高压氧对肾脏缺血再灌注损伤的保护作用及其机制研究

目的:观察高压氧(hyperbaric oxygen,HBO)对肾脏缺血再灌注损伤的保护作用并探讨其作用机制.方法:56只SD大鼠被随机分为三组,假手术组(n=8);I/R组(n=24),夹闭双肾动脉45分钟后恢复血流灌注;I/R+HBO组(n=24),夹闭双肾动脉45分钟并在恢复血流后1h、24 h、48 h行HBO治疗,每次HBO后采血并取双肾,比色法测定血浆尿素氮(BUN)、肌酐(Cr)值,原位末端标记(TUNEL)法检测肾小管上皮细胞凋亡情况,实时定量PCR法检测促凋亡基因Bax的mRNA含量.结果:与sham组(BUN值为9.563± 1.384 mmol/L;Cr值为45.912±2.685 mmo1/L,TUNEL值为2.088％)比较,I/R组大鼠再灌注1小时尿素氮(12.5±1.487 mmol/L)和血肌酐水平(51.388±3.092 mmol/L)升高,但差异无统计学意义,而TUNEL阳性细胞数(9.775％)和Bax的mR-NA(3.219± 0.427)表达水平均显著升高(P＜0.05),再灌注24小时及48小时后尿素氮(28.087± 2.012 mmol/L、41.225± 1.397mmol/L)和血肌酐(241.75± 11.853 mmol/L、278.75± 12.578 mmol/L)水平、TUNEL阳性细胞数(12.512％、14.413％)和Bax的mRNA(5.541±0.227、6.407± 0.291)表达水平均显著升高(P＜0.05);而HBO治疗可显著降低再灌注24小时及48小时的大鼠尿素氮(14.15±1.397 mmol/L、25.962± 2.497 mmol/L)和血肌酐(146.375± 8.782 mmolL、210.125± 11.519 mmol/L)水平(P＜0.05),但仍显著高于假手术组(P＜0.05).结论:HBO治疗可以改善I/R后肾功能,其作用机制可能与在早期明显降低Bax的mRNA表达,减轻肾小管上皮细胞凋亡有关.     

Beneficial effect of verapamil in ischemic acute renal failure in the rat

To investigate the possible protective effect of Ca2+ blockers in ischemic acute renal failure (ARF), verapamil, in a dose of 10 micrograms/kg body wt/min was administered for 100 min, starting 15 min before the total occlusion of the left renal artery after right nephrectomy in rats. Mean 24-hr creatinine clearance, blood urea, and serum creatinine levels, 24 hr after declamping, were used as a measure of kidney function. These values which were 135 +/- 1.9 microliter/min, 231 +/- 22 mg%, and 2.25 +/- 0.22 mg%, respectively, in the untreated rats, were found to be significantly different, i.e., 326.3 +/- 33.2 microliter/min, P less than 0.001, 112 +/- 25 mg%, P less than 0.001, and 1.26 +/- 0.28 mg%, P less than 0.01, respectively, in the verapamil-treated animals. Increased 24-hr total urine creatinine, sodium, osmolality, and a lower fractional excretion of sodium were also observed in the verapamil-treated rats with ARF. The combination of propranolol 1 mg/kg body wt/min and verapamil 10 micrograms/kg body wt/min for 100 min had no additive effect on renal function. In another group of ARF rats in which verapamil was started after declamping, no alleviating effect was observed. It is concluded that verapamil, an inhibitor of cellular membrane transport, when given prior to the renal ischemia, offers a partial but significant protection in this model of ischemic ARF.     

Free radical generation in the brain precedes hyperbaric oxygen-induced convulsions.

