The safety of occupational exposure to inhaled anesthetics remains a concern among the medical staff in hospitals. Few reports are seen about the impact of inhaled anesthetics on the reproductive system, particularly that of males. Several clinical and basic studies on isoflurane and others suggest that inhaled anesthetics affect the reproductive system of rodents by decreasing the sperm count, inducing sperm morphological abnormality, reducing sperm motility, and changing the levels of reproductive hormones, the underlying mechanisms of which are mainly associated with the alteration of the hypothalamic-pituitary-gonadal axis and DNA damage and apoptosis of reproductive cells. This article reviews the main impacts of inhaled anesthetics on the male reproductive system and the possible mechanisms.
Anesthetics, Inhalation ; pharmacology ; Apoptosis ; DNA Damage ; Genitalia, Male ; drug effects ; Humans ; Isoflurane ; pharmacology ; Male ; Occupational Exposure ; Sperm Count ; Sperm Motility ; drug effects ; Spermatozoa ; drug effects

Anesthetics, Inhalation ; pharmacology ; Child ; Electrocardiography ; Heart Rate ; drug effects ; Humans ; Isoflurane ; analogs & derivatives ; pharmacology ; Methyl Ethers ; pharmacology

BACKGROUNDSepsis is a major cause of mortality in Intensive Care Units. Anesthetic dose isoflurane and 100% oxygen were proved to be beneficial in sepsis; however, their application in septic patients is limited because long-term hyperoxia may induce oxygen toxicity and anesthetic dose isoflurane has potential adverse consequences. This study was scheduled to find the optimal combination of isoflurane and oxygen in protecting experimental sepsis and its mechanisms.

METHODSThe effects of combined therapy with isoflurane and oxygen on lung injury and sepsis were determined in animal models of sepsis induced by cecal ligation and puncture (CLP) or intraperitoneal injection of lipopolysaccharide (LPS) or zymosan. Mouse RAW264.7 cells or human peripheral blood mononuclear cells (PBMCs) were treated by LPS to probe mechanisms. The nuclear factor kappa B (NF-κB) signaling molecules were examined by Western blot and cellular immunohistochemistry.

RESULTSThe 0.5 minimum alveolar concentration (MAC) isoflurane in 60% oxygen was the best combination of oxygen and isoflurane for reducing mortality in experimental sepsis induced by CLP, intraperitoneal injection of LPS, or zymosan. The 0.5 MAC isoflurane in 60% oxygen inhibited proinflammatory cytokines in peritoneal lavage fluids (tumor necrosis factor-alpha [TNF-β]: 149.3 vs. 229.7 pg/ml, interleukin [IL]-1β: 12.5 vs. 20.6 pg/ml, IL-6: 86.1 vs. 116.1 pg/ml, and high-mobility group protein 1 [HMGB1]: 323.7 vs. 449.3 ng/ml; all P< 0.05) and serum (TNF-β: 302.7 vs. 450.7 pg/ml, IL-1β: 51.7 vs. 96.7 pg/ml, IL-6: 390.4 vs. 722.5 pg/ml, and HMGB1: 592.2 vs. 985.4 ng/ml; all P< 0.05) in septic animals. In vitro experiments showed that the 0.5 MAC isoflurane in 60% oxygen reduced inflammatory responses in mouse RAW264.7 cells, after LPS stimulation (all P< 0.05). Suppressed activation of NF-κB pathway was also observed in mouse RAW264.7 macrophages and human PBMCs after LPS stimulation or plasma from septic patients. The 0.5 MAC isoflurane in 60% oxygen also prevented the increases of phospho-IKKβ/β, phospho-IκBβ, and phospho-p65 expressions in RAW264.7 macrophages after LPS stimulation (all P< 0.05).

CONCLUSIONCombined administration of a sedative dose of isoflurane with 60% oxygen improves survival of septic animals through reducing inflammatory responses.

Adult ; Anesthesia ; methods ; Animals ; Blotting, Western ; Bronchoalveolar Lavage Fluid ; Disease Models, Animal ; Female ; Humans ; Inflammation ; drug therapy ; Isoflurane ; therapeutic use ; Leukocytes, Mononuclear ; metabolism ; Lipopolysaccharide Receptors ; metabolism ; Lipopolysaccharides ; pharmacology ; Lung Injury ; drug therapy ; immunology ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; NF-kappa B ; metabolism ; Oxygen ; therapeutic use ; Peroxidase ; metabolism ; RAW 264.7 Cells ; Rats, Sprague-Dawley ; Sepsis ; drug therapy ; immunology ; Tumor Necrosis Factor-alpha ; metabolism

OBJECTIVEAnesthetic isoflurane plus surgery has been reported to induce cognitive impairment. The underlying mechanism and targeted intervention remain largely to be determined. Ginsenoside Rb1 was reported to be neuroprotective. We therefore set out to determine whether ginsenoside Rb1 can attenuate isoflurane/surgery-induced cognitive dysfunction via inhibiting neuroinflammation and oxidative stress.

