Hypothermia Improves Oral and Gastric Mucosal Microvascular Oxygenation during Hemorrhagic Shock in Dogs

Hypothermia is known to improve tissue function in different organs during physiological and pathological conditions. The aim of this study was to evaluate the effects of hypothermia on oral and gastric mucosal microvascular oxygenation (μHbO2) and perfusion (μflow) under physiological and hemorrhagic conditions. Five dogs were repeatedly anesthetized. All animals underwent each experimental protocol (randomized cross-over design): hypothermia (34°C), hypothermia during hemorrhage, normothermia, and normothermia during hemorrhage. Microcirculatory and hemodynamic variables were recorded. Systemic (DO2) and oral mucosal (μDO2) oxygen delivery were calculated. Hypothermia increased oral μHbO2 with no effect on gastric μHbO2. Hemorrhage reduced oral and gastric μHbO2 during normothermia (−36 ± 4% and −27 ± 7%); however, this effect was attenuated during additional hypothermia (−15 ± 5% and −11 ± 5%). The improved μHbO2 might be based on an attenuated reduction in μflow during hemorrhage and additional hypothermia (−51 ± 21 aU) compared to hemorrhage and normothermia (−106 ± 19 aU). μDO2 was accordingly attenuated under hypothermia during hemorrhage whereas DO2 did not change. Thus, in this study hypothermia alone improves oral μHbO2 and attenuates the effects of hemorrhage on oral and gastric μHbO2. This effect seems to be mediated by an increased μDO2 on the basis of increased μflow

PTRH2 is Necessary for Purkinje Cell Differentiation and Survival and its Loss Recapitulates Progressive Cerebellar Atrophy and Ataxia Seen in IMNEPD Patients

Hom ozygous variants in the peptidyl-tRNA hydrolase 2 gene (PTRH2) cause infantile-onset multisystem neurologic, endocrine, and pancreatic disease. The objective is to delineate the mechanisms underlying the core cerebellar phenotype in this disease. For this, we generated constitutive (Ptrh2LoxPxhCMVCre, Ptrh2−/− mice) and Purkinje cell (PC) specific (Ptrh2LoxPxPcp2Cre, Ptrh2ΔPCmice) Ptrh2 mutant mouse models and investigated the effect of the loss of Ptrh2 on cerebellar development. We show that Ptrh2−/− knockout mice had severe postnatal runting and lethality by postnatal day 14. Ptrh2ΔPC PC specific knockout mice survived until adult age; however, they showed progressive cerebellar atrophy and functional cerebellar deficits with abnormal gait and ataxia. PCs of Ptrh2ΔPC mice had reduced cell size and density, stunted dendrites, and lower levels of ribosomal protein S6, a readout of the mammalian target of rapamycin pathway. By adulthood, there was a marked loss of PCs. Thus, we identify a cell autonomous requirement for PTRH2 in PC maturation and survival. Loss of PTRH2 in PCs leads to downregulation of the mTOR pathway and PC atrophy. This suggests a molecular mechanism underlying the ataxia and cerebellar atrophy seen in patients with PTRH2 mutations leading to infantile-onset multisystem neurologic, endocrine, and pancreatic disease

Hypothermia Improves Oral and Gastric Mucosal Microvascular Oxygenation during Hemorrhagic Shock in Dogs

Hypothermia is known to improve tissue function in different organs during physiological and pathological conditions. The aim of this study was to evaluate the effects of hypothermia on oral and gastric mucosal microvascular oxygenation ( HbO 2 ) and perfusion ( flow) under physiological and hemorrhagic conditions. Five dogs were repeatedly anesthetized. All animals underwent each experimental protocol (randomized cross-over design): hypothermia (34 ∘ C), hypothermia during hemorrhage, normothermia, and normothermia during hemorrhage. Microcirculatory and hemodynamic variables were recorded. Systemic (DO 2 ) and oral mucosal ( DO 2 ) oxygen delivery were calculated. Hypothermia increased oral HbO 2 with no effect on gastric HbO 2 . Hemorrhage reduced oral and gastric HbO 2 during normothermia (−36 ± 4% and −27 ± 7%); however, this effect was attenuated during additional hypothermia (−15 ± 5% and −11 ± 5%). The improved HbO 2 might be based on an attenuated reduction in flow during hemorrhage and additional hypothermia (−51 ± 21 aU) compared to hemorrhage and normothermia (−106 ± 19 aU). DO 2 was accordingly attenuated under hypothermia during hemorrhage whereas DO 2 did not change. Thus, in this study hypothermia alone improves oral HbO 2 and attenuates the effects of hemorrhage on oral and gastric HbO 2 . This effect seems to be mediated by an increased DO 2 on the basis of increased flow

Hypercapnic Acidosis Preserves Gastric Mucosal Microvascular Oxygen Saturation in a Canine Model of Hemorrhage.

