival rate were also analyzed. Endotoxemic non-treated animals, endotoxemic animals treated with norepinephrine (0.2 μg.kg-1.min-1), and non-endotoxemic hamsters served as controls.ResultsMilrinone (0.5 μg.kg-1.min-1) was effective in reducing lipopolysaccharide-induced arteriolar vasoconstriction, capillary perfusion deficits, and inflammatory response, and in increasing survival. Norepinephrine treated animals showed the best mean arterial pressure levels but the worst functional capillary density values among all endotoxemic groups.ConclusionOur data suggests that milrinone yielded protective effects on endotoxemic animals’ microcirculation, showed anti-inflammatory properties, and improved survival. Norepinephrine did not recruit the microcirculation nor demonstrated anti-inflammatory effects.

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BackgroundRelative hypovolemia is frequently found in early stages of severe sepsis and septic shock and prompt and aggressive fluid therapy has become standard of care improving tissue perfusion and patient outcome. This paper investigates the role of the nitric oxide pathway on beneficial microcirculatory effects of fluid resuscitation.MethodsAfter skinfold chamber implantation procedures and endotoxemia induction by intravenous Escherichia coli lipopolysaccharide administration (2 mg.kg−1), male golden Syrian hamsters were fluid resuscitated and then sequentially treated with L-Nω-Nitroarginine and L-Arginine hydrochloride (LPS/FR/LNNA group). Intravital microscopy of skinfold chamber preparations allowed quantitative analysis of microvascular variables including venular leukocyte rolling and adhesion. Macro-hemodynamic, biochemical and hematological parameters as well as survival rate were also evaluated. Endotoxemic hamsters treated with fluid therapy alone (LPS/FR group) and non-treated animals (LPS group) served as controls.ResultsFluid resuscitation was effective in reducing lipopolysaccharide-induced microcirculatory changes. After 3 hours of lipopolysaccharide administration, non-fluid resuscitated animals (LPS group) had the lowest functional capillary density (1% from baseline for LPS group vs. 19% for LPS/FR one; p <0.05). At the same time point, arteriolar mean internal diameter was significantly wider in LPS/FR group than in LPS one (100% vs. 50% from baseline). Fluid resuscitation also reduced leukocyte-endothelium interactions and sequestration (p <0.05 for LPS vs. LPS/FR group) and increased survival (median survival time: 2 and 5.5 days for LPS and LPS/FR groups, respectively; p <0.05). Nitric oxide synthase inhibition prevented these protective effects, while L-Arginine administration markedly restored many of them.ConclusionOur results suggest that the underlying mechanism of fluid therapy is the restoration of nitric oxide bioavailability, because inhibition of NOS prevented many of its beneficial effects. Nevertheless, further investigations are required in experimental models closer to conditions of human sepsis to confirm these results.

OBJECTIVE: Apart from its anticoagulant properties, heparin has vasodilator and anti-inflammatory effects that could assist in the reversal of septic microcirculatory changes. This paper investigates the effects of heparin on endotoxemia-related microcirculatory changes and compares them to those observed with the use of recombinant human activated protein C. METHODS: After skinfold chamber implantation procedures and endotoxemia induction by intravenous Escherichia coli lipopolysaccharide administration (2 mg.kg 21), male golden Syrian hamsters were treated with intravenous unfractionated heparin (0.2 mg.kg 21). Intravital microscopy of skinfold chamber preparations allowed quantitative analysis of microvascular variables and venular leukocyte rolling and adhesion. Macrohemodynamic parameters were also analyzed. Endotoxemic hamsters treated with recombinant human activated protein C and non-treated animals served as controls. RESULTS: Heparin decreased lipopolysaccharide-induced leukocyte rolling and arteriolar vasoconstriction; it also increased survival when compared with non-treated animals, while recombinant human activated protein C decreased leukocyte adhesion. Administration of heparin plus recombinant human activated protein C was associated with a significant attenuation of lipopolysaccharide-induced capillary perfusion deficits. CONCLUSIONS: Heparin yields protective effects on endotoxemic animals' microcirculation. Those benefits were potentiated when heparin was administered in conjunction with recombinant human activated protein C.

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