Chronic Cocaine Administration Reversibly Increases Isoflurane Minimum Alveolar Concentration in Sheep

Background: Significant numbers of patients are seen for surgery and anesthesia with a history of chronic cocaine use. However, little is known about how cocaine use influences anesthetic physiology and pharmacology. The purpose of this study was to investigate the effect of chronic cocaine exposure on the minimum alveolar concentration (MAC) of isoflurane in sheep.

Methods: Isoflurane MAC was determined at baseline in 12 sheep using a standard protocol. The animals were subsequently exposed to cocaine for 18 days. Cocaine exposure consisted of a continuous subcutaneous cocaine infusion at 0.2 mg *symbol* kg sup -1 *symbol* h sup -1, twice daily 4-mg/kg intravenous boluses and repeated hourly 4 mg/kg cocaine boluses for 8 h on day 18. Minimum alveolar concentration determinations were repeated again on days 15, 18, and on day 28 after 10 days of cocaine abstinence.

Results: Compared to baseline MAC (1.53+/-0.12%) cocaine exposure significantly increased isoflurane MAC on days 15 (1.91 +/-0.14%) and 18 (1.78+/-0.13%; P = .005). MAC decreased after discontinuation of cocaine and was not different from baseline on day 28 (1.67+/-0.11).     

大鼠睾丸间质细胞移植的实验研究

目的:观察大鼠同种异体睾丸间质细胞移植后的血清睾酮变化水平。方法:采用Percoll方法分离提取SD大鼠两侧睾丸间质细胞,异体移植后每月测定受体血清睾酮1次,连续3次。结果:睾丸间质细胞移植后,受体动物血清睾酮含量逐渐升高。移植术后3个月,血清睾酮水平明显上升,与出生后2个月内的动物比较,差异具有显著性。结论:异体睾丸间质细胞移植治疗男性原发性性腺功能低下症可能具有良好的应用前景。     

The Preventive Effect of Dexmedetomidine Against Postoperative Intra-abdominal Adhesions in Rats

This study aimed to determine the possible preventive effects of dexmedetomidine on postoperative intra-abdominal adhesions. Dexmedetomidine is a highly selective and potent α₂ adrenergic agonist with sedative, analgesic, anxiolytic, sympatholytic, hemodynamic, and diuretic properties. In recent years, investigations have shown that dexmedetomidine possesses secondary antioxidant and also anti-inflammatory effects. Thirty Wistar albino male rats were randomized and divided into 3 groups of 10 animals each: group 1, sham-operated; group 2, cecal abrasion + peritoneal dissection; group 3, cecal abrasion + peritoneal dissection followed by daily intravenous injection of 10 μg/kg dexmedetomidine for 10 days. The animals were killed on postoperative day 21. Blood and cecal samples were taken for biochemical and histopathologic evaluation. In this study, biochemical and pathologic parameters were significantly better in the cecal abrasion + peritoneal dissection + dexmedetomidine group when compared with the cecal abrasion + peritoneal dissection group. Tissue malondialdehyde, myeloperoxidase, total sulfhydryl, and catalase were found to be significantly different between the cecal abrasion/peritoneal dissection + dexmedetomidine and the cecal abrasion/peritoneal dissection groups. Plasma malondialdehyde and total sulfhydryl values were also statistically different between these groups (P < 0.05). Statistical analyses of mean pathologic scores showed that the histopathologic damage in the cecal abrasion/peritoneal dissection + dexmedetomidine group was significantly less than the damage in the control group (P < 0.05 for all pathologic parameters). The results of this study show that dexmedetomidine had a significant preventive effect on postoperative intra-abdominal adhesions. We concluded that these effects might be due to antioxidant and anti-inflammatory activities.Key words: Intraabdominal adhesions, Dexmedetomidine, Oxidative stress, Antioxidant, Anti-inflammatoryIntraperitoneal adhesions are fibrous tissue bands inside the peritoneal cavity that occur as a consequence of inflammation or surgical manipulation.¹ Adhesions may remain silent or cause pathologic complications. Postsurgical adhesions severely affect the quality of life of millions of people worldwide, causing small-bowel obstruction, difficult reoperations, chronic abdominal and pelvic pain, and female infertility.² Although not commonly recognized, adhesions develop in up to 94% of patients after abdominal operations.³ The goal of adhesion prevention is to abolish or reduce the incidence, severity, extent, and consequences of adhesions while retaining normal healing and preventing infection.⁴ Prevention strategies can be grouped into 4 categories: general principles, surgical techniques, mechanical barriers, and chemical agents.⁵ Over the years, although numerous approaches have been used to prevent adhesions, none of the measures have proved to completely prevent adhesion development.Dexmedetomidine, which was approved by the US Food and Drug Administration in 1999 for the sedation of patients hospitalized in an intensive care setting, is a potent α₂ adrenergic agonist with sedative, analgesic, sympatholytic, hemodynamic, and diuretic properties.⁶ It has been increasingly used in clinical practice for anxiolysis, analgesia, sedation, and anesthetic sparing.⁷ Both in vivo and in vitro studies have demonstrated that dexmedetomidine has a protective effect against ischemia-reperfusion (I/R) injury of the heart, kidney, brain, and testis in animal models.⁸ In preclinical studies on oxidative stress and free radical formation, prophylactic administration of dexmedetomidine in various experimental I/R injury models has been found to protect tissues against the formation of free radicals after reperfusion. Moreover, preclinical studies have shown that dexmedetomidine could decrease systemic inflammation and increase the survival rate following sepsis caused by endotoxins.⁹ Whole studies have demonstrated that apart from its anesthetic property, dexmedetomidine possesses anti-inflammatory, antioxidant, and antiapoptotic effects.In the light of all these features of dexmedetomidine, the aim of this study was to investigate the effects of dexmedetomidine on experimental intraperitoneal adhesions and the possible mechanisms of these effects. To the best of our knowledge, the effect of dexmedetomidine on intra-abdominal adhesions has not been previously investigated in the literature.     