The authors aimed to clarify the effects of hypercapnic acidosis and its timing on gastric mucosal oxygenation in a canine model of hemorrhage. This was designed as a prospective, controlled, randomized animal study set in a university research laboratory. Five chronically instrumented dogs were used. Dogs were repeatedly anesthetized (sevoflurane 1.5 MAC), mechanically ventilated, and randomized to each of the following protocols. In a control series (CON), animals underwent hemorrhage during normoventilation (etCO(2), 35 mmHg). In a second series, hypercapnia (etCO(2), 70 mmHg) was applied before onset of hemorrhage (prophylactic hypercapnia), whereas in the third series, hypercapnia was applied after hemorrhage (therapeutic hypercapnia, THE). Microvascular oxygenation (mu HbO(2)) of the gastric mucosa was continuously assessed by tissue reflectance spectrophotometry. Cardiac output was continuously measured, and oxygen delivery (DO2) was intermittently calculated. In CON, hemorrhage decreased DO2 (from 11 +/- 3 mL.kg(-1).min(-1) to 8 +/- 2 mL.kg(-1).min(-1) and 8 +/- 2 mL.kg(-1).min(-1) after 30 and 75 min, respectively) and mu HbO(2) (from 57% +/- 4% to 43% +/- 11% and 50% +/- 11%). Prophylactic hypercapnia attenuated the effects of hemorrhage on DO2 (12 +/- 2 mL.kg(-1).min(-1) to 10 +/- 2 mL.kg(-1).min(-1) and 11 +/- 2 mL.kg(-1).min(-1)) and preserved mu HbO(2) (52% +/- 3% to 47% +/- 5% and 57% T 3%). Initial effects of hemorrhage in THE were comparable to CON (DO2 from 11 +/- 2 mL.kg(-1).min(-1) to 8 +/- 1 mL.kg(-1).min(-1); mu HbO(2) from 56% +/- 7% to 43% +/- 9%), but after application of hypercapnic acidosis, baseline levels were restored (DO2 10 +/- 3 mL.kg(-1).min(-1); mu HbO(2) 52% +/- 14%). Hypercapnic acidosis applied before or after hemorrhage (THE) preserves microvascular mucosal oxygenation. If these experimental findings may be transferred to the clinical setting, deliberate hypercapnic acidosis could serve to augment oxygenation of the splanchnic region in states of compromised circulation, e. g., hemorrhage

Propofol improves colonic but impairs hepatic mitochondrial function in tissue homogenates from healthy rats

Evidence suggests that propofol infusion syndrome (PRIS) is caused by an altered mitochondrial function. The aim of this study was to examine the effects of propofol and the vehicle MCT on mitochondrial function in hepatic and colonic tissue. Mitochondrial oxygen consumption was determined in colon and liver homogenates after incubation with buffer (control), propofol (50, 75, 100, 500 mu M) or the carrier substances DMSO and MCT. State 2 (substrate-dependent) and state 3 (ADP-dependent respiration) were assessed. RCI (respiratory control index) - an indicator for coupling between electron transport chain system (ETS) and oxidative phosphorylation (OXPHOS) and ADP/O ratio - a parameter for efficacy of OXPHOS were calculated. Data were presented as % of control. In hepatic mitochondria, 500 mu M propofol reduced RCI formulation-independently (propofol/MCT 500 mu M: complex I: 66.3 +/- 8.7%*, complex II: 75.5 +/- 9.2%*; propofol/DMSO 500 mu M: complex I: 29.1 +/- 8.8%*, complex II: 49.3 +/- 15.5%*). 75 mu M Propofol/MCT reduced ADP/O for complex I (73.5 +/- 27.3%*). DMSO did not affect hepatic mitochondria whereas MCT reduced RCI for complex II (87.2 +/- 9.8%*) and ADP/0 for complex I (93.7 +/- 31.7%*). In colon 50 mu M Propofol/MCT increased RCI for complex I and II (complex I: 127.2 +/- 10.7%*, complex II: 136.8 +/- 33.9%") and 100 mu M Propofol/MCT for complex I (131.4 +/- 18.7%*). 500 mu M Propofol/DMSO increased ADP/O for complex I (139.4 +/- 41.4%*). DMSO did not affect RCI but increased ADP/O for both complexes (complex I: 119.9 +/- 25.8%*, complex II: 110.2 +/- 14.2%*). MCT increased RCI for complex I (123.0 +/- 31.6%*). In hepatic mitochondria propofol uncoupled ETS from OXPHOS formulation-independently and propofol/MCT reduced efficacy of OXPHOS. In colonic mitochondria, propofol/MCT strengthened the coupling and propofol/DMSO enhanced the efficacy of OXPHOS

