Effect of inhibition of gluconeogenesis on ammonia production in the perfused rat kidney.

1. Gluconeogenesis from lactate or from glutamine is inhibited by 90-100% by sodium quinolinate (1 mmol/l) or 3-mercaptopicolinate (150 nmol/l) in the perfused rat kidney. L-Tryptophan is not metabolized and is without effect. 2. Lactate uptake and glucose production are inhibited to the same degree by 3-mercaptopicolinate in the kidneys of well-fed or starved rats. 3. Inhibition of gluconeogenesis from glutamine (1 mmol/l) by 3-mercaptopicolinate is accompanied by 50% inhibition of ammonia production, and 34% inhibition of glutamine uptake, in the kidneys of acidotic rats. Ammonia production from glutamine was not inhibited in kidneys from non-acidotic rats. 4. It is concluded that the increased rate of gluconeogenesis from glutamine which occurs in acidotic rats is an essential and primary event regulating all of the increase in ammonia formation.     

Renal disposition and effects of naproxen and its l-enantiomer in the isolated perfused rat kidney

Renal handling, metabolism and effects on kidney function of naproxen and its l-enantiomer were examined in the isolated perfused rat kidney (IPK). Urinary excretion rate of naproxen was much lower than the filtration rate, indicating extensive reabsorption. Naproxen is accumulated considerably in the IPK. This accumulation is concentration-dependent and is probably the result of active secretion of naproxen. Considerable amounts of desmethyl-naproxen were formed in the IPK. The kinetic behavior of the l-enantiomer of naproxen did not differ from naproxen. Addition of 37.5 to 3750 micrograms naproxen caused a decrease in urinary flow, glomerular filtration rate and fractional excretion of sodium, chloride, potassium, magnesium and calcium. The presence of prostaglandin E2 in the perfusate fully opposed the effects of naproxen on kidney function. Addition of 375 micrograms l-enantiomer of naproxen did not influence kidney function. Addition of very high doses (1 x 10(5) micrograms) of naproxen and its l-enantiomer to the IPK caused diuresis and increased the fractional excretion of sodium, chloride, potassium, glucose and calcium. We conclude that the pharmacokinetic behavior and the metabolism of naproxen in the IPK is probably not stereoselective; that relatively low doses of naproxen exert a specific, stereoselective effect on kidney function caused by inhibition of the prostaglandin E2 synthesis and that high doses of naproxen exert a nonstereoselective effect on kidney function.     

Determination of choline,betaine, and dimethylglycine in plasma by a high-throughput method based on normal-phase chromatography-tandem mass spectrometry

BACKGROUND: The quaternary ammonium compounds, choline and betaine, and dimethylglycine (DMG) reside along a metabolic pathway linked to the synthesis of neurotransmitters and membrane phospholipids and to homocysteine remethylation and, therefore, folate status. Lack of a convenient, high-throughput method for the determination of these compounds has prevented population-based studies of their possible associations with lifestyle, nutrition, and chronic diseases. METHODS: Serum or plasma samples were deproteinized by mixing with three volumes of acetonitrile that contained d(9)-choline and d(9)-betaine as internal standards. We used a normal-phase silica column for the separation of choline (retention time, 2.8 min), betaine (1.3 min), DMG (1.15 min), and internal standards, which were detected as positive ions by tandem mass spectroscopy in the multiple-reaction monitoring mode, using the molecular transitions m/z 104-->60 (choline), m/z 113-->69 (d(9)-choline), m/z 118-->59 (betaine), m/z 127-->68 (d(9)-betaine), and m/z 104-->58 (DMG). RESULTS: For all three metabolites, the assay was linear in the range 0.4-400 micromol/L, and the lower limit of the detection (signal-to-noise ratio = 5) was < or =0.3 micromol/L. The within- and between-day imprecision (CVs) was 2.1-7.2% and 3.5-8.8%, respectively. The analytical recovery was 87-105%. The fasting plasma concentrations (median, 25th-75th percentiles) were 8.0 (7.0-9.3) micromol/L for choline, 31.7 (27.0-41.1) micromol/L for betaine, and 1.66 (1.30-2.02) micromol/L for DMG in 60 healthy blood donors. In individuals who had eaten a light breakfast, plasma concentrations of all three metabolites were significantly (25-30%) higher than in fasting individuals. CONCLUSION: This is the first method for the combined measurement of choline, betaine, and DMG in human plasma or serum. The assay is characterized by simple sample preparation, no derivatization, high throughput, imprecision (CV) <10%, detection limits below the values seen in volunteers, and the high specificity provided by tandem mass spectroscopy.     