The Comparative Toxicity of Cocaine and Its Metabolites in Conscious Rats

Background: The metabolites of cocaine, benzoylecgonine and ecgonine methyl ester, have been considered pharmacologically inactive when administered systemically. However, recent in vitro studies suggest that this may not be true. The current study was designed to evaluate the systemic toxicity of cocaine and its metabolites when administered systemically to awake rats fitted with catheters for long-term monitoring.

Methods: Cocaine, norcocaine, cocaethylene, benzoylecgonine, and ecgonine methyl ester were infused intravenously to produce sequential behavioral alterations and central nervous system and cardiovascular toxic effects. Arterial blood pressure and heart rate were monitored continuously. Plasma and tissue samples were analyzed for all compounds by capillary gas chromatography-mass spectrometry.

Results: The dose of norcocaine necessary to produce toxic effects was smaller than that of cocaine and cocaethylene. Benzoylecgonine and ecgonine methyl ester did not produce toxic manifestations at infusion rates that produced toxicity in the cocaine, norcocaine, and cocaethylene groups. Furthermore, 30- and 60-fold higher doses of benzoylecgonine and ecgonine methyl ester, respectively, were necessary to produce only mild neurobehavioral changes. Benzoylecgonine was not lethal even at doses 100 times greater than cocaine.     

Swimming Training Increases the Post-Yield Energy of Bone in Young Male Rats

The purpose of this study is to investigate the effects of non-weight-bearing exercise on growing bone. Male Wistar rats (7 week-old) were assigned to one baseline control group, one control group and two swimming training groups, which were trained with 2 and 4% body-weight mass added, respectively. After an 8-week training period, three groups showed significant development compared to the baseline control group. Among the three 15-week-old groups, swimming-trained rats were lower in body weight (BW), densitometry and size-related measurements. In femoral biomechanical testing, swimming training groups were significantly lower in yield moment and ultimate moment, which may be due to a significantly lower long bone cross-sectional moment of inertia. However, the two swimming groups were higher in post-yield energy absorption and displacement. Further, in estimated tissue-level biomaterial properties, no differences were shown in yield stress, strain or toughness among the three groups. Using BW as a covariate, results of ANCOVA showed no differences in size-related parameters among the three groups, and some parameters were even higher in the two swimming groups. Regarding Pearson’s correlation, size-related parameters correlated well to BW and whole bone strength but not to tissue post-yield behaviors. In conclusion, when compared to age-matched control group, swimming rats showed lower bone strength and lower yield energy absolutely at the structural level, but similar yield stress and yield toughness at the tissue level. Moreover, swimming training benefited growing bone in post-yield behaviors. Further studies should investigate the parameters that contribute to this exercise-induced post-yield behavior.     