Effect of Topical Iloprost and Nitroglycerin on Gastric Microcirculation and Barrier Function during Hemorrhagic Shock in Dogs

Background: Topical drug application is used to avoid systemic side effects. The aim of this study was to analyze whether locally applied iloprost or nitroglycerin influence gastric mucosal perfusion, oxygenation, and barrier function during physiological and hemorrhagic conditions. Methods: In repeated experiments, 5 anesthetized dogs received iloprost, nitroglycerin, or normal saline during physiological and hemorrhagic (-20% blood volume) conditions. Macro and microcirculatory variables were recorded continuously. Gastric barrier function was assessed via translocation of sucrose into the blood. Results: During hemorrhage, gastric mucosal oxygenation decreased from 77 +/- 4 to 37 +/- 7%. This effect was attenuated by nitroglycerin (78 +/- 6 to 47 +/- 13%) and iloprost (82 +/- 4 to 54 +/- 9%). Sucrose plasma levels increased during hemorrhage from 7 +/- 4 to 55 +/- 15 relative amounts. This was alleviated by nitroglycerin (5 8 to 29 +/- 38 relative amounts). These effects were independent of sys-temic hemodynamic variables. Conclusions: During hemorrhage, topical nitroglycerin and iloprost improve regional gastric oxygenation without affecting perfusion. Nitroglycerin attenuated the shock-induced impairment of the mucosal barrier integrity. Thus, local drug application improves gastric microcirculation without compromising systemic hemodynamic variables, and it may also protect mucosal barrier function. (C) 2017 S. Karger AG, Base

Local gastric RAAS inhibition improves gastric microvascular perfusion in dogs

During circulatory shock, gastrointestinal microcirculation is impaired, especially via activation of the renin-angiotensin-aldosterone system. Therefore, inhibition of the renin-angiotensin-aldosterone system might be beneficial in maintaining splanchnic microcirculation. The aim of this study was to analyze whether locally applied losartan influences gastric mucosal perfusion (mu flow, mu velo) and oxygenation (mu HbO(2)) without systemic hemodynamic changes. In repetitive experiments six anesthetized dogs received 30 mg losartan topically on the oral and gastric mucosa during normovolemia and hemorrhage (-20% blood volume). Microcirculatory variables were measured with reflectance spectrometry, laser Doppler flowmetry and incident dark field imaging. Transpulmonary thermodilution and pulse contour analysis were used to measure systemic hemodynamic variables. Gastric barrier function was assessed via differential absorption of inert sugars. During normovolemia, losartan increased gastric mu flow from 99 +/- 6 aU to 147 +/- 17 aU and mu velo from 17 +/- 1 aU to 19 +/- 1 all. During hemorrhage, losartan did not improve mu flow. mu velo decreased from 17 +/- 1 aU to 14 +/- 1 aU in the control group. Application of losartan did not significantly alter mu velo (16 +/- 1 aU) compared to the control group and to baseline levels (17 +/- 1 aU). No effects of topical losartan on macrohemodynamic variables or microcirculatory oxygenation were detected. Gastric microcirculatory perfusion is at least partly regulated by local angiotensin receptors. Topical application of losartan improves local perfusion via vasodilation without significant effects on systemic hemodynamics. During mild hemorrhage losartan had minor effects on regional perfusion, probably because of a pronounced upstream vasoconstriction