蛋白酶抑制剂对肝缺血-再灌注损伤的保护作用

目的：探讨蛋白酶抑制剂及中性粒细胞在肝缺血－再灌注损伤中的作用。方法：采用大鼠部分肝缺血－再灌注模型，将健康雄性SD大鼠32只随机分为4组，手术对照组（A组），肝缺血90分钟组（B组），肝缺血90分钟，再灌注120分钟组（C组），肝缺血90分钟，再灌注120分钟加缺血前30分钟静注乌司他丁组（D组），观察动物肝组织病理切片；分别测定血浆中天冬氨酸转氨酶（AST），丙氨酸转氨酶（ALT），乳酸脱氢酶（LDH）浓度，测定肝组织中髓过氧化物酶（MPO）含量，结果：光镜下B，C2组与A组比较，肝小叶结构紊乱，肝血窦和中央静脉有程度不同的淤血，有的肝血窦变窄，内皮细胞及肝细胞普遍水肿变性；C组肝细胞坏死较B组明显；D组上述改变明显减轻，血浆中肝功能酶学指标显著升高（B，C组与A组比较，P均＜0．05），肝组织中MPO活性升高，以再灌注120分钟组为著（C组与A组比较，P＜0．01），D组血浆中ALT，AST，LDH和MPO含量均较C组明显下降，结论：肝缺血－再灌注时，聚集，黏附在肝组织中的大量中性粒细胞通过释放蛋白酶造成肝损伤，蛋白酶抑制剂乌司他丁能明显减轻这种损伤，保护肝功能。     

血管紧张素转化酶抑制剂对脓毒症患者急性肾损伤的影响

目的 探讨血管紧张素转化酶抑制剂贝那普利对脓毒症患者肾功能的影响.方法 选取脓毒症患者常规组45例(A组)和干预组42例(B组,加用贝那普利),分别在第1、3、7天检测患者血清肌酐与胱抑素C和尿量,记录APACHEⅡ评分,比较两组血清肌酐、胱抑素C和APACHEⅡ评分,并比较两组急性肾损伤的发生率和胱抑素C异常发生率.结果 在第7天,B组患者在3、7天血清肌酐及胱抑素C均较A组低,B组患者的急性肾损伤发生率明显低于A组,B组患者的胱抑素C异常发生率明显低于A组,B组患者的APACHEⅡ评分亦较A组低.结论 血管紧张素转换酶抑制剂贝那普利能减轻脓毒症患者急性肾损伤,并能改善病情.     

Effect of inorganic nitrates on the morphofunctional condition of the kidney in the rat

AIM: The aim of our experimental study was to determine the effect of exogenic nitrates on certain biological parameters in relation to renal insufficiency. RESULTS: Chronic treatment of rats for 5 months with varying nitrate concentrations (50, 100, 150 and 500 mg/L) induced a dose-dependent reduction in plasma concentrations of total proteins and a dose-dependent increase in plasma urea concentrations and creatinine. DISCUSSION: This histological study of the kidney shows that nitrates at doses of 150 and 500 mg/L cause a deterioration in the epithelia of the renal tubules. CONCLUSION: In conclusion, a high nitrate intake induces morphofunctional disturbances of the kidney and could thus be regarded as a causative factor in renal insufficiency.     

Effect of polycations on the function of the isolated perfused rat kidney

1. In minimal change nephrotic syndrome the occurrence of heavy proteinuria can be explained on the basis of a reduction in charge selectivity of the glomerular filtration barrier, and it has been proposed that this might be caused by the neutralization of anionic groups by a circulating polycationic factor. 2. The effects of two polycations, protamine and poly-L-lysine, on the function of the isolated perfused rat kidney have been examined. 3. Poly-L-lysine polymers of relatively high molecular weight (8800 and 17,800) induced heavy proteinuria, while simultaneously causing a marked increase in renal vascular resistance and a fall in filtration rate. Protamine (approximate molecular weight 7000) at relatively high concentration induced modest proteinuria in the absence of effects on vascular resistance or filtration rate. 4. A poly-L-lysine polymer of lower molecular weight (3800) did not induce proteinuria. Protamine at a concentration of 40 micrograms/ml and below did not affect protein excretion either. Both provoked substantial natriuresis. This appeared to be largely due to an effect on the tubular handling of sodium since the filtration rate remained steady while fractional sodium excretion rose markedly. 5. The natriuretic effect of protamine was blocked by heparin, but not by indomethacin or verapamil, suggesting that the mechanism of natriuresis did not depend upon either prostaglandin production or entry of calcium through verapamil-sensitive channels.     