Thoracic Epidural Anesthesia Increases Mucosal Perfusion in Ileum of Rats

Background: Previous studies reported that thoracic epidural anesthesia (TEA) protected against a decrease in gastric intramucosal pH, suggesting that TEA increased gut mucosal perfusion. The current study examines the effects of TEA on ileal mucosa using intravital microscopy in anesthetized rats.

Methods: Nineteen rats were equipped with epidural catheters, with the tip placed at T7 through T9. Rats were anesthetized and mechanically ventilated. After midline abdominal incision, the ileum was prepared for intravital microscopy. Videomicroscopy on the ileal mucosa was performed before and after epidural infusion of 20 [mu]l of bupivacaine 0.4% (TEA group, n = 11 rats) or normal saline (control group, n = 8 rats). Microvascular blood flow in ileum mucosa was assessed offline using computerized image analysis.

Results: Control rats exhibited unchanged mean arterial pressure and microvascular perfusion. During TEA, mean arterial pressure was decreased compared with the control group (93 +/- 10 vs. 105 +/- 9 mmHg;P < 0.05). Epidural bupivacaine increased red cell velocity in terminal arterioles from 888 +/- 202 to 1,215 +/- 268 [mu]m/s (control, 793 +/- 250 to 741 +/- 195 [mu]m/s;P < 0.001 between groups). Because arteriolar diameter was not affected, this increase in red cell velocity may represent an increase in arteriolar blood flow. Total intercapillary area (inversely related to perfused capillary density) was unchanged, but for the TEA group the difference between total intercapillary area and the intercapillary area calculated for continuously perfused capillaries was decreased compared with the control group (16 +/- 12 vs. 40 +/- 19%;P < 0.001), indicating a decrease in intermittent (stop-and-go) blood flow in the villus microcirculation.     

Gastric Bypass Increases Ethanol and Water Consumption in Diet-Induced Obese Rats

Background

Roux-en-Y gastric bypass surgery (RYGB) is an effective treatment for morbid obesity. Increased alcohol abuse after RYGB resulted in recommendations to exclude patients with alcohol abuse histories from RYGB. The purpose of our study was to examine the effects of a RYGB on ethanol intake in diet-induced obese rats (high-fat diet).

Methods

The animals underwent RYGB and were habituated along with their sham-operated obese controls and with lean rats to increasing concentrations of ethanol in a two-bottle choice paradigm.

Results

RYGB rats' daily consumption of ethanol averaged 2?g/kg at 2?% habituation and 3.8?g/kg at 4?% habituation, twice as much as sham-operated obese controls and 50?% more than normal-diet lean controls. Obese controls drank on average 1?g/kg of ethanol (2 and 4?%), significantly less (50?%) than lean controls did. RYGB rats when given higher ethanol concentrations (6 and 8?%) or no ethanol drank significantly more water than lean and obese controls did (66 and 100?%, respectively), and their enhanced total fluid intake was associated with increased food intake, which was significantly higher than in lean (66?% more calories; food + alcohol) and obese controls (44?% more calories). The lower alcohol intake in the obese controls than in the lean rats suggests that obesity may interfere with alcohol's rewarding effects and RYGB may remove this protective effect.

Conclusions

The overall enhancement of consummatory behaviors (both ethanol and water) suggests that RYGB may facilitate alcohol consumption, which in vulnerable individuals could lead to abuse and addiction.     

Dexmedetomidine Does Not Alter the Sweating Threshold, But Comparably and Linearly Decreases the Vasoconstriction and Shivering Thresholds

Background: Clonidine decreases the vasoconstriction and shivering thresholds. It thus seems likely that the alpha2 agonist dexmedetomidine will also impair control of body temperature. Accordingly, the authors evaluated the dose-dependent effects of dexmedetomidine on the sweating, vasoconstriction, and shivering thresholds. They also measured the effects of dexmedetomidine on heart rate, blood pressures, and plasma catecholamine concentrations.

