Topical Melatonin Improves Gastric Microcirculatory Oxygenation During Hemorrhagic Shock in Dogs but Does Not Alter Barrier Integrity of Caco-2 Monolayers

Truse, Richard; Nolten, Inga; Schulz, Jan; Herminghaus, Anna; Holtmanns, Tobias; Gördes, Lukas; Raupach, Annika; Bauer, Inge; Picker, O.; Vollmer, Christian

doi:10.3389/fmed.2020.00510

Cited by 6 publications

(7 citation statements)

References 43 publications

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“…In the same trial nitroglycerin improved intestinal barrier function ( 17 ). Likewise, local application of melatonin ( 18 ) and losartan ( 19 ) were able to ameliorate the decrease of gastric mucosal oxygenation in a state of acute hemorrhage. Systemic hypercapnia and hyperoxia proved to exert favorable effects in the context of hemorrhagic shock ( 11 , 20 ).…”

Section: Introductionmentioning

confidence: 99%

Local Mucosal CO2 but Not O2 Insufflation Improves Gastric and Oral Microcirculatory Oxygenation in a Canine Model of Mild Hemorrhagic Shock

et al. 2022

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IntroductionAcute hemorrhage results in perfusion deficit and regional hypoxia. Since failure of intestinal integrity seem to be the linking element between hemorrhage, delayed multi organ failure, and mortality, it is crucial to maintain intestinal microcirculation in acute hemorrhage. During critical bleeding physicians increase FiO2to raise total blood oxygen content. Likewise, a systemic hypercapnia was reported to maintain microvascular oxygenation (μHbO2). Both, O2and CO2, may have adverse effects when applied systemically that might be prevented by local application. Therefore, we investigated the effects of local hyperoxia and hypercapnia on the gastric and oral microcirculation.MethodsSix female foxhounds were anaesthetized, randomized into eight groups and tested in a cross-over design. The dogs received a local CO2-, O2-, or N2-administration to their oral and gastric mucosa. Hemorrhagic shock was induced through a withdrawal of 20% of estimated blood volume followed by retransfusion 60 min later. In control groups no shock was induced. Reflectance spectrophotometry and laser Doppler were performed at the gastric and oral surface. Oral microcirculation was visualized by incident dark field imaging. Systemic hemodynamic parameters were recorded continuously. Statistics were performed using a two-way-ANOVA for repeated measurements andpost hocanalysis was conducted by Bonferroni testing (p< 0.05).ResultsThe gastric μHbO2decreased from 76 ± 3% to 38 ± 4% during hemorrhage in normocapnic animals. Local hypercapnia ameliorated the decrease of μHbO2from 78 ± 4% to 51 ± 8%. Similarly, the oral μHbO2decreased from 81 ± 1% to 36 ± 4% under hemorrhagic conditions and was diminished by local hypercapnia (54 ± 4%). The oral microvascular flow quality but not the total microvascular blood flow was significantly improved by local hypercapnia. Local O2-application failed to change microvascular oxygenation, perfusion or flow quality. Neither CO2nor O2changed microcirculatory parameters and macrocirculatory hemodynamics under physiological conditions.DiscussionLocal hypercapnia improved microvascular oxygenation and was associated with a continuous blood flow in hypercapnic individuals undergoing hemorrhagic shock. Local O2application did not change microvascular oxygenation, perfusion and blood flow profiles in hemorrhage. Local gas application and change of microcirculation has no side effects on macrocirculatory parameters.

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Section: Introductionmentioning

confidence: 99%

Local Mucosal CO2 but Not O2 Insufflation Improves Gastric and Oral Microcirculatory Oxygenation in a Canine Model of Mild Hemorrhagic Shock

et al. 2022

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“…Only MFI improved in the late course of hemorrhagic shock indicating favorable properties of carbachol on oral microcirculation. However, results from oral microcirculatory measurements cannot be transferred doubtless to other parts of the gastrointestinal tract, since our group could identify a different response of the oral and gastric microcirculation to topical melatonin treatment (36) and hypothermia (34) in a similar canine model of hemorrhagic shock. The observation that carbachol improves gastric but not oral oxygenation might indicate that during hemorrhage there is a more pronounced sympathetic activation in the oral region whereas the gastric region can still be modulated.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, drugs were applicated locally to avoid systemic side effects. In the past, our group used various local treatment regimens to improve gastric tissue oxygenation ( 34 – 36 ). None of those trials revealed systemic complications.…”

Section: Discussionmentioning

confidence: 99%

“…The systemic application of nitroglycerine, iloprost and carbachol could further diminish hemodynamic stability. In this context, our group reported the gastrointestinal microcirculation to be susceptible for topical therapies without systemic side effects during hemorrhagic shock ( 34 – 36 ). Thus, we studied the impact of local application of all substances.…”

Section: Introductionmentioning

confidence: 99%

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Local carbachol application induces oral microvascular recruitment and improves gastric tissue oxygenation during hemorrhagic shock in dogs

Hof,

Lingens,

Michels

et al. 2024

Front. Immunol.