We tested the hypothesis that hyperbaric oxygenation (HBO) generates free radicals in the brain before the onset of neurological manifestations of central nervous system (CNS) oxygen poisoning. Chronically cannulated, conscious rats were individually placed in a transparent pressure chamber and exposed to (1) 5 atmospheres absolute (ATA) oxygen for 15 min (n = 4); (2) 5 ATA oxygen for 30 min (n = 5), during which no visible convulsions occurred; (3) 5 ATA oxygen for 30 min with recurrent convulsions (n = 6); (4) 5 ATA oxygen until the appearance of the first visible convulsions (n = 5); (5) 4 ATA oxygen for 60 min during which no convulsions occurred (n = 5); and (6) 5 ATA air for 30 min (n = 5, controls). Immediately before compression, 1 mL of 0.1 M of alpha-phenyl-N-tert-butyl nitrone (PBN) was administered intravenously (iv) for spin trapping. At the termination of each experiment, rats were euthanized by pentobarbital iv and decompressed within 1 min. Brains were rapidly removed for preparation of lipid extracts (Folch). The presence of PBN spin adducts in the lipid extracts was examined by electron spin resonance (ESR) spectroscopy. ESR spectra from unconvulsed rats exposed to 5 ATA oxygen for 30 min revealed both oxygen-centered and carbon-centered PBN spin adducts in three of the five brains. One of the five rats in this group showed an ascorbyl signal in the ESR spectrum.(ABSTRACT TRUNCATED AT 250 WORDS)     

丁咯地尔和α-硫辛酸对糖尿病大鼠肾功能的保护作用研究

目的：研究丁咯地尔和α-硫辛酸（ALA）对糖尿病（DM）大鼠肾功能的保护作用。方法：雄性SD大鼠用链脲佐菌素（60mg/kg）腹腔注射诱导DM。大鼠随机分为健康组（NC）、DM组（DMC）、DM＋ALA组（ALA组）、DM＋丁咯地尔组（丁咯地尔组）。ALA组和丁咯地尔组每天给予ALA100mg／kg灌胃和丁咯地尔（0．1g／kg）腹腔注射,NC组和DMC组大鼠给予等量生理盐水每日灌胃。干预4周后,测观察治疗后大鼠血糖、尿素氮、血肌苷,内生肌苷清除率、24小时尿蛋白排泄率,比色法检测血清抗氧化酶和丙二醛（MDA）含量。结果：①丁咯地尔和α-硫辛酸降低糖尿病大鼠的尿素氮、血肌苷、24h尿白蛋白排泄率、丙二醛,增加超氧化物歧化酶②两种药物联合用药具有协同作用。结论：丁咯地尔和ALA可能通过抑制机体氧化应激水平,减低早期DM大鼠肾脏损害。     

Nitric oxide and cerebral blood flow responses to hyperbaric oxygen.

We have tested the hypothesis that cerebral nitric oxide (NO) production is involved in hyperbaric O(2) (HBO(2)) neurotoxicity. Regional cerebral blood flow (rCBF) and electroencephalogram (EEG) were measured in anesthetized rats during O(2) exposure to 1, 3, 4, and 5 ATA with or without administration of the NO synthase inhibitor (N(omega)-nitro-L-arginine methyl ester), L-arginine, NO donors, or the N-methyl-D-aspartate receptor inhibitor MK-801. After 30 min of O(2) exposure at 3 and 4 ATA, rCBF decreased by 26-39% and by 37-43%, respectively, and was sustained for 75 min. At 5 ATA, rCBF decreased over 30 min in the substantia nigra by one-third but, thereafter, gradually returned to preexposure levels, preceding the onset of EEG spiking activity. Rats pretreated with N(omega)-nitro-L-arginine methyl ester and exposed to HBO(2) at 5 ATA maintained a low rCBF. MK-801 did not alter the cerebrovascular responses to HBO(2) at 5 ATA but prevented the EEG spikes. NO donors increased rCBF in control rats but were ineffective during HBO(2) exposures. The data provide evidence that relative lack of NO activity contributes to decreased rCBF under HBO(2), but, as exposure time is prolonged, NO production increases and augments rCBF in anticipation of neuronal excitation.     