Methods: Nine male volunteers participated in this randomized, double-blind, cross-over protocol. The study drug was administered by computer-controlled infusion, targeting plasma dexmedetomidine concentrations of 0.0, 0.3, and 0.6 ng/ml. Each day, skin and core temperatures were increased to provoke sweating and then subsequently reduced to elicit vasoconstriction and shivering. Core-temperature thresholds were computed using established linear cutaneous contributions to control of sweating, vasoconstriction, and shivering. The dose-dependent effects of dexmedetomidine on thermoregulatory response thresholds were then determined using linear regression. Heart rate, arterial blood pressures, and plasma catecholamine concentrations were determined at baseline and at each threshold.

Results: Neither dexmedetomidine concentration increased the sweating threshold from control values. In contrast, dexmedetomidine administration reduced the vasoconstriction threshold by 1.61 +/- 0.80 [degree sign] Celsius [center dot] ng sup -1 [center dot] ml (mean +/- SD) and the shivering threshold by 2.40 +/- 0.90 [degree sign] Celsius [center dot] ng sup -1 [center dot] ml. Hemodynamic responses and catecholamine concentrations were reduced from baseline values, but they did not differ at the two tested dexmedetomidine doses.     

Fructose Administration Increases Intraoperative Core Temperature by Augmenting Both Metabolic Rate and the Vasoconstriction Threshold

Background: The authors tested the hypothesis that intravenous fructose ameliorates intraoperative hypothermia both by increasing metabolic rate and the vasoconstriction threshold (triggering core temperature).

Methods: Forty patients scheduled to undergo open abdominal surgery were divided into two equal groups and randomly assigned to intravenous fructose infusion (0.5 g [middle dot] kg-1 [middle dot] h-1 for 4 h, starting 3 h before induction of anesthesia and continuing for 4 h) or an equal volume of saline. Each treatment group was subdivided: Esophageal core temperature, thermoregulatory vasoconstriction, and plasma concentrations were determined in half, and oxygen consumption was determined in the remainder. Patients were monitored for 3 h after induction of anesthesia.

Results: Patient characteristics, anesthetic management, and circulatory data were similar in the four groups. Mean final core temperature (3 h after induction of anesthesia) was 35.7[degrees] +/- 0.4[degrees]C (mean +/- SD) in the fructose group and 35.1[degrees] +/- 0.4[degrees]C in the saline group (P = 0.001). The vasoconstriction threshold was greater in the fructose group (36.2[degrees] +/- 0.3[degrees]C) than in the saline group (35.6[degrees] +/- 0.3[degrees]C; P < 0.001). Oxygen consumption immediately before anesthesia induction in the fructose group (214 +/- 18 ml/min) was significantly greater than in the saline group (181 +/- 8 ml/min; P < 0.001). Oxygen consumption was 4.0 l greater in the fructose patients during 3 h of anesthesia; the predicted difference in mean body temperature based only on the difference in metabolic rates was thus only 0.4[degrees]C. Epinephrine, norepinephrine, and angiotensin II concentrations and plasma renin activity were similar in each treatment group.     

Angiotensin II Receptor Content Within the Circumventricular Organs Increases After Experimental Hydrocephalus in Rats

Summary  Hydrocephalus is known to cause various endocrinological abnormalities. These abnormalities are either though a direct effect on anterior hypothalamus or pituitary gland. However almost nothing is known about the effects of hydrocephalus on the intrinsic angiotensin system of the brain. The aim of this study is to investigate the effect of hydrocephalus on neurotransmitter-rich circumventricular organ systems. Such an effect was investigated by means of angiotensin receptor content in subfornical organ (SFO), organum vasculosum lamina terminalis (OVLT), area postrema (AP) and the median eminence (ME). Experimental hydrocephalus was created in rats by the intracisternal kaolin injection method as descibed by Shapiro et al.. The receptor content was measured at 4–6 weeks by in-vitro autoradiography method as descibed by Israel et al.. Angiotensin II receptor content in hydrocephalic animals was found to be statistically increased in SFO, OVLT and ME but not in AP when compared with the normal animals. Receptor content was found to have increased by 182.4% at SFO, 76.7% at ME, 7.7% at AP and 22.1% at OVLT after kaolin injection. These findings may indicate the possible role of CVO's on pathological conditions such as hydrocephalus.     

