Inhibitory Effects Of Sevoflurane Research Articles

Multiple Exposures to Sevoflurane General Anesthesia During Pregnancy Inhibit CaMKII/CREB Axis by Downregulating HCN2 to Induce an Autism-Like Phenotype in Offspring Mice.

The objective of this investigation was to examine the impact of multiple exposures to general anesthesia (GA) with sevoflurane on the offspring of pregnant mice, as well as to elucidate the underlying mechanism. Neurodevelopmental assessments, including various reflexes and behavioral tests, were conducted on the offspring in the GA group to evaluate neuronal cell development. Furthermore, neonatal mouse neuronal cells were isolated and transfected with a high-expression CREB vector (pcDNA3.1-CREB), followed by treatment with sevoflurane (0.72mol/L), ZD7288 (50μmol/L), and KN-62 (10μmol/L), or a combination of these compounds. The expression of relevant genes was then analyzed using qRT-PCR and western blot techniques. In comparison to the sham group, neonatal mice in the GA group exhibited significantly prolonged latencies in surface righting reflex, geotaxis test, and air righting reflex. Furthermore, there was a notable deceleration in the development of body weight and tail in the GA group. These mice also displayed impairments in social ability, reduced reciprocal social interaction behaviors, diminished learning capacity, and heightened levels of anxious behaviors. Additionally, synaptic trigger malfunction was observed, along with decreased production of c-Fos and neurotrophic factors. Sevoflurane was found to notably decrease cellular c-Fos and neurotrophic factor production, as well as the expression of HCN2 and CaMKII/CREB-related proteins. The inhibitory effects of sevoflurane on HCN2 or CaMKII channels were similar to those observed with ZD7288 or KN-62 inhibition. However, overexpression of CREB mitigated the impact of sevoflurane on neuronal cells. Repetitive exposure to sevoflurane general anesthesia while pregnant suppresses the CaMKII/CREB pathway, leading to the development of autism-like characteristics in offspring mice through the reduction of HCN2 expression.

Sevoflurane depresses neurons in the medial parabrachial nucleus by potentiating postsynaptic GABAA receptors and background potassium channels

Despite persistent clinical use for over 170 years, the neuronal mechanisms by which general anesthetics produce hypnosis remain unclear. Previous studies suggest that anesthetics exert hypnotic effects by acting on endogenous arousal circuits. Recently, it has been shown that the medial parabrachial nucleus (MPB) is a novel wake-promoting component in the dorsolateral pons. However, it is not known whether and how the MPB contributes to anesthetic-induced hypnosis. Here, we investigated the action of sevoflurane, a widely used volatile anesthetic agent that best represents the drug class of halogenated ethers, on MPB neurons in mice. Using in vivo fiber photometry, we found that the population activities of MPB neurons were inhibited during sevoflurane-induced loss of consciousness. Using in vitro whole-cell patch-clamp recordings, we revealed that sevoflurane suppressed the firing rate of MPB neurons in concentration-dependent and reversible manners. At a concentration equal to MAC of hypnosis, sevoflurane potentiated synaptic GABAA receptors (GABAA-Rs), and the inhibitory effect of sevoflurane on the firing rate of MPB neurons was completely abolished by picrotoxin, which is a selective GABAA-R antagonist. At a concentration equivalent to MAC of immobility, sevoflurane directly hyperpolarized MPB neurons and induced a significant decrease in membrane input resistance by increasing a basal potassium conductance. Moreover, pharmacological blockade of GABAA-Rs in the MPB prolongs induction and shortens emergence under sevoflurane inhalation at MAC of hypnosis. These results indicate that sevoflurane inhibits MPB neurons through postsynaptic GABAA-Rs and background potassium channels, which contributes to sevoflurane-induced hypnosis.