Preventive effects of hyperbaric oxygen treatment on glycerol-induced myoglobinuric acute renal failure in rats

Myoglobinuric acute renal failure (ARF) is a uremic syndrome caused by traumatic or non-traumatic skeletal muscle breakdown and intracellular elements that are released into the bloodstream. We hypothesized that hyperbaric oxygen (HBO) therapy could be beneficial in the treatment of myoglobinuric ARF caused by rhabdomyolysis. A total of 32 rats were used in the study. The rats were divided into four groups: control, control+hyperbaric oxygen (control+HBO), ARF, and ARF+hyperbaric oxygen (ARF+HBO). Glycerol (8 ml/kg) was injected into the hind legs of each of the rats in ARF and ARF+HBO groups. 2.5 atmospheric absolute HBO was applied to the rats in the control+HBO and ARF+HBO groups for 90 min on two consecutive days. Plasma urea, creatinine, sodium, potassium, calcium, aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase, creatinine kinase and urine creatinine and sodium were examined. Creatinine clearance and fractional sodium excretion could then be calculated. Superoxide dismutase, catalase, glutathione and malondialdehyde (MDA) levels were assessed in renal tissue. Tissue samples were evaluated by Hematoxylin-eosin, PCNA and TUNEL staining histopathologically. MDA levels were found to be significantly decreased whereas SOD and CAT were twofold higher in the ARF+HBO group compared to the ARF group. Renal function tests were ameliorated by HBO therapy. Semiquantitative evaluation of histopathological findings indicated that necrosis and cast formation was decreased by HBO therapy and TUNEL staining showed that apoptosis was inhibited. PCNA staining showed that HBO therapy did not increase regeneration. Ultimately, we conclude that, in accordance with our hypothesis, HBO could be beneficial in the treatment of myoglobinuric ARF.     

Heparin effects during hyperbaric oxygenation in rats

The effects of heparin were studied concurrently with development of neurological and respiratory signs of oxygen toxicity in awake unrestrained rats exposed to 3 atmosphere absolute (ATA) oxygen. The modification of the early electrophysiological manifestations of CNS oxygen toxicity by heparin in the absence of obvious signs of pulmonary oxygen toxicity was also determined at 5 ATA oxygen by electrocorticographic recording. The femoral artery of all rats was cannulated two days before the exposures to hyperbaric oxygenation (HBO), and the effect of intraarterial injection of 10 U/100g/3h heparin or an equivalent volume of saline was studied in experimental and control rats, respectively. In rats exposed to 3 ATA oxygen, the latency of the onset of the first oxygen-induced convulsions, the time interval between the first convulsion and death, and the survival time were measured. Exposure to 5 ATA oxygen was continued until the onset of the first preconvulsive paroxysmal electrical discharges (FED), considered to be an early electrophysiological indicator of CNS oxygen toxicity. The onset of convulsions was slightly delayed in heparin-treated rats exposed to 3 ATA oxygen, and the time interval between the first convulsions and death was significantly reduced in heparinized rats. No difference in survival time between heparin- and saline-treated rats was observed. Heparin significantly delayed the time of onset of the FED during exposure to 5 ATA oxygen. Gross postmortem examination of the lungs and internal organs revealed only a bloody froth in the trachea of the heparin-treated rats exposed to 3 ATA oxygen. It is concluded that the heparin-hyperoxic interaction during development of pulmonary and CNS oxygen toxicity may be related to the anticoagulant effect of heparin and hyperoxic-induced pulmonary lesions.     

HBO suppresses Nogo-A,Ng-R,or RhoA expression in the cerebral cortex after global ischemia

Nogo-A, a myelin-associated neurite outgrowth inhibitory protein, binds with the Ng-R receptor to activate RhoA intracellular signals and inhibit the plasticity after CNS injury. We evaluated the effect of hyperbaric oxygen (HBO) on the expression of Nogo-A, Ng-R, and RhoA after transient global ischemia in a rat 2 vessel occlusion global ischemic model. Male SD rats (n=78) were randomly divided into 13 groups: 1 sham group, 6 groups of global ischemia, and 6 groups of HBO treatment after global ischemia. HBO (3ATA) was applied for 2 hr at 1 hr after global ischemia. Rats were sacrificed at 6, 12, 24, 48, and 96 hr and 7 days. Global ischemia (10 min) produced a marked increase of Nogo-A/B, Nogo-A, Ng-R, and RhoA expression. Immunohistochemistry showed increased Nogo-A/B and Nogo-A located in the myelin sheath of ischemic brain cortex. Ng-R expressed on the surface of neurons and their processes, and RhoA expressed inside the cytoplasm of neurons in ischemic brain. HBO significantly reduced neurological injury, decreased the levels of Nogo-A, Ng-R, and RhoA in ischemic injured cortex (p<0.05).     

