European journal of pharmacology · 2025
Effects of midazolam and dexmedetomidine on liver and intestinal mitochondrial respiration.
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Kuebart Anne, Kaltenbach Nicola, Hoffmann Christina, Picker Olaf, Herminghaus Anna
Аннотация
BACKGROUND: Mitochondrial dysfunction frequently occurs in critically ill patients and is thought to contribute to metabolic shutdown and hepatic or gastrointestinal failure. In addition to hypoxemia and inflammation, sedatives are considered potential contributors to further impairment of mitochondrial function.
OBJECTIVE: This study investigated the effect of the sedatives midazolam and dexmedetomidine on liver and colon mitochondrial function. Especially colon mitochondrial affection by both drugs was evaluated here for the first time.
DESIGN: Liver and colon tissue homogenates from healthy Wistar rats (n = 60) were treated with therapeutical and supra-therapeutical doses of midazolam (0.25, 5, 50, 100, 500 μM) and dexmedetomidine (1, 5, 50, 100, 1000 nM). Samples were analyzed using the Clark electrode (Strathkelvin 782). Data analyses were performed via GraphPad Prism® 8 using the Kruskal-Wallis + Dunn's post-hoc test. p < 0.05 was considered significant.
RESULTS: In liver homogenates, treatment with 500 μM midazolam (48.6 ± 6.6 %) showed a significantly decreased respiratory control index (RCI) compared with the control (107.1 ± 14.8 %, p < 0.01) for complex II but without decreases in ADP/O ratio. Colon homogenate did not show significant alterations after midazolam treatment. Dexmedetomidine treatment did not affect colon or liver mitochondrial respiration in any dosage.
CONCLUSIONS: In clinical dosages on healthy organs, midazolam and dexmedetomidine did not show any effects on mitochondrial respiration in the colon and liver. However, in supra-therapeutical dosages, midazolam showed an organ-specific, dose-dependent, and complex-dependent effect on mitochondrial respiration by reducing the coupling of ETS and OXPHOS but without decreasing efficacy.
OBJECTIVE: This study investigated the effect of the sedatives midazolam and dexmedetomidine on liver and colon mitochondrial function. Especially colon mitochondrial affection by both drugs was evaluated here for the first time.
DESIGN: Liver and colon tissue homogenates from healthy Wistar rats (n = 60) were treated with therapeutical and supra-therapeutical doses of midazolam (0.25, 5, 50, 100, 500 μM) and dexmedetomidine (1, 5, 50, 100, 1000 nM). Samples were analyzed using the Clark electrode (Strathkelvin 782). Data analyses were performed via GraphPad Prism® 8 using the Kruskal-Wallis + Dunn's post-hoc test. p < 0.05 was considered significant.
RESULTS: In liver homogenates, treatment with 500 μM midazolam (48.6 ± 6.6 %) showed a significantly decreased respiratory control index (RCI) compared with the control (107.1 ± 14.8 %, p < 0.01) for complex II but without decreases in ADP/O ratio. Colon homogenate did not show significant alterations after midazolam treatment. Dexmedetomidine treatment did not affect colon or liver mitochondrial respiration in any dosage.
CONCLUSIONS: In clinical dosages on healthy organs, midazolam and dexmedetomidine did not show any effects on mitochondrial respiration in the colon and liver. However, in supra-therapeutical dosages, midazolam showed an organ-specific, dose-dependent, and complex-dependent effect on mitochondrial respiration by reducing the coupling of ETS and OXPHOS but without decreasing efficacy.