Sevoflurane Inhibits Growth and Metastasis of Cervical Cancer Through Up-Regulating miR-203 by Targeting Tumor Protein Translationally Controlled 1

Background: Cervical cancer is a type of malignancy with high incidence and high mortality in women all over the world. Recent findings revealed the role of sevoflurane in the inhibition of development of various cancer types. This study aimed to explore whether sevoflurane could suppress cells proliferation and metastasis through adjusting miR-203 expression in cervical cancer. Methods: The effects of sevoflurane on HeLa cell viability was assessed using CCK-8 assay. miR-203 level in Hela cells was determined by qRT-PCR. In addition, cells apoptosis, migration and invasion were evaluated using flow cytometry and transwell analysis respectively after sevoflurane treatment or miR-203 expression changes. Bioinformatics software (TargetScan) was used to predict the potential target genes for miR-203 and the prediction was validated using dual-luciferase reporter system. Results: Sevoflurane effectively inhibited cell viability, metastasis and stimulated apoptosis in cervical cancer. miR-203 demonstrated a low expression in cervical cancer tissues and cells and sevoflurane significantly up-regulated miR-203 expression in cervical cancer cells. Upregulation of miR-203 significantly suppressed cell growth and metastasis and induced apoptosis, while down-regulation of miR-203 presented the opposite effects in cervical cancer cells. In addition, the inhibitory effects of sevoflurane were eliminated by down-regulating miR-203 in cervical cancer cells. In addition, TPT1 was confirmed as a target gene for miR-203. Conclusion: Sevoflurane inhibited cervical cancer cells viability and metastasis through up-regulation of miR-203 expression by targeting TPT1.

Repeated inhalation of sevoflurane inhibits the information transmission of Purkinje cells and delays motor development via the GABAA receptor ε subunit in neonatal mice.

General anesthesia is widely used in pediatric surgery, although the influence of general anesthesia on cerebellar information transmission and motor function is unclear. In the present study, neonatal mice received repeated inhalation of sevoflurane, and electrophysiological alterations in Purkinje cells (PCs) and the development of motor functions were detected. In addition, γ-aminobutyric acidA receptor ε (GABAA-R ε) subunit knockout mice were used to investigate the mechanism of action of sevoflurane on cerebellar function. In the neonatal mice, the field potential response of PCs induced by sensory stimulation and the motor function indices were markedly inhibited by sevoflurane, and the inhibitory effect was positively associated with the number of repetitions of anesthesia. In additional the GABAA-R ε subunit level of PCs was promoted by sevoflurane in a dose-dependent manner, and the inhibitory effects of sevoflurane on PC field potential response and motor function were alleviated in GABAA-R ε subunit knockout mice. The GABAA-R ε subunit was activated by sevoflurane, leading to inhibition of sensory information transmission in the cerebellar cortex, field potential responses of PCs and the development of cerebellar motor function. The present study provided experimental evidence for the safe usage of sevoflurane in clinical anesthesia, and suggested that GABAA-R ε subunit antagonists may be considered for combined application with general anesthesia with repeated inhalation of sevoflurane, for adverse effect prevention in the clinic.

Sevoflurane inhibits the migration and invasion of glioma cells by upregulating microRNA-637.

Cancer cell migration and invasion are essential features of the metastatic process. Volatile anesthetic sevoflurane inhibits the migration and invasion of multiple cancer cell lines; however, its effects on glioma cells are unclear. Emerging evidence suggests that microRNA(miRNA)-637 regulates glioma cell migration and invasion through the Akt1 pathway. Sevoflurane has been shown to modulate a number of miRNAs. In the present study, we examined whether sevoflurane inhibits glioma cell migration and invasion and, if so, whether these beneficial effects are mediated by miRNA-637. U251 glioma cells were treated without(control) or with sevoflurane at low, moderate or high concentrations for6h. To explore the molecular mechanisms, an additional group of U251 cells was treated with a miRNA‑637 inhibitor prior to treatment with a high concentration of sevoflurane. Compared with the control group, sevoflurane inhibited the migration and invasion of U251 cells in a dose-dependent manner. Molecular analyses revealed that sevoflurane increased the expression of miRNA‑637 and decreased the expression of Akt1 and phosphorylated Akt1 in a dose-dependent manner. Moreover, the inhibitory effects of sevoflurane on U251 cell migration and invasion were completely abolished by pre-treatment with miRNA‑637 inhibitor, which reversed the sevoflurane-induced reduction in the expression of Akt1 and phosphorylated Akt1 in the U251 cells. These results demonstrate that sevoflurane inhibits glioma cell migration and invasion and that these beneficial effects are mediated by the upregulation of miRNA‑637, which suppresses Akt1 expression and activity. These findings may have significant clinical implications for anesthesiologists regarding the choice of volatile anesthetic agents for the surgical resection of gliomas to prevent metastases and improve patient outcomes.

