Methylene blue reduces lung fluid filtration during the early phase of endotoxemia in awake sheep

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Abstract
To determine whether methylene blue (MB), an inhibitor of soluble guanylate cyclase and nitric oxide synthase, alters lung hemodynamics and fluid filtration after endotoxin in sheep. Prospective, randomized, controlled experimental study with repeated measurements. University animal laboratory. Eight yearling, awake sheep. Sheep were instrumented for a chronic study with vascular and lung lymph catheters. In two experiments, separated by 1 wk of recovery, the animals received intravenously either an injection of MB 10 mg/kg or a corresponding volume of 0.9% sodium chloride as pretreatment. Thirty minutes later, sheep received a bolus injection of Escherichia coli endotoxin 1 μg/kg, followed by either an infusion of MB 2.5 mg/kg/hr or a corresponding volume of 0.9% sodium chloride for 5 hrs. MB decreased the early phase endotoxin-induced rises in pulmonary capillary pressure and pulmonary vascular resistance. MB also reduced the increments in lung lymph flow (&OV0422;L) and protein clearance (CL) as well as the rightward shift of the permeability-surface area product (PS). In addition, MB diminished the decrease in cardiac output, stabilized mean arterial pressure, and precluded the rise in plasma and lung lymph cyclic guanosine 3′-5′ monophosphate. However, during the late phase, MB-treated sheep presented with a faster rise in &OV0422;L with no difference in CL and PS from the endotoxemic controls. During the early phase of endotoxemia in sheep, MB attenuates lung injury by decreasing the enhanced lung fluid filtration as a result of reduced pulmonary capillary pressure and permeability. However, MB does not counteract the late phase increase in lung fluid filtration.