Alteration of Striatal Dopamine Levels Under Various Partial Pressure of Oxygen in Pre-convulsive and Convulsive Phases in Freely-Moving rats

The purpose of this study was to investigate the change in the striatal dopamine (DA) level in freely-moving rat exposed to different partial pressure of oxygen (from 1 to 5 ATA). Some works have suggested that DA release by the substantia nigra pars compacta (SNc) neurons in the striatum could be disturbed by hyperbaric oxygen (HBO) exposure, altering therefore the basal ganglia activity. Such changes could result in a change in glutamatergic and GABAergic control of the dopaminergic neurons into the SNc. Such alterations could provide more information about the oxygen-induced seizures observed at 5 ATA in rat. DA-sensitive electrodes were implanted into the striatum under general anesthesia. After 1 week rest, awaked rats were exposed to oxygen–nitrogen mixture at a partial pressure of oxygen of 1, 2, 3, 4 and 5 ATA. DA level was monitored continuously (every 3 min) by in vivo voltammetry before and during HBO exposure. HBO induced a decrease in DA level in relationship to the increase in partial pressure of oxygen from 1 ATA to 4 ATA (?15 % at 1 ATA, ?30 % at 2 ATA, ?40 % at 3 ATA, ?45 % at 4 ATA), without signs of oxygen toxicity. At 5 ATA, DA level strongly decreases (?75 %) before seizure which occurred after 27 min ± 7 HBO exposure. After the epileptic seizure the decrease in DA level disappeared. These changes and the biphasic effect of HBO were discussed in function of HBO action on neurochemical regulations of the nigro striatal pathway.     

Nitric oxide-mediated central sympathetic excitation promotes CNS and pulmonary O2 toxicity

In hyperbaric oxygen (HBO(2)) at or above 3 atmospheres absolute (ATA), autonomic pathways link central nervous system (CNS) oxygen toxicity to pulmonary damage, possibly through a paradoxical and poorly characterized relationship between central nitric oxide production and sympathetic outflow. To investigate this possibility, we assessed sympathetic discharges, catecholamine release, cardiopulmonary hemodynamics, and lung damage in rats exposed to oxygen at 5 or 6 ATA. Before HBO(2) exposure, either a selective inhibitor of neuronal nitric oxide synthase (NOS) or a nonselective NOS inhibitor was injected directly into the cerebral ventricles to minimize effects on the lung, heart, and peripheral circulation. Experiments were performed on both anesthetized and conscious rats to differentiate responses to HBO(2) from the effects of anesthesia. EEG spikes, markers of CNS toxicity in anesthetized animals, were approximately four times as likely to develop in control rats than in animals with central NOS inhibition. In inhibitor-treated animals, autonomic discharges, cardiovascular pressures, catecholamine release, and cerebral blood flow all remained below baseline throughout exposure to HBO(2). In control animals, however, initial declines in these parameters were followed by significant increases above their baselines. In awake animals, central NOS inhibition significantly decreased the incidence of clonic-tonic convulsions or delayed their onset, compared with controls. The novel findings of this study are that NO produced by nNOS in the periventricular regions of the brain plays a critical role in the events leading to both CNS toxicity in HBO(2) and to the associated sympathetic hyperactivation involved in pulmonary injury.     

Abnormal renal response to twenty-four-hour dehydration and fasting in Nagase analbuminemic rats.