Recurrent Hypoxia in Rats during Development Increases Subsequent Respiratory Sensitivity to Fentanyl

Background: In children with a history of significant obstructive sleep apnea who undergo adenotonsillectomy, postsurgical administration of opiates has been alleged to be associated with an increased risk for respiratory complications, including respiratory depression. The authors hypothesize that this association is due to an effect of recurrent hypoxemia that accompanies more severe obstructive sleep apnea on altered responsiveness to subsequent exogenous opiates.

Methods: The current study was designed to test the effect of recurrent hypoxia in the developing rat on respiratory responses to subsequent administration of the [mu]-opioid agonist fentanyl. Rats were exposed to 12% oxygen balance nitrogen for 7 h daily for 17 days, from postnatal day 17 to 33, a period equivalent to human childhood. After 17 additional days in room air, rats were given a fentanyl dose and tested for their respiratory response to fentanyl using a whole body plethysmograph. Rats undergoing similar protocols without recurrent hypoxia served as controls.

Results: As compared with controls, rats preexposed to recurrent hypoxia displayed a more profound depression with fentanyl in minute ventilation, respiratory frequency, tidal volume, and tidal volume divided by inspiratory time that represents respiratory drive. These results indicated an increased respiratory sensitivity to fentanyl after recurrent hypoxia.     

The Protective Effects of Dexmedetomidine Preconditioning on Hepatic Ischemia/Reperfusion Injury in Rats

BackgroundIschemia/reperfusion (IR) injury is 1 of the major problems in liver surgery. This study aims to evaluate the histologic and biochemical effects of dexmedetomidine on ischemia/reperfusion injury in the liver of rats.MethodsTwenty-two Sprague-Dawley male rats were separated into 3 groups: group sham, IR (IR injury), and IR-D (IR with dexmedetomidine). Ischemia was induced for 45 minutes with portal clampage and the reperfusion period was 120 minutes. Group IR-D received 3 μg/kg of dexmedetomidine with loading for 10 minutes and then 3 μg/kg/h of dexmedetomidine was continuously injected intravenously 30 minutes before portal clampage. Biochemical factors (alanine aminotransferase and aspartate aminotransferase), variable cytokines (B cell lymphoma-2 (Bcl-2), Bax, caspase 3, caspase 8, nuclear factor-kappa B, interleukin (IL)-1β, IL-6, IL-10, mixed lineage kinase domain-like protein, and receptor-interacting protein kinase-3), and histologic findings were investigated.ResultsDexmedetomidine preconditioning significantly suppressed the histologic damage. In the IR-D group, the expression of IL-6 was decreased and the Bcl-2 was increased when compared with the IR group.ConclusionDexmedetomidine suppresses hepatic IR injury and the protective mechanism appears to involve the decrease of IL-6 and upregulation of Bcl-2 expression, which result in the attenuation of inflammatory response and the inhibition of apoptosis.     

The Role of Dexmedetomidine in Hepatic Ischemia-Reperfusion Injury Via a Nitric Oxide-Dependent Mechanism in Rats

