Ketamine reduces nitric oxide biosynthesis in human umbilical vein endothelial cells by down-regulating endothelial nitric oxide synthase expression and intracellular calcium levels*

Chen, Ruei Ming; Chen, Ta-Liang; Lin, Yi-Ling; Chen, Tyng-Guey; Tai, Yu‐Ting

doi:10.1097/01.ccm.0000163246.33366.51

Cited by 62 publications

(37 citation statements)

References 37 publications

(43 reference statements)

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“…In hepatocytes, CYP3A4 is a major enzyme that participates in the metabolism of xenobiotics (Martínez-Jiménezet al, 2007). Our previous studies showed that a therapeutic concentration of ketamine can suppress macrophage activities and reduce endothelial nitric-oxide synthesis (Chang et al, 2005;Chen et al, 2005). In this study, we further demonstrated that clinically relevant concentrations of ketamine can lead to dysfunction of HepG2 cells due to suppression of cytoskeletal remodeling, calcium mobilization, ATP synthesis, and enzyme activity rather than the death mechanism.…”

Section: Discussionmentioning

confidence: 54%

Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

Chang¹,

Chen²,

Chen

2008

Drug Metab Dispos

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ABSTRACT:Ketamine is an intravenous anesthetic agent often used for inducing and maintaining anesthesia. Cytoskeletons contribute to the regulation of hepatocyte activity of drug biotransformation. In this study, we attempted to evaluate the effects of ketamine on F-actin and microtubular cytoskeletons in human hepatoma HepG2 cells and its possible molecular mechanisms. Exposure of HepG2 cells to ketamine at <100 M, which corresponds to clinically relevant concentrations for 1, 6, and 24 h, did not affect cell viability. Meanwhile, administration of therapeutic concentrations of ketamine obviously interrupted F-actin and microtubular cytoskeletons. In parallel, levels of intracellular calcium concentration-and timedependently decreased after ketamine administration. Analysis by confocal microscopy further revealed that ketamine suppressed calcium mobilization from an extracellular buffer into HepG2 cells.Exposure to ketamine decreased cellular ATP levels. The mitochondrial membrane potential and complex I NADH dehydrogenase activity were both reduced after ketamine administration. Ketamine did not change the production of actin or microtubulin mRNA in HepG2 cells. Consequently, ketamine-caused cytoskeletal interruption led to suppression of CYP3A4 expression and its metabolizing activity. Therefore, this study shows that therapeutic concentrations of ketamine can disrupt F-actin and microtubular cytoskeletons possibly through suppression of intracellular calcium mobilization and cellular ATP synthesis due to downregulation of the mitochondrial membrane potential and complex I enzyme activity. Such disruption of the cytoskeleton may lead to reductions in CYP3A4 activity in HepG2 cells.

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Section: Discussionmentioning

confidence: 54%

Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

Chang¹,

Chen²,

Chen

2008

Drug Metab Dispos

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“…24 Briefly, osteoblasts (2 Â 10 4 ) were seeded in 96-well tissue culture plates overnight. After drug treatment, osteoblasts were cultured with new medium containing 0.5 mg/mL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide for a further 3 h. The blue formazan products in osteoblasts were dissolved in dimethyl sulfoxide and spectrophotometrically measured at a wavelength of 550 nm.…”

Section: Assay Of Cell Viabilitymentioning

confidence: 99%

Nitric oxide protects osteoblasts from oxidative stress‐induced apoptotic insults via a mitochondria‐dependent mechanism