Inhibitory effects of sevoflurane on pacemaking activity of sinoatrial node cells in guinea‐pig heart

The volatile anaesthetic sevoflurane affects heart rate in clinical settings. The present study investigated the effect of sevoflurane on sinoatrial (SA) node automaticity and its underlying ionic mechanisms. Spontaneous action potentials and four ionic currents fundamental for pacemaking, namely, the hyperpolarization-activated cation current (I(f) ), T-type and L-type Ca²⁺ currents (I(Ca,T) and I(Ca,L) , respectively), and slowly activating delayed rectifier K⁺ current (I(Ks) ), were recorded in isolated guinea-pig SA node cells using perforated and conventional whole-cell patch-clamp techniques. Heart rate in guinea-pigs was recorded ex vivo in Langendorff mode and in vivo during sevoflurane inhalation. In isolated SA node cells, sevoflurane (0.12-0.71 mM) reduced the firing rate of spontaneous action potentials and its electrical basis, diastolic depolarization rate, in a qualitatively similar concentration-dependent manner. Sevoflurane (0.44 mM) reduced spontaneous firing rate by approximately 25% and decreased I(f) , I(Ca,T) , I(Ca,L) and I(Ks) by 14.4, 31.3, 30.3 and 37.1%, respectively, without significantly affecting voltage dependence of current activation. The negative chronotropic effect of sevoflurane was partly reproduced by a computer simulation of SA node cell electrophysiology. Sevoflurane reduced heart rate in Langendorff-perfused hearts, but not in vivo during sevoflurane inhalation in guinea-pigs. Sevoflurane at clinically relevant concentrations slowed diastolic depolarization and thereby reduced pacemaking activity in SA node cells, at least partly due to its inhibitory effect on I(f) , I(Ca,T) and I(Ca,L) . These findings provide an important electrophysiological basis of alterations in heart rate during sevoflurane anaesthesia in clinical settings.

Sevoflurane Inhibits the µ-Opioid Receptor Function Expressed in Xenopus Oocytes

Sevoflurane is widely used for anesthesia, and is commonly used together with opioids in clinical practice. However, the effects of sevoflurane on µ-opioid receptor (µOR) functions is still unclear. In this study, the effects of sevoflurane on µOR functions were analyzed by using Xenopus oocytes expressing a µOR fused to chimeric Gα protein G_qi5 (µOR-G_qi5). Sevoflurane by itself did not elicit any currents in oocytes expressing µOR-G_qi5, whereas sevoflurane inhibited the [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (DAMGO)-induced Cl^– currents at clinically used concentrations. Sevoflurane did not affect the Cl^– currents induced by AlF₄^–, which directly led to activation of G proteins. The inhibitory effects of sevoflurane on the DAMGO-induced currents were not observed in oocytes pretreated with the protein kinase C (PKC) inhibitor GF109203X. These findings suggest that sevoflurane would inhibit µOR function. Further, the mechanism of inhibition by sevoflurane would be mediated by PKC.

Effects of different doses of dexmedetomidine on MACBAR of sevoflurane in patients undergoing lower abdominal surgery