METHODSFive-months-old C57BL/6J female mice were treated with 1.4% isoflurane plus abdominal surgery for two hours. Sixty mg/kg ginsenoside Rb1 were given intraperitoneally from 7 days before surgery. Cognition of the mice were assessed by Barnes Maze. Levels of postsynaptic density-95 and synaptophysin in mice hippocampus were measured by Western blot. Levels of reactive oxygen species, tumor necrosis factor-α and interleukin-6 in mice hippocampus were measured by ELISA.

RESULTSHere we show for the first time that the ginsenoside Rb1 treatment attenuated the isoflurane/surgery-induced cognitive impairment. Moreover, ginsenoside Rb1 attenuated the isoflurane/surgery-induced synapse dysfunction. Finally, ginsenoside Rb1 mitigated the isoflurane/surgery-induced elevation levels of reactive oxygen species, tumor necrosis factor-α and interleukin-6 in the mice hippocampus.

CONCLUSIONThese results suggest that ginsenoside Rb1 may attenuate the isoflurane/surgery-induced cognitive impairment by inhibiting neuroinflammation and oxidative stress pending future studies.

Anesthetics, Inhalation ; adverse effects ; Animals ; Cognition ; Cognitive Dysfunction ; etiology ; prevention & control ; Female ; Ginsenosides ; pharmacology ; Hippocampus ; drug effects ; Inflammation ; etiology ; prevention & control ; Isoflurane ; adverse effects ; Medicine, Chinese Traditional ; Mice ; Mice, Inbred C57BL ; Oxidative Stress ; Postoperative Complications ; etiology ; prevention & control ; Random Allocation ; Surgical Procedures, Operative ; adverse effects ; Synapses ; metabolism

OBJECTIVEThe inhalation anesthetic isoflurane has been shown to induce mitochondrial dysfunction and caspase activation, which may lead to learning and memory impairment. Ginsenoside Rg1 is reported to be neuroprotective. We therefore set out to determine whether ginsenoside Rg1 can attenuate isoflurane-induced caspase activation via inhibiting mitochondrial dysfunction.

METHODSWe investigated the effects of ginsenoside Rg1 at concentrations of 12.5, 25, and 50 μmol/L and pretreatment times of 12 h and 24 h on isoflurane-induced caspase-3 activation in H4 naïve and stably transfected H4 human neuroglioma cells that express full-length human amyloid precursor protein (APP) (H4-APP cells). For mitochondrial dysfunction, we assessed mitochondrial permeability transition pore (mPTP) and adenosine-5'-triphosphate (ATP) levels. We employed Western blot analysis, chemiluminescence, and flowcytometry.

RESULTSHere we show that pretreatment with 50 µmol/L ginsenoside Rg1 for 12 h attenuated isoflurane-induced caspase-3 activation and mitochondrial dysfunction in H4-APP cells, while pretreatment with 25 and 50 µmol/L ginsenoside Rg1 for 24 h attenuated isoflurane-induced caspase-3 activation and mitochondrial dysfunction in both H4 naïve and H4-APP cells.

CONCLUSIONThese data suggest that ginsenoside Rg1 may ameliorate isoflurane-induced caspase-3 activation by inhibiting mitochondrial dysfunction. Pending further studies, these findings might recommend the use of ginsenoside Rg1 in preventing and treating isoflurane-induced neurotoxicity.

Amyloid beta-Protein Precursor ; metabolism ; Caspase 3 ; genetics ; metabolism ; Cell Line, Tumor ; Gene Expression Regulation, Enzymologic ; drug effects ; Ginsenosides ; administration & dosage ; pharmacology ; Glioma ; drug therapy ; Humans ; Ionomycin ; pharmacology ; Isoflurane ; pharmacology ; Mitochondria ; drug effects ; metabolism