Effect of fluconazole on the disposition of phenytoin

In a randomized, placebo-controlled, parallel study, phenytoin was given in the presence and absence of fluconazole. Twenty healthy male subjects received phenytoin, 200 mg orally, on study days 1 to 3 and 18 to 20 and 250 mg intravenously on study days 4 and 21. Ten subjects received fluconazole, 200 mg orally, and 10 received placebo daily on study days 8 to 21. Serial blood samples were collected during a 24-hour period after the intravenous phenytoin dose. Fluconazole trough concentrations were determined on days 14, 18, and 21. Serum phenytoin area under the concentration-time curve from 0 to 24 hours increased 75% and minimum plasma drug concentration increased 128% after administration of fluconazole, 200 mg/day, for 14 days. These values were significantly greater than the 5% increase in area under the concentration-time curve from 0 to 24 hours and 11.6% increase in minimum plasma drug concentration in the placebo group. Fluconazole trough concentrations remained unchanged during the coadministration of phenytoin. The increased phenytoin concentrations in the presence of fluconazole suggest that fluconazole inhibits phenytoin metabolism. Serum concentration monitoring with a reduction in phenytoin dosage is clinically warranted in patients receiving phenytoin and concomitant fluconazole therapy.     

Effect of cimetidine on verapamil disposition

The effects of multiple doses of cimetidine on single-dose verapamil kinetics were studied in nine healthy men. Baseline hepatic blood flow was estimated by indocyanine green elimination on day 1. On day 2, the subjects received verapamil, 10 mg iv, after which the plasma concentration-time profile was determined. After a 2-day washout, cimetidine, 300 mg, was taken by mouth four times a day for 5 days. The indocyanine green study was repeated on day 9 and verapamil was taken on day 10. Cimetidine reduced verapamil clearance by 21% and increased the elimination t1/2 by 50%. The volume of distribution at steady state did not change. Cimetidine increased hepatic blood flow in some subjects, while decreasing it in others. There was no correlation between individual changes in verapamil clearance and hepatic blood flow. These data indicate that cimetidine reduces verapamil clearance by mechanism(s) other than a change in hepatic blood flow or volume of distribution.     

Effect of quinolones on caffeine disposition

Six healthy volunteers received a single caffeine dose after pretreatment with norfloxacin, pipemidic acid, or placebo in a crossover, randomized, single-blind clinical trial. Quinolones altered the pharmacokinetics of caffeine, with a significant increase in the AUCs and a decrease in plasma clearance. The elimination half-life increased significantly with pipemidic acid. The apparent volume of distribution, mean renal clearance, and time to reach maximum caffeine concentrations remained unaltered. There was a decline in caffeine metabolite levels in the 24-hour urine samples for both quinolone treatments, suggesting that pipemidic acid and, to a lesser degree, norfloxacin inhibit metabolism of the N-demethylation pathways of caffeine. The practical consequence of this observation could be caffeine accumulation during repeated intake of coffee. In two additional healthy volunteers under a controlled multiple-dose regimen of caffeine ingestion, administration of pipemidic acid for 2 days caused a fourfold increase in the plasma concentrations of caffeine.     

缬沙坦对糖尿病大鼠肾脏MCP-1表达的影响

目的 :研究缬沙坦对糖尿病大鼠肾脏MCP 1表达的影响 ,探讨缬沙坦对糖尿病大鼠肾脏的保护作用机制。方法 :将Wistar大鼠随机分为三组 :正常对照组 (NC组 )、糖尿病模型组 (DM组 )、糖尿病模型 +缬沙坦治疗组 (DV组 ) ,于 8周时用免疫组织化学的方法检测STZ诱导的糖尿病大鼠肾组织中MCP 1的表达。结果 :8周时肾组织中MCP 1的表达DM组明显高于DV组、NC组 (P <0 0 1) ,DV组明显高于NC组 (P <0 0 5 ) ,而且与UAER呈明显正相关 (r =0 665 9,P <0 0 1)。结论 :缬沙坦能显著减少糖尿病大鼠肾组织中MCP 1的表达 ,明显改善肾功能     

Cimetidine alters the disposition kinetics of the monoamine oxidase-A inhibitor moclobemide

The influence of cimetidine on the absorption and disposition of moclobemide was examined in eight healthy male subjects. A single 100 mg intravenous and 100 mg oral dose of moclobemide was administered before and after 2 weeks of cimetidine administration (200 mg five times a day). The data on intravenous administration indicated that cimetidine produced a statistically significant alteration in the following disposition parameters (mean values for control versus cimetidine): systemic clearance, 46.6 versus 28.3 L/hr; mean residence time, 2.1 versus 3.2 hours; elimination half-life, 1.6 versus 2.3 hours. There was no significant difference in the steady-state volume of distribution. The absolute oral bioavailability of moclobemide increased significantly after cimetidine administration (54% versus 68%), as did the maximum plasma concentration after a single oral dose (575 versus 787 ng/ml). There were no differences in the mean absorption time or time to achieve maximum concentration. The values of systemic and apparent oral clearances of moclobemide after cimetidine administration were directly related to the corresponding control values before cimetidine. In contrast, the percentage change in clearance was essentially independent of the corresponding initial control clearance value.