Objective To investigate the effects of different doses of dexmedetomidine on the minimum alveolar concentration of sevoflurane for blunting responses to skin incision ( MACBAR ) in patients undergoing lower abdominal surgery. Methods Sixty ASA Ⅰ or Ⅱ patients, aged 25-55 yr, weighing 45-75 kg, undergoing electire lower abdominal surgery under general anesthesia, were randomly divided into 4 groups ( n = 15 each): control group (Do group) and 3 dexmedetomidine groups (D1, D2 and D3 groups). The patients were unpremedicated.Dexmedetomidine was not used in group D0. A loading dose of dexmedetomidine 0.1μg/kg was injected iv over 10 min, and then dexmedetomidine was infused at a rate of 0.4, 0.8 and 1.2 μg· kg- 1 · h - 1 for 30 min in groups D1-3 respectively. Anesthesia was induced with inhalation of 8 % sevoflurane. Laryngeal mask airway was inserted when BIS value decreased to 45-55. The patients were mechanically ventilated with inhalation of sevoflurane and a mixture of 50% nitrous oxide and 50% oxygen, and the fresh gas flow was set at 1 L/min. In D0-3 groups, the initial end-tidal concentrations of sevoflurane were 3.0%, 2.5%, 2.0% and 1.5% respectively. The patients' response to skin incision was described as effective if MR or MAP increased by ＜ 15%, or ineffective (MR or MAP increased by ≥ 15%). When the response was effective, the end-tidal concentration of sevoflurane was decreased in the next patient, when ineffective, increased, and the ratio between the two successive concentrations was 0.9.The MRCBAR of sevoflurane was determined by up-and-down method, and 95% confidence interval was calculated.Results The MRCBAR (95% confidence interval) of sevoflurane was 2.85% (2.44%-3.32%), 1.91%(1.61%-2.26%), 1.52% (1.31%-1.77%), and 1.34% (1.15%-1.57%)in D0-3 groups respectively. The MRCBAR of sevoflurane was significantly lower in D1-3 groups than in D0 group, and in D2 and D3 groups than in group D1 (P ＜0.05＝. There was no significant difference in MRCBAR of sevoflurane between D2 and D3 groups (P ＞0.05) .Conclusion Continuous infusion of dexmedetomidine at 0.4, 0.8 and 1.2 μg·kg-1 ·h-1 for 30 min results in a decrease in MACBAR of sevoflurane and enhances the inhibitory effect of sevoflurane on the stress response, and in a dose-dependent manner. Key words: Dexmedetomidine; Dose-response relationship,drug; Stress; Sevoflurane

Sevoflurane inhibits angiotensin II-induced Rho kinase-mediated contraction of vascular smooth muscle from spontaneously hypertensive rat

Angiotensin II (Ang II)-induced vasoconstriction is mediated by changes in intracellular free Ca(2+) concentration ([Ca(2+)](i)) and myofilament Ca(2+) sensitivity. Protein kinase C- and Rho kinase-mediated signaling pathways are proposed for the regulation of the Ca(2+) sensitization mechanisms. We have demonstrated that sevoflurane inhibits Rho kinase-mediated contraction of isolated rat aortic smooth muscle. A recent study demonstrated that Rho-kinase mediated Ca(2+) sensitization was involved in the pathophysiology of hypertension. This study was designed to investigate the effects of sevoflurane on Ang II-induced Rho kinase-mediated vascular contraction in spontaneously hypertensive rats (SHR). The effects of sevoflurane on vasoconstriction, increase in [Ca(2+)](i), and membrane translocation of Rho kinase in response to Ang II were investigated in normotensive Wistar-Kyoto rats (WKY) and SHR, using an isometric force transducer, a fluorometer, and Western blotting, respectively. The inhibitory effects of sevoflurane on Ang II (10(-7)M)-induced contraction were greater (P < 0.05) in SHR than in WKY at the highest concentration of sevoflurane (5.1%). Y27632 (3 × 10(-7)M), a specific inhibitor of Rho kinase, inhibited the Ang II-induced contraction in SHR, but not in WKY. Sevoflurane did not affect the increases in [Ca(2+)](i) in response to Ang II in either strain. Ang II stimulated Rho kinase activity in SHR, which was almost abolished by sevoflurane at a concentration of 5.1% (P < 0.05). These findings suggest that the inhibition of the Ang II-induced contraction by sevoflurane in SHR may be, at least in part, due to the attenuation of the Rho kinase-mediated signaling pathway.

Effects of different target concentrations of sufentanil on MAC_(BAR) of sevoflurane in patients undergoing abdominal surgery