We assessed renal function in fasting adult Nagase analbuminemic rats (NAR). Sodium output in male and female NAR was 68% and 46%, respectively, of the output of age- and sex-matched normal Sprague-Dawley (SD) rats. Potassium excretion was significantly greater in female NAR but there was no difference between male NAR and SD rats. The renal clearances of urea and creatinine were reduced in NAR with corresponding increases in plasma concentrations; however, the urea and creatinine concentrations were not different in plasma samples taken from normally fed and hydrated SD and NAR rats. Exchangeable body sodium and sodium space was significantly larger in normally fed and hydrated NAR than in SD but there were no differences in plasma sodium concentrations or plasma volumes. Although plasma concentrations of albumin in NAR were only about 0.07% of the concentration in SD rats, the renal clearance of albumin in NAR was threefold greater. Kidney weights in NAR were 10 to 16% less than in SD rats but liver weights were 22 to 42% greater. Clearly, renal function was markedly abnormal in Nagase rats during a 24-hour fast.     

Hyperbaric oxygen improves contractile function of regenerating rat skeletal muscle after myotoxic injury.

There is growing interest in hyperbaric oxygen (HBO) as an adjunctive treatment for muscle injuries. This experiment tested the hypothesis that periodic inhalation of HBO hastens the functional recovery and myofiber regeneration of skeletal muscle after myotoxic injury. Injection of the rat extensor digitorum longus (EDL) muscle with bupivacaine hydrochloride causes muscle degeneration. After injection, rats breathed air with or without periodic HBO [100% O(2) at either 2 or 3 atmospheres absolute (ATA)]. In vitro maximum isometric tetanic force of injured EDL muscles and regenerating myofiber size were unchanged between 2 ATA HBO-treated and untreated rats at 14 days postinjury but were approximately 11 and approximately 19% greater, respectively, in HBO-treated rats at 25 days postinjury. Maximum isometric tetanic force of injured muscles was approximately 27% greater, and regenerating myofibers were approximately 41% larger, in 3 ATA HBO-treated rats compared with untreated rats at 14 days postinjury. These findings demonstrate that periodic HBO inhalation increases maximum force-producing capacity and enhances myofiber growth in regenerating skeletal muscle after myotoxic injury with greater effect at 3 than at 2 ATA.     

艾塞那肽对糖尿病大鼠肾脏损伤的保护作用

目的：探讨GLP-1类似物艾塞那肽（exenatide）对链脲佐菌素诱导的糖尿病大鼠肾脏的保护作用。方法：SD大鼠随机分为正常组（NC组,n=8）和模型组;模型组给予高脂高糖饲料,喂养4周后腹腔注射STZ（30 mg·kg^-1）建模,72 h后以血糖≥ 16.7 mmol·L^-1为糖尿病成模标准,将成模大鼠随机分为糖尿病对照组（DM组,n=10）、3 μg·kg^-1艾塞那肽干预（Ex-1）组和6μg·kg^-1艾塞那肽干预（Ex-2）组;艾塞那肽组连续皮下注射艾塞那肽（bid）12周,NC组和DM组注射等容积溶剂;测定各组大鼠糖脂代谢变化和肾功能指标如血肌酐（Scr）、尿肌酐（Ucr）、尿素氮（BUN）、24 h尿微量白蛋白排出率（24 h UMA）并计算肌酐清除率（Ccr）;测定肾组织氧化应激指标超氧化物歧化酶（SOD）、丙二醛（MDA）和谷胱甘肽过氧化物酶（GSH-Px）;HE染色观察肾组织病理形态及ELISA法测定肾组织糖基化终末产物AGEs水平。结果：与糖尿病组相比,艾塞那肽可明显改善糖尿病大鼠糖脂代谢,血糖、糖基化血红蛋白（HbAlc）、甘油三脂及胆固醇值均下降（P < 0.05）,肾功能指标明显好转（P < 0.05）且肌酐清除率下降（P < 0.05）,提示肾小球高滤过状态;同时改善糖尿病引起的肾组织病理结构改变,AGEs浓度下降（P < 0.05）,氧化应激指标SOD和GSH-Px活力升高,MDA含量降低（P < 0.05）。结论：艾塞那肽具有肾脏保护作用,其机制可能与抑制糖尿病大鼠肾组织的AGEs生成和改善氧化应激有关。     

Exposure to Hyperbaric Oxygen Intensified Vancomycin-Induced Nephrotoxicity in Rats