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IntroductionHemorrhagic shock is characterized by derangements of the gastrointestinal microcirculation. Topical therapy with nitroglycerine or iloprost improves gastric tissue oxygenation but not regional perfusion, probably due to precapillary adrenergic innervation. Therefore, this study was designed to investigate the local effect of the parasympathomimetic carbachol alone and in combination with either nitroglycerine or iloprost on gastric and oral microcirculation during hemorrhagic shock.MethodsIn a cross-over design five female foxhounds were repeatedly randomized into six experimental groups. Carbachol, or carbachol in combination with either nitroglycerine or iloprost were applied topically to the oral and gastric mucosa. Saline, nitroglycerine, or iloprost application alone served as control groups. Then, a fixed-volume hemorrhage was induced by arterial blood withdrawal followed by blood retransfusion after 1h of shock. Gastric and oral microcirculation was determined using reflectance spectrophotometry and laser Doppler flowmetry. Oral microcirculation was visualized with videomicroscopy. Statistics: 2-way-ANOVA for repeated measurements and Bonferroni post-hoc analysis (mean ± SEM; p < 0.05).ResultsThe induction of hemorrhage led to a decrease of gastric and oral tissue oxygenation, that was ameliorated by local carbachol and nitroglycerine application at the gastric mucosa. The sole use of local iloprost did not improve gastric tissue oxygenation but could be supplemented by local carbachol treatment. Adding carbachol to nitroglycerine did not further increase gastric tissue oxygenation. Gastric microvascular blood flow remained unchanged in all experimental groups. Oral microvascular blood flow, microvascular flow index and total vessel density decreased during shock. Local carbachol supply improved oral vessel density during shock and oral microvascular flow index in the late course of hemorrhage.ConclusionThe specific effect of shifting the autonomous balance by local carbachol treatment on microcirculatory variables varies between parts of the gastrointestinal tract. Contrary to our expectations, the improvement of gastric tissue oxygenation by local carbachol or nitroglycerine application was not related to increased microvascular perfusion. When carbachol is used in combination with local vasodilators, the additional effect on gastric tissue oxygenation depends on the specific drug combination. Therefore, modulation of tissue oxygen consumption, mitochondrial function or alterations in regional blood flow distribution should be investigated.

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“…Therefore, many investigators choose a corresponding shock model to test if a therapeutic intervention results in a survival advantage ( 23 , 24 ). More moderate shock states are used when the focus is not on survival rates, but, e.g., on repetitive measurements in individual animals ( 25 – 27 ). As stated above, also the shock duration can be adjusted ( 28 ).…”

Section: Animal Disease Models To Study Hemorrhagic and Septic Shockmentioning

confidence: 99%

A Toolbox to Investigate the Impact of Impaired Oxygen Delivery in Experimental Disease Models

et al. 2022

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Impaired oxygen utilization is the underlying pathophysiological process in different shock states. Clinically most important are septic and hemorrhagic shock, which comprise more than 75% of all clinical cases of shock. Both forms lead to severe dysfunction of the microcirculation and the mitochondria that can cause or further aggravate tissue damage and inflammation. However, the detailed mechanisms of acute and long-term effects of impaired oxygen utilization are still elusive. Importantly, a defective oxygen exploitation can impact multiple organs simultaneously and organ damage can be aggravated due to intense organ cross-talk or the presence of a systemic inflammatory response. Complexity is further increased through a large heterogeneity in the human population, differences in genetics, age and gender, comorbidities or disease history. To gain a deeper understanding of the principles, mechanisms, interconnections and consequences of impaired oxygen delivery and utilization, interdisciplinary preclinical as well as clinical research is required. In this review, we provide a “tool-box” that covers widely used animal disease models for septic and hemorrhagic shock and methods to determine the structure and function of the microcirculation as well as mitochondrial function. Furthermore, we suggest magnetic resonance imaging as a multimodal imaging platform to noninvasively assess the consequences of impaired oxygen delivery on organ function, cell metabolism, alterations in tissue textures or inflammation. Combining structural and functional analyses of oxygen delivery and utilization in animal models with additional data obtained by multiparametric MRI-based techniques can help to unravel mechanisms underlying immediate effects as well as long-term consequences of impaired oxygen delivery on multiple organs and may narrow the gap between experimental preclinical research and the human patient.

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Topical Melatonin Improves Gastric Microcirculatory Oxygenation During Hemorrhagic Shock in Dogs but Does Not Alter Barrier Integrity of Caco-2 Monolayers

Cited by 6 publications

References 43 publications

Local Mucosal CO2 but Not O2 Insufflation Improves Gastric and Oral Microcirculatory Oxygenation in a Canine Model of Mild Hemorrhagic Shock

Local Mucosal CO2 but Not O2 Insufflation Improves Gastric and Oral Microcirculatory Oxygenation in a Canine Model of Mild Hemorrhagic Shock

Local carbachol application induces oral microvascular recruitment and improves gastric tissue oxygenation during hemorrhagic shock in dogs

A Toolbox to Investigate the Impact of Impaired Oxygen Delivery in Experimental Disease Models

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