Objective To investigate the effects of three different effect-site concentration (Ce) of sufentanil given by TCI on the minimum alveolar concentration of sevoflurane for blunting adrenergic responses to skin incision(MAC_(BAR))in patients undergoing abdominal surgery.Methods Eighty ASAⅠ orⅡ patients,aged 20-60 yr,body mass index<30 kg/m~2,undergoing elective abdominal surgery,were randomly divided into 4 groups(n=20 each):control group(group so)and 3 sufentanil groups(group S_1,S_2,S_3).The patients were unpremedicated.Anesthesia was induced with TCI of propofol(target plasma concentration 3.5 μg/ml)and TCI of remifentanil(Ce 4 ng/ml).nacheal intubation was facilitated with rocuronium 0.6 mg/kg after the patients lost consciousness.The patients were mechanically ventilated.And then propofol and remifentanil were immediately stopped and anesthesia was maintained with inhalation of sevoflurane and a mixture of nitrous oxide and oxygen,fresh gas flow set at 10 L/min maintaining for at least 20 min.In group S_0,sufentanil was not given after intubation.In group S_1,S_2 and S_3,TCI of sufentamil was started after intubation at Ce of 0.12,0.18 and 0.24 ng/ml respectively.In group S_0,S_1,S_2 and S_3,sevoflurane inhalation was started with the initial end-tidal concentration of 3.0%,1.8%,1.3% and 1.1% respectively.The patients'response to skin incision was described as positive if MAP or HR increased by≥25%,or negative(MAP or HR increased by<25%).If the response was positive,the end-tidal concentration of sevoflurane for the next patient was increased by 1.2 times,while if negative,decreased by 1.2 times.The sevoflurane MAC_(BAR) was determined by up-and-down sequential trial.Results Compared with group S_0,the MAC_(BAR) of sevotlurane was significantly decreased in group S_1,S_2 and S_3(P<0.05).Compared with group S_1,the MACB_(BAR) of sevoflurane was significantly decreased in group S_2 and S_3(P<0.05).No significant difference was found in the MACB_(BAR) of sevoflurane between group S_2 and S_3 (P<0.05).Conclusion TCI of sufentanil at Ce of 0.12,0.18 and 0.24 ng/ml can significantly reduce MAC_(BAR) of sevoflurane and enhance the inhibitory effect of sevoflurane on stress response in a concentration-dependent manner. Key words: Anesthetics,inhalation; Sufentanil; Drug delivery systems; Dose-response relationship,drug; Stress

Inhibitory effects of sevoflurane on the cAMP-induced short circuit current and basolateral K+ channels in murine tracheal epithelium

Inhibitory effects of sevoflurane on the cAMP-induced short circuit current and basolateral K+ channels in murine tracheal epithelium

Neuromuscular effects of sevoflurane in myasthenia gravis patients

Little information is available regarding the neuromuscular effects of sevoflurane in patients with myasthenia gravis (MG). We evaluated the neuromuscular effects of sevoflurane alone in patients with MG and in those with normal neuromuscular transmission. Sixteen patients with generalized type MG (MG group) and 12 otherwise healthy patients (control group) entered into this study. Anaesthesia was induced with propofol, fentanyl, and midazolam followed by nitrous oxide in oxygen. Neuromuscular monitoring was recorded from the adductor pollicis muscle using electromyography with train-of-four stimulation of the ulnar nerve. After a stabilization period, and before sevoflurane administration, baseline T4/T1 was obtained and MG patients were classified as non-fade MG group (baseline T4/T1 > or = 0.90) (n = 10) and fade MG group (baseline T4/T1 < 0.90) (n = 6). End-tidal sevoflurane concentration was kept constant at 1.7% for 30 min and doubled thereafter to 3.4% and maintained for a further 30 min. Sevoflurane produced a concentration-dependent decrease in T1 and T4/T1 values. At 3.4% sevoflurane, T1 and T4/T1 decreased significantly from baseline values in all three groups. From baseline until the patient woke up from anaesthesia, the T4/T1 of the fade MG group was significantly lower than the other groups. At the end of anaesthesia, T4/T1 returned to values similar to the baseline in all three groups. During sevoflurane anaesthesia, concentration-dependent inhibition of neuromuscular transmission was observed in MG and control patients. The inhibitory effects of sevoflurane were more prominent in MG patients with baseline T4/T1 <0.90.