It has been suggested that oxidative stress is a potential mechanism for vancomycin-induced nephrotoxicity and hyperbaric oxygen therapy (HBO) has been shown to be effective in treating renal toxicity that has been pharmacologically induced in animal models. The aim of this study was to investigate the effect of HBO therapy on vancomycin-induced nephrotoxicity in rats. The study group comprised 36 Sprague Dawley male rats. We treated 30 with 500 mg/kg of intraperitoneal vancomycin once a day for 7 days. Half of these rats received a daily 1-hour treatment with HBO at 2 Atmospheres (ATM) on the same 7 days and formed the HBO+ group. The other 15 subjects received no HBO treatment (HBO- group). The remaining six rats served as the control group, three received HBO treatments alone and no treatment was administered to the other three rats. Laboratory results were obtained on day 8 and the intervention and control groups were compared. Rats in the HBO+ group gained less weight than the HBO- group (11.6 grams vs 22.6 grams; P = 0,008) and had significantly higher serum blood urea nitrogen (99.6 vs 52.6 mg/dL; P<0.001), serum creatinine (0.42 vs 0.16 mg/dL; P = 0.001) and magnesium (3.6 vs 3.1mg/dL; P = 0.014). The vancomycin blood levels were also higher in the HBO+ group (27.8 vs 6.7 μg/mL; P = 0.078). There were no pathological kidney changes in the control group. All the kidneys from the treated groups (vancomycin +HBO and vancomycin HBO-) showed moderate to severe histopathological changes with no statistical significance between them. This study demonstrated that exposure to hyperbaric oxygen intensified vancomycin-induced nephrotoxicity in rats.     

Protective effects of hydralazine in a renal ischemia model in the rat

Renal ischemia was produced in anesthetized rats by a bilateral ligation of the renal artery, vein, and ureter. Pretreatment with hydralazine (0.3-10.0 mg/kg i.v.) resulted in a dose dependent reduction in elevated plasma creatinine levels 24 hr after a 60 min ischemic episode, indicating a protective effect on post-ischemic renal function. Hydralazine (3.0 mg/kg, i.v.) produced a fall in arterial blood pressure and exaggerated and/or extended post-ischemic depressions in renal blood flow, renal transport activity (in vitro para-aminohippurate uptake) and renal ATP levels. These results indicate that the hypotensive activity of hydralazine may have indirectly benefited the post-ischemic kidney by prolonging a relative anoxic condition which possibly allowed renal cells to recover under conditions where minimal tubular activity was present.     

6周大强度训练对大鼠肾功能的影响及其机制

目的：研究6周大强度训练对大鼠肾功能影响及运动性蛋白尿的机制。方法：6周龄SD雄性大鼠36只随机分为：安静对照组（C组,n=12）和大强度训练组（M组,n=24）。大鼠适应性饲养4 d后,C组不进行任何运动,M组采用6周递增负荷游泳训练。每周训练6 d,每天1次。第4周起开始负重（体重的1%）并逐渐递增（体重的6%）。各组大鼠末次训练结束后30 min取单次尿,24 h后腹主静脉取血,取双侧肾脏待测。HE染色观察肾脏肾小球结构,酶联免疫吸附法测定尿总蛋白、尿微量白蛋白、中性粒细胞明胶酶相关脂质运载蛋白,碱性苦味酸法测试尿肌酐,比色法测定血清肌酐、尿素氮,蛋白质免疫印迹法检测肾组织Nephrin蛋白表达量,放射免疫法测试血清睾酮、皮质酮和肾组织及血液中肾素-血管紧张素系统相关指标变化。结果：与C组比较,M组血清睾酮/皮质酮显著降低（P<0.01）;尿液蛋白总量、微量白蛋白、微量白蛋白与肌酐比值、中性粒细胞明胶酶相关脂质运载蛋白、血清尿素氮、肌酐均显著升高（P<0.01）;肾小球结构明显改变,且Paller评分明显增高（P<0.01）;肾组织Nephrin蛋白表达量明显降低（P<0.01）;肾脏内部与循环血液中肾素活性、血管紧张素Ⅱ显著增高（P<0.01）。结论：6周大强度训练对大鼠肾功能影响及运动性蛋白尿的机制可能为过度训练诱导肾脏内部及循环系统中肾素-血管紧张素系统持续兴奋,并下调Nephrin蛋白的表达,进而导致肾脏结构与功能异常,出现蛋白尿。     