BackgroundDexmedetomidine is known to protect against ischemia-reperfusion (IR) in various organs; however, the mechanisms of dexmedetomidine in the liver remain unclear. We investigated whether dexmedetomidine preconditioning leads to hepatic protection and whether nitric oxide was associated with this protective mechanism by employing N-nitro-l-arginine methyl ester (l-NAME), a nitrous oxide synthase inhibitor.MethodsExperiment 1 included 24 rats in 4 groups: sham, IR, 30 μg/kg of dexmedetomidine, and 50 μg/kg of dexmedetomidine. Experiment 2 included 36 rats in 6 groups: IR, 50 μg/kg of dexmedetomidine, 10 mg/kg of l-NAME, 10 mg/kg of l-NAME + 50 μg/kg of dexmedetomidine, 30 of mg/kg l-NAME, and 30 mg/kg of l-NAME + 50 μg/kg of dexmedetomidine. All drugs were administered intraperitoneally. The levels of serum transaminases, malondialdehyde, superoxide dismutase, tumor necrosis factor-α, nuclear factor-κB, and c-Jun N-terminal kinase were measured 6 hours after hepatic surgery.ResultsDexmedetomidine demonstrated a dose-dependent decrease in serum transaminase levels. The 50-μg/kg dexmedetomidine group showed a significant decrease in malondialdehyde levels (P = .002), increase in superoxide dismutase levels (P = .002), and a significantly lower level of phosphorylated tumor necrosis factor-α, nuclear factor-κB, and c-Jun N-terminal kinase (P = .002, respectively) compared with the IR injury group. These protective effects of dexmedetomidine were partially reversed by pretreatment with l-NAME (P < .01 for 20 and 30 mg/kg of l-NAME).ConclusionIn hepatic IR injury, dexmedetomidine might protect the liver via antioxidative and anti-inflammatory responses, and nitric oxide production could play a role in these protective mechanisms.     

Fibroblast Growth Factor 21 Action in the Brain Increases Energy Expenditure and Insulin Sensitivity in Obese Rats

OBJECTIVE

The hormone fibroblast growth factor 21 (FGF21) exerts diverse, beneficial effects on energy balance and insulin sensitivity when administered systemically to rodents with diet-induced obesity (DIO). The current studies investigate whether central FGF21 treatment recapitulates these effects.

RESEARCH DESIGN AND METHODS

After preliminary dose-finding studies, either saline vehicle or recombinant human FGF21 (0.4 μg/day) was infused continuously for 2 weeks into the lateral cerebral ventricle of male Wistar rats rendered obese by high-fat feeding. Study end points included measures of energy balance (body weight, body composition, food intake, energy expenditure, and circulating and hepatic lipids) and glucose metabolism (insulin tolerance test, euglycemic-hyperinsulinemic clamp, and hepatic expression of genes involved in glucose metabolism).

RESULTS

Compared with vehicle, continuous intracerebroventricular infusion of FGF21 increased both food intake and energy expenditure in rats with DIO, such that neither body weight nor body composition was altered. Despite unchanged body fat content, rats treated with intracerebroventricular FGF21 displayed a robust increase of insulin sensitivity due to increased insulin-induced suppression of both hepatic glucose production and gluconeogenic gene expression, with no change of glucose utilization.

CONCLUSIONS

FGF21 action in the brain increases hepatic insulin sensitivity and metabolic rate in rats with DIO. These findings identify the central nervous system as a potentially important target for the beneficial effects of FGF21 in the treatment of diabetes and obesity.Fibroblast growth factor (FGF) 21 is a FGF family member produced by liver and other tissues that plays an important role in the control of energy balance and glucose metabolism (1). In addition, when administered at pharmacologic doses, FGF21 induces wide-ranging beneficial effects in animal models of obesity and diabetes (2). Specifically, in obese rodents, pharmacologic FGF21 treatment reduces body fat content and improves glucose tolerance, insulin sensitivity, and lipid parameters (both circulating and hepatic) (3–5). Consequently, FGF21 has emerged as a novel target for the treatment of obesity and associated metabolic dysfunction (2). FGF21-mediated weight loss appears to involve increased fat oxidation and metabolic rate with no change of food intake (3). Whether the insulin-sensitizing effects of FGF21 are dependent on reduced body fat or involve other, independent mechanisms has not been established. Interestingly, these insulin-sensitizing effects are attributable largely to enhanced insulin action in the liver (6), and yet recent evidence suggests that FGF21 regulates hepatic substrate metabolism via a mechanism that cannot be explained by a direct effect on hepatocytes (6).The diverse and indirect nature of these pharmacologic effects raises the possibility that at least some actions of FGF21 might be mediated centrally. This hypothesis is consistent with growing evidence implicating the hypothalamus and other regions of the central nervous system (CNS) in adaptive adjustments of insulin sensitivity triggered by changing levels of key hormones and nutrients in the circulation (7). To determine whether metabolic effects observed during systemic FGF21 treatment might involve a central site of action, we infused FGF21 into the brain of diet-induced obesity (DIO) rats at a low dose that does not leak into the circulation in detectable amounts.