Different Inhibitory Effects of Sevoflurane on Hyperreactive Airway Smooth Muscle Contractility in Ovalbumin-sensitized and Chronic Cigarette-smoking Guinea Pig Models

The authors hypothesized that sevoflurane had different inhibitory effects on hyperreactive airway smooth muscle contractility in different types of hyperreactive airway models. The effects of sevoflurane on hyperreactive airways in ovalbumin-sensitized and chronic cigarette-smoking guinea pig models were investigated by measuring (1) total lung resistance, (2) smooth muscle tension and intracellular concentration of free Ca, (3) voltage-dependent Ca channel activity, and (4) cyclic adenosine monophosphate levels. Ovalbumin and muscarinic airway hyperreactivity was seen in ovalbumin-sensitized animals. Enlarged alveolar ducts/alveoli and lesser muscarinic hyperreactivity were observed in chronic cigarette-smoke animals. Although sevoflurane inhibited the acetylcholine-induced increase in total lung resistance in the control and ovalbumin-sensitized models, the anesthetic had a smaller effect in the chronic cigarette-smoking model. Similarly, in the chronic cigarette-smoking model, sevoflurane had a smaller inhibitory effect on carbachol-induced muscle contraction and increase in intracellular concentration of free Ca. Sevoflurane also had a smaller inhibitory effect on voltage-dependent Ca channel activity in the chronic cigarette-smoking group than in the other two groups. The sevoflurane-induced increase in cyclic adenosine monophosphate that was seen in the control and ovalbumin-sensitized groups was significantly suppressed in the chronic cigarette-smoking group. Although sevoflurane potently inhibited airway contractility in control and ovalbumin-sensitized models, the anesthetic had a smaller effect in a chronic cigarette-smoking model. The different inhibitory effects of sevoflurane on airway contractility depend, at least in part, on different effects on voltage-dependent Ca channel activity and cyclic adenosine monophosphate level.

Influence of Sevoflurane on the Metabolism and Renal Effects of Compound A in Rats

Background. The sevoflurane degradation product compound A is nephrotoxic in rats. In contrast, patient exposure to compound A during sevoflurane anesthesia has no clinically significant renal effects. The mechanism for this difference is incompletely understood. One possibility is that the metabolism and toxicity of compound A in humans is prevented by sevoflurane. However, the effect of sevoflurane on compound A metabolism and nephrotoxicity is unknown. Thus, the purpose of this investigation was to determine the effect of sevoflurane on the metabolism and renal toxicity of compound A in rats.Methods. Male rats received 0.25 mmol/kg intraperitoneal compound A, alone and during sevoflurane anesthesia (3%, 1.3 minimum alveolar concentration, for 3 h). Compound A metabolites in urine were quantified, and renal function was evaluated by serum creatinine and urea nitrogen, urine volume, osmolality, protein excretion, and renal tubular histology.Results. Sevoflurane coadministration with compound A inhibited compound A defluorination while increasing relative metabolism through pathways of sulfoxidation and beta-lyase-catalyzed metabolism, which mediate toxicity. Sevoflurane coadministration with compound A increased some (serum creatinine and urea nitrogen, and necrosis) but not other (urine volume, osmolality, and protein excretion) indices of renal toxicity.Conclusions. Sevoflurane does not suppress compound A nephrotoxicity in rats in vivo. These results do not suggest that lack of nephrotoxicity in surgical patients exposed to compound A during sevoflurane anesthesia results from an inhibitory effect of sevoflurane on compound A metabolism and toxicity. Rather, these results are consistent with differences between rats and humans in compound A exposure and inherent susceptibility to compound A nephrotoxicity.

Influence of Sevoflurane on the Metabolism and Renal Effects of Compound A in Rats

The sevoflurane degradation product compound A is nephrotoxic in rats. In contrast, patient exposure to compound A during sevoflurane anesthesia has no clinically significant renal effects. The mechanism for this difference is incompletely understood. One possibility is that the metabolism and toxicity of compound A in humans is prevented by sevoflurane. However, the effect of sevoflurane on compound A metabolism and nephrotoxicity is unknown. Thus, the purpose of this investigation was to determine the effect of sevoflurane on the metabolism and renal toxicity of compound A in rats. Male rats received 0.25 mmol/kg intraperitoneal compound A, alone and during sevoflurane anesthesia (3%, 1.3 minimum alveolar concentration, for 3 h). Compound A metabolites in urine were quantified, and renal function was evaluated by serum creatinine and urea nitrogen, urine volume, osmolality, protein excretion, and renal tubular histology. Sevoflurane coadministration with compound A inhibited compound A defluorination while increasing relative metabolism through pathways of sulfoxidation and beta-lyase-catalyzed metabolism, which mediate toxicity. Sevoflurane coadministration with compound A increased some (serum creatinine and urea nitrogen, and necrosis) but not other (urine volume, osmolality, and protein excretion) indices of renal toxicity. Sevoflurane does not suppress compound A nephrotoxicity in rats in vivo. These results do not suggest that lack of nephrotoxicity in surgical patients exposed to compound A during sevoflurane anesthesia results from an inhibitory effect of sevoflurane on compound A metabolism and toxicity. Rather, these results are consistent with differences between rats and humans in compound A exposure and inherent susceptibility to compound A nephrotoxicity.