Hyperoxic vasoconstriction in the brain is realized by inactivation of nitric oxide by superoxide anions

We tested a hypothesis that the cerebral blood flow (CBF) is reduced at hyperbaric oxygen due to inactivation of nitric oxide (NO) by superoxide anions (O2). In our experiments, the CBF was measured under hyperbaric oxygenation (HBO) 4ATA after inhibition of NO synthesis and inactivation of O2. The CBF was reduced at HBO exposure. Inhibition of NO--synthase type I and III (NOS) by L-NAME in the air caused the same decreasing of the CBF as at 4 ATA HBO. Hyperbaric vasoconstriction was diminished after NOS inhibition. Intravenous injection of superoxide dismutase (CuZn SOD) increased the CBF in the air and HBO exposure. This effect disappeared at preliminary NOS inhibition. These data suggest that inactivation of NO by O2 is a more effective mechanism of HBO vasoconstriction.     

Hyperoxic exposure affects the ventilatory response to hypoxia in awake rats

We tested whether hyperbaric O2 (HBO) has an adverse effect on the hypoxic ventilatory drive. Four groups of rats were exposed for 550 min to O2 at 1.67, 1.90, and 2.15 ATA and to air at 1.90 ATA, respectively. Ventilatory parameters (frequency, tidal volume, and minute ventilation) were measured using whole-body plethysmography, before the hyperbaric exposure, immediately after the exposure, and up to 20 days after the exposure. Resting ventilation was not affected after exposure at 1.90 ATA to air or at 1.67 ATA to O2. HBO at 1.90 and 2.15 ATA caused a reduction of frequency and an elevation of tidal volume at different inspired gases: air, 5% CO2 balance O2, 80% O2, and 4.5% O2. However, minute ventilation on the day after the hyperoxic exposure was not different from the control at either air, 5% CO2, or 80% O2 but was markedly attenuated on the first three breaths at 4.5% O2. The hypoxic ventilation decreased to 48 +/- 13 (SD) and 32 + 11% after 1.90 and 2.15 ATA, respectively. The ventilatory parameters recovered in the days after HBO. We conclude that HBO reversibly depresses the hypoxic ventilatory drive, most probably by a direct effect on the carotid O2 chemoreceptors.     

Carvedilol: a beta blocker with antioxidant property protects against gentamicin-induced nephrotoxicity in rats

Gentamicin is an antibiotic effective against gram negative infections, whose clinical use is limited by its nephrotoxicity. Since the pathogenesis of gentamicin-induced nephrotoxicity involves oxygen free radicals, the antioxidant carvedilol may protect against gentamicin-induced renal toxicity. We therefore tested this hypothesis using a rat model of gentamicin nephrotoxicity. Carvedilol (2 mg/kg) was administered intraperitoneally 3 days before and 8 days concurrently with gentamicin (80 mg/kg BW). Estimations of urine creatinine, glucose, blood urea, serum creatinine, plasma and kidney tissue malondialdehyde (MDA) were carried out, after the last dose of gentamicin. Kidneys were also examined for morphological changes. Gentamicin caused marked nephrotoxicity as evidenced by increase in blood urea, serum creatinine and decreased in creatinine clearance. Blood urea and serum creatinine was increased by 883% and 480% respectively with gentamicin compared to control. Carvedilol protected the rats from gentamicin induced nephrotoxicity. Rise in blood urea, serum creatinine and decrease in creatinine clearance was significantly prevented by carvedilol. There was 190% and 377% rise in plasma and kidney tissue MDA with gentamicin. Carvedilol prevented the gentamicin induced rise in both plasma and kidney tissue MDA. Kidney from gentamicin treated rats, histologically showed necrosis and desquamation of tubular epithelial cells in renal cortex, whereas it was very much comparable to control with carvedilol. In conclusion, carvedilol with its antioxidant property protected the rats from gentamicin-induced nephrotoxicity.