PURPOSE: This study aims to investigate the most appropriate effect-site concentration of remifentanil to minimize cardiovascular changes during inhalation of high concentration desflurane. MATERIALS AND METHODS: Sixty-nine American Society of Anesthesiologists physical status class I patients aged 20-65 years were randomly allocated into one of three groups. Anesthesia was induced with etomidate and rocuronium. Remifentanil was infused at effect-site concentrations of 2, 4 and 6 ng/mL in groups R2, R4 and R6, respectively. After target concentrations of remifentanil were reached, desflurane was inhaled to maintain the end-tidal concentration of 1.7 minimum alveolar concentrations for 5 minutes (over-pressure paradigm). The systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR) and end-tidal concentration of desflurane were measured for 5 minutes. RESULTS: The end-tidal concentration of desflurane increased similarly in all groups. The SBP, DBP, MAP and HR within group R4 were not significantly different as compared with baseline values. However, measured parameters within group R2 increased significantly 1-3 minutes after desflurane inhalation. The MAP within group R6 decreased significantly at 1, 2, 4, and 5 minutes (p<0.05). There were significant differences in SBP, DBP, MAP and HR among the three groups 1-3 minutes after inhalation (p<0.05). The incidence of side effects such as hyper- or hypo-tension, and tachy- or brady-cardia in group R4 was 4.8% compared with 21.8% in group R2 and 15.0% in group R6. CONCLUSION: The most appropriate effect-site concentration of remifentanil for blunting hemodynamic responses by inhalation of high concentration desflurane is 4 ng/mL.
Adult ; Aged ; Androstanols/adverse effects/pharmacology ; Anesthetics/adverse effects/pharmacology ; Anesthetics, Inhalation/adverse effects/*pharmacology ; Blood Pressure/drug effects ; Etomidate/adverse effects/pharmacology ; Female ; Heart/*drug effects ; Heart Rate/drug effects ; Humans ; Isoflurane/adverse effects/*analogs & derivatives/pharmacology ; Male ; Middle Aged ; Piperidines/adverse effects/*therapeutic use ; Protective Agents/adverse effects/*therapeutic use

PURPOSE: Despite the fact that desflurane prolongs the QTC interval in humans, little is known about the mechanisms that underlie these actions. We investigated the effects of desflurane on action potential (AP) duration and underlying electrophysiological mechanisms in rat ventricular myocytes. MATERIALS AND METHODS: Rat ventricular myocytes were enzymatically isolated and studied at room temperature. AP was measured using a current clamp technique. The effects of 6% (0.78 mM) and 12% (1.23 mM) desflurane on transient outward K+ current (I(to)), sustained outward current (I(sus)), inward rectifier K+ current (I(KI)), and L-type Ca2+ current were determined using a whole cell voltage clamp. RESULTS: Desflurane prolonged AP duration, while the amplitude and resting membrane potential remained unchanged. Desflurane at 0.78 mM and 1.23 mM significantly reduced the peak I(to) by 20+/-8% and 32+/-7%, respectively, at +60 mV. Desflurane (1.23 mM) shifted the steady-state inactivation curve in a hyperpolarizing direction and accelerated inactivation of the current. While desflurane (1.23 mM) had no effects on I(sus) and I(KI), it reduced the L-type Ca2+ current by 40+/-6% (p<0.05). CONCLUSION: Clinically relevant concentrations of desflurane appear to prolong AP duration by suppressing Ito in rat ventricular myocytes.
Action Potentials/*drug effects ; Anesthetics, Inhalation/*pharmacology ; Animals ; Calcium Channels, L-Type/physiology ; Heart Conduction System/drug effects/physiology ; Heart Ventricles/drug effects ; Isoflurane/*analogs & derivatives/pharmacology ; Myocardial Contraction/*drug effects/physiology ; Myocytes, Cardiac/*drug effects/physiology ; Patch-Clamp Techniques ; Potassium Channels/physiology ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo investigate the effects of gestational isoflurane exposure on postnatal memory and learning and growth-associated protein-43 (GAP-43), neuropeptide Y(NPY) expression in the hippocampus of pups.

METHODSTwelve maternal Sprague-Dawley rats at gestation d 18(E18) were randomly divided into isoflurane group (n=6) and control group (n=6). Rats in isoflurane group were exposed to 1.3 % isoflurane for 6 h. For control group, animals breathed in 30 % oxygen and air mixed gas at the same condition. Spatial learning and memory of the offspring were determined with the Morris Water Maze(MWM) after postnatal 4 weeks. The changes of GAP-43 and NPY expression in the hippocampal CA1 region of the pups were determined by immunohistochemistry.

RESULTSIn MWM training, the escape latency to platform of the pups in isoflurane group was significantly longer, and the time spent in the third quadrant and times of original platform crossing were less than those of control animals (P<0.05). The number and optical density of GAP-43 and NPY positive neurons in the hippocampus of pups decreased significantly in the isoflurane group compared with the controls (P <0.01).

CONCLUSIONIsoflurane exposure in pregnant rats significantly impairs the spatial memory and learning of their pups at a juvenile age, which may be associated with the down-regulation of GAP-43 and NPY in the hippocampus.