The Inhibitory Effects of Sevoflurane on Angiotensin II- Induced, p44/42 Mitogen-Activated Protein Kinase-Mediated Contraction of Rat Aortic Smooth Muscle

Sevoflurane dilates blood vessels and reduces arterial blood pressure in a dose-dependent manner. Angiotensin II (Ang II) is one of the primary regulators of vascular tension and arterial blood pressure, and the p44/42 mitogen-activated protein kinases (p44/42 MAPK) are involved in Ang II-mediated vascular smooth muscle contraction. We designed this study to examine the effects of sevoflurane on Ang II-induced, p44/42 MAPK-mediated contraction of rat aortic smooth muscle. The effects of the p44/42 MAPK kinase (MEK1/2) inhibitor, PD 098059 (10(-5) molar [M], 5 x 10(-5) M and 10(-4) M), and sevoflurane (1.7%, 3.4%, and 5.1%) on Ang II-induced contraction and p44/42 MAPK phosphorylation were tested in rat aortic smooth muscle, using isometric force measurement and Western blot analysis, respectively. Ang II induced both a transient contractile response and phosphorylation of p44/42 MAPK, which were significantly attenuated by PD 098059 (P < 0.05-0.01). Sevoflurane inhibited Ang II-induced contractile response in a dose-dependent manner (P < 0.05 and 0.01 in response to 3.4% and 5.1% sevoflurane, respectively). Sevoflurane also dose-dependently depressed Ang II-elicited p44/42 MAPK phosphorylation (P < 0.01 in response to 3.4% and 5.1% sevoflurane). These results suggest that the inhibitory effect of sevoflurane on Ang II-induced vasoconstriction is, at least in part, caused by the inhibition of the p44/42 MAPK-mediated signaling pathway. The present study demonstrates that sevoflurane can dose-dependently inhibit both angiotensin II (Ang II)-induced contraction and p44/42 MAPK phosphorylation of rat aortic smooth muscle. These data suggest that sevoflurane-produced inhibition of Ang II-induced vasoconstriction is, at least in part, caused by depression of the p44/42 MAPK-mediated signaling pathway.

Effects of isoflurane, sevoflurane, and desflurane on platelet function: A prospective, randomized, single-blind, in vivo study