Chang

Liao

Lin

et al. 2006

Journal Orthopaedic Research

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Nitric oxide (NO) contributes to the regulation of osteoblast activities. In this study, we evaluated the protective effects of NO pretreatment on oxidative stress-induced osteoblast apoptosis and its possible mechanism using neonatal rat calvarial osteoblasts as the experimental model. Exposure of osteoblasts to sodium nitroprusside (SNP) at a low concentration of 0.3 mM significantly increased cellular NO levels without affecting cell viability. However, when the concentration reached a high concentration of 2 mM, SNP increased the levels of intracellular reactive oxygen species and induced osteoblast injuries. Thus, administration of 0.3 and 2 mM SNP in osteoblasts were respectively used as sources of NO and oxidative stress. Pretreatment with NO for 24 h significantly ameliorated the oxidative stress-caused morphological alterations and decreases in alkaline phosphatase activity, and reduced cell death. Oxidative stress induced osteoblast death via an apoptotic mechanism, but NO pretreatment protected osteoblasts against the toxic effects. The mitochondrial membrane potential was significantly reduced following exposure to the oxidative stress. However, pretreatment with NO significantly lowered the suppressive effects. Oxidative stress increased cellular Bax protein production and cytochrome c release from mitochondria. Pretreatment with NO significantly decreased oxidative stress-caused augmentation of Bax and cytochrome c protein levels. In parallel with cytochrome c release, oxidative stress induced caspase-3 activation and DNA fragmentation. Pretreatment with NO significantly reduced the oxidative stress-enhanced caspase-3 activation and DNA damage. Results of this study show that NO pretreatment can protect osteoblasts from oxidative stress-induced apoptotic insults. The protective action involves a mitochondria-dependent mechanism. ß

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“…Ogawa et al [57] zeigten an Pulmonalarterienringen von Kaninchen, dass Ketamin der durch Acetylcholin und Bradykinin induzierten Vasodilation über eine Hemmung von NOund "endothelium-derived hyperpolarizing factor" (EDHF)-vermittelten Metaboliten entgegenwirkt. In einer kürzlich von Chen et al [15] publizierten Studie wurde der Einfluss von Ketamin auf die Vasoregulation über das NO-cGMP-System genauer untersucht: An Endothelzellen aus menschlichen Umbilikalvenen, die mit unterschiedlichen Konzentrationen von Ketamin inkubiert wurden, konnte demonstriert werden, dass Ketamin in therapeutischen Dosierungen die NO-Biosynthese reduziert. Des Weiteren berichtete dieselbe Arbeitsgruppe, dass die NO-Synthesehemmung nicht nur auf einer prätransla-tionalen Inhibition der eNOS-Expression beruht, sondern auch auf einer Ca 2+ -abhängigen poststranslationalen Reduktion der eNOS-Aktivität.…”

Section: Interaktion Mit Dem No-cgmp-systemunclassified

Einsatz von Ketamin bei Sepsis und systemischen Entzündungsreaktionen

Lange¹,

Bröking²,

Aken³

et al. 2006

Anaesthesist

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Ketamine is the only intravenous anesthetic that causes an increase in mean arterial pressure without compromising cardiac output. These beneficial effects are basically linked to stimulation of the sympathetic nervous system, inhibition of adenosine triphosphate-sensitive potassium channels and interactions with the nitric oxide pathway. Experimental and clinical studies have shown that ketamine exerts antiinflammatory properties by inhibiting the release of proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6. In addition, there is increasing evidence that early ketamine administration reduces mortality in experimental sepsis models. In view of the current literature ketamine appears to represent a beneficial therapeutic option for long-term sedation of patients with arterial hypotension resulting from sepsis and systemic inflammatory response syndrome (SIRS). However, it has to be taken into account that ketamine inhibits endothelial nitric oxide synthase, thereby potentially aggravating impaired (micro) regional blood flow in sepsis. Future studies are required to investigate the role of ketamine in the treatment of patients with sepsis and SIRS.

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Ketamine reduces nitric oxide biosynthesis in human umbilical vein endothelial cells by down-regulating endothelial nitric oxide synthase expression and intracellular calcium levels*

Cited by 62 publications

References 37 publications

Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

Cytoskeleton Interruption in Human Hepatoma HepG2 Cells Induced by Ketamine Occurs Possibly through Suppression of Calcium Mobilization and Mitochondrial Function

Nitric oxide protects osteoblasts from oxidative stress‐induced apoptotic insults via a mitochondria‐dependent mechanism

Einsatz von Ketamin bei Sepsis und systemischen Entzündungsreaktionen

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