Animals ; Female ; GAP-43 Protein ; metabolism ; Hippocampus ; drug effects ; metabolism ; Isoflurane ; pharmacology ; Maze Learning ; drug effects ; Neuropeptide Y ; metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects ; Rats ; Rats, Sprague-Dawley

The term "burst-suppression" is used to describe the electroencephalogram (EEG) pattern characterized by theta or delta waves, at times intermixed with faster waves, and intervening periods of relative quiescence. Burst-suppression pattern can reflect the seriously suppressed brain activity under deep anesthesia. To investigate the relationship between burst-suppression features and anesthetic concentration, we adopted four straightforward indexes, i. e., burst-suppression ratio (BSR), burst frequency, burst amplitude and suppression amplitude, and used them to analyze the EEG recordings in ten isoflurane-anesthetized rats. It was found that all the four burst-suppression indexes changed along with anesthetic concentration, that BSR and burst amplitude increased with higher concentration of isoflurane while burst frequency and suppression amplitude decreased, and that BSR was the most sensitive and consistent measurement to indicate isoflurane concentration so it constituted a valuable tool for timely evaluation of burst-suppression feature under deep anesthesia. The result also showed that the composition of carrier gas (i. e. pure oxygen vs. mixed oxygen) did not influence the effect of anesthesia significantly; and the four indexes of burst-suppression features could keep relatively stable within 60 min under the isoflurane concentration of 2%. The present study provides quantitative information of burst-suppression features under different anesthetic depth and may help to develop a clinically satisfied system that could quantify the characteristics of EEG and rigorously evaluate the cerebral state of patients.
Anesthesia, Inhalation ; Anesthetics, Inhalation ; pharmacology ; Animals ; Brain ; metabolism ; Electroencephalography ; drug effects ; Isoflurane ; pharmacology ; Male ; Rats ; Rats, Wistar ; Signal Processing, Computer-Assisted

OBJECTIVETo test the ability of isoflurane-induced preconditioning against oxygen and glucose deprivation (OGD) injury in vitro.

METHODSRat hippocampal slices were exposed to 1 volume percentage (vol%), 2vol% or 3vol% isoflurane respectively for 20 minutes under normoxic conditions (95% O₂/5% CO₂) once or twice (12 slices in each group) before OGD, with 15-minute washout after each exposure. During OGD experiments, hippocampus slices were bathed with artificial cerebrospinal fluid (ACSF) lacking glucose and perfused with 95% N₂ and 5% CO₂ for 14 minutes, followed by a 30-minute reperfusion in normal ACSF. The CA1 population spike (PS) was measured and used to quantify the degree of neuronal function recovery after OGD. To assess the role of mitogen-activated protein kinases (MAPKs) in isoflurane preconditioning, U0126, an inhibitor of extracellular signal-regulated protein kinase (ERK1/2), and SB203580, an inhibitor of p38 MAPK, were used before two periods of 3vol% isoflurane exposure.

RESULTSThe degree of neuronal function recovery of hippocampal slices exposed to 1vol%, 2vol%, or 3vol% isoflurane once was 41.88%±9.23%, 55.05% ± 11.02%, or 63.18% ± 10.82% respectively. Moreover, neuronal function recovery of hippocampal slices exposed to 1vol%, 2vol%, or 3vol% isoflurane twice was 53.75% ± 12.04%, 63.50% ± 11.06%, or 76.25% ± 12.25%, respectively. Isoflurane preconditioning increased the neuronal function recovery in a dose-dependent manner. U0126 blocked the preconditioning induced by dual exposure to 3vol% isoflurane (6.13% ± 1.56%, P < 0.01) and ERK1/2 activities.

CONCLUSIONSIsoflurane is capable of inducing preconditioning in hippocampal slices in vitro in a dose-dependent manner, and dual exposure to isoflurane with a lower concentration is more effective in triggering preconditioning than a single exposure. Isoflurane-induced neuroprotection might be involved with ERK1/2 activities.

Anesthetics, Inhalation ; pharmacology ; Animals ; Enzyme Inhibitors ; pharmacology ; Hippocampus ; cytology ; drug effects ; metabolism ; Hypoxia-Ischemia, Brain ; pathology ; Ischemic Preconditioning ; Isoflurane ; pharmacology ; MAP Kinase Signaling System ; physiology ; Mitogen-Activated Protein Kinase 1 ; metabolism ; Mitogen-Activated Protein Kinase 3 ; metabolism ; Neurons ; drug effects ; physiology ; Neuroprotective Agents ; pharmacology ; Rats ; p38 Mitogen-Activated Protein Kinases ; metabolism