Background: The primary physiologic function of platelets is to facilitate hemostasisby aggregation. Volatile anesthetics have been reported to decrease platelet aggregation in vivo and in vitro. Objective: The aim of this study was to investigate the hematologic effectsof the anesthetics isoflurane, sevoflurane, and desflurane on hemoglobin (Hb), hematocrit (Hct), platelet count, activated partial thromboplastin time (aPTT), prothrombin time (PT), international normalized ratio (INR), and platelet aggregation after minor surgery. Methods: Patients aged 20 to 60 years who were scheduled to undergominor surgery and American Society of Anesthesiologists physical status P1 or P2 (healthy or mild systemic disease) were randomized to 1 of 3 groups: 1 minimum alveolar concentration (MAC) of isoflurane, sevoflurane, or desflurane. None of the patients received premedication. Anesthesia was induced using IV thiopental 5 to 6 mg/kg, fentanyl 1 to 2 μg/kg, and vecuronium 0.1 mg/kg, and maintained with 1 MAC of isoflurane, sevoflurane, or desflurane in 66% nitrous oxide and 33% oxygen. Vecuronium 0.03 mg/kg was given when necessary for muscle relaxation. All patients were monitored throughout surgery; isotonic saline was given at a rate of 5 mL/kg · h. Hematologic studies were performed preoperatively, 15 minutes after intubation, and 1 hour after the end of surgery. Platelet aggregation tests were performed in a laboratory using a platelet function analyzer (PFA), collagen/epinephrine PFA test cartridges, collagen/adenosine diphosphate PFA test cartridges, and PFA trigger solution. Results: This prospective, randomized, single-blind, in vivo study was conducted at Gevher Nesibe Teaching Hospital, Erciyes University, Kayseri, Turkey. Thirty patients (15 men, 15 women) were randomized to the 3 treatment groups (each, n = 10). Hb, Hct, platelet count, aPTT, PT, and INR were statistically similar between all 3 groups. The measured parameters were not significantly different between the isoflurane and desflurane groups at any time point. However, in the sevoflurane group, mean (5D) platelet aggregation was significantly delayed 15 minutes after intubation and 1 hour after surgery compared with the preoperative values (collagen/epinephrine, 81.70 [9.85] seconds vs 196.20 [27.84] seconds and 115.40 [25.80] seconds; both, P < 0.05). Conclusions: In this study of the effects of isoflurane, sevoflurane, and desflurane in patients undergoing minor surgery, clinically relevant antithrombotic effects were observed 15 minutes after intubation with all 3 drugs, although the effects in patients receiving sevoflurane were significantly greater compared with those in patients receiving isoflurane and desflurane. The antithrombotic effects of isoflurane and desflurane were not continued at 1 hour after surgery; however, the inhibitory effects of sevoflurane on platelet function were continued at 1 hour after surgery but were significantly decreased from levels found at 15 minutes after intubation.

Inhibitory effects of sevoflurane on U-wave in ECG

Inhibitory effects of sevoflurane on U-wave in ECG

Sevoflurane inhibits guanosine 5'-[gamma-thio]triphosphate-stimulated, Rho/Rho-kinase-mediated contraction of isolated rat aortic smooth muscle.

The Rho/Rho-kinase signaling pathway plays an important role in mediating Ca2+ sensitization of vascular smooth muscle. The effect of anesthetics on Rho/Rho-kinase-mediated vasoconstriction has not been determined to date. This study is designed to examine the possible inhibitory effects of sevoflurane on the Rho/Rho-kinase pathway by measuring guanosine 5'-[gamma-thio]triphosphate (GTP gamma S)-stimulated contraction and translocation of RhoA (one of the three Rho subtypes) and Rock-2 (one of the two Rho-kinase subtypes) from the cytosol to the membrane in rat aortic smooth muscle. GTP gamma S-induced contraction of rat aortic endothelium-denuded rings was measured using an isometric force transducer, and GTP gamma S-stimulated membrane translocation of RhoA and Rock-2 in smooth muscle cells was detected with Western blotting in the presence and absence of sevoflurane. GTP gamma S (10(-4) m) induced a sustained contraction, which was significantly inhibited by the Rho-kinase inhibitor, Y27632 (3 x 10(-6) m). Before treatment with GTP gamma S, RhoA and Rock-2 were detected primarily in the cytosolic fraction. GTP gamma S (10(-4) m) stimulated the translocation of RhoA and Rock-2 from the cytosol to the membrane, which was sustained for more than 60 min. Sevoflurane (1.7, 3.4, and 5.1%) concentration dependently inhibited the GTP gamma S-induced constriction of rat aortic smooth muscle with a reduction of constriction of 52-75% (P < 0.01, n = 8), and attenuated the translocation of RhoA and Rock-2 by 31-66% and 34-78%, respectively (P < 0.05-0.01, respectively; n = 4). The current findings show that sevoflurane depresses the GTP gamma S-stimulated contraction and translocation of both Rho and Rho-kinase from the cytosol in a concentration-dependent manner, indicating that sevoflurane is able to inhibit vasoconstriction mediated by the Rho/Rho-kinase pathway in rat aortic smooth muscle.

The Involvement of Cytochrome P450 Subtype 2E1 Enzyme in the Inhibitory Effect of Sevoflurane on Acetylcholine-Induced Endothelium Dependent Vasorelaxation of Rat Aorta

The Involvement of Cytochrome P450 Subtype 2E1 Enzyme in the Inhibitory Effect of Sevoflurane on Acetylcholine-Induced Endothelium Dependent Vasorelaxation of Rat Aorta