Abstract
Systemic administration of melatonin exerts tissue protective effects in the context of hemorrhagic shock. Intravenous application of melatonin prior to hemorrhage improves gastric microcirculatory perfusion and maintains intestinal barrier function in dogs. The aim of the present study was to analyze the effects of a topical mucosal melatonin application on gastric microcirculation during hemorrhagic shock in vivo and on mucosal barrier function in vitro. In a randomized cross-over study, six anesthetized female foxhounds received 3.3 mg melatonin or the vehicle as a bolus to the gastric and oral mucosa during physiological and hemorrhagic (−20% blood volume) conditions. Microcirculation was analyzed with reflectance spectrometry and laser doppler flowmetry. Systemic hemodynamic variables were measured with transpulmonary thermodilution. For analysis of intestinal mucosal barrier function in vitro Caco-2 monolayers were used. The transepithelial electrical resistance (TEER) and the passage of Lucifer Yellow (LY) from the apical to the basolateral compartment of Transwell chambers were measured. Potential barrier protective effects of melatonin against oxidative stress were investigated in the presence of the oxidant H2O2. During physiologic conditions topical application of melatonin had no effect on gastric and oral microcirculation in vivo. During hemorrhagic shock, gastric microcirculatory oxygenation (μHbO2) was decreased from 81 ± 8% to 50 ± 15%. Topical treatment with melatonin led to a significant increase in μHbO2 to 60 ± 13%. Topical melatonin treatment had no effect on gastric microcirculatory perfusion, oral microcirculation or systemic hemodynamics. Incubation of H2O2 stressed Caco-2 monolayers with melatonin did neither influence transepithelial electrical resistance nor LY translocation. Topical treatment of the gastric mucosa with melatonin attenuates the shock induced decrease in microcirculatory oxygenation. As no effects on local microcirculatory and systemic perfusion were recorded, the improved μHbO2 is most likely caused by a modulation of local oxygen consumption. In vitro melatonin treatment did not improve intestinal barrier integrity in the context of oxidative stress. These results extend the current knowledge on melatonin's protective effects during hemorrhage in vivo. Topical application of melatonin exerts differential effects on local microcirculation compared to systemic pretreatment and might be suitable as an adjunct for resuscitation of hemorrhagic shock.
Highlights
Profound hemorrhage and associated hypovolemic shock are leading causes of potentially preventable deaths in the inhospital and pre-hospital setting, resulting in annual deaths of more than five million people worldwide [1]
In a previous investigation we were able to show that intravenous administration of melatonin prior to subsequent hemorrhage improves regional gastric microcirculatory perfusion during mild hemorrhagic shock in dogs and blunted the shock-induced damage to the intestinal barrier [7]
The objective of this study was to test whether the topical application of melatonin to the gastric mucosa may influence gastric microcirculation similar to systemic melatonin application in the context of hemorrhagic shock in dogs
Summary
Profound hemorrhage and associated hypovolemic shock are leading causes of potentially preventable deaths in the inhospital and pre-hospital setting, resulting in annual deaths of more than five million people worldwide [1]. Maintaining adequate splanchnic perfusion, especially during circulatory shock is considered crucial for prevention and therapy of critical illness [4, 5]. In this context melatonin is known to improve microcirculation and has been found in many tissues of the gastrointestinal tract. Exogenous administration of melatonin improves hepatic microcirculation and liver function and reduces stress-induced gastric lesions [6]. In a previous investigation we were able to show that intravenous administration of melatonin prior to subsequent hemorrhage improves regional gastric microcirculatory perfusion during mild hemorrhagic shock in dogs and blunted the shock-induced damage to the intestinal barrier [7]. To further elucidate the protective properties of melatonin on gastrointestinal mucosal barrier function independent of microcirculatory changes, we analyzed its effects on the integrity of a Caco-2 cell monolayer during stress conditions
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