甘草酸及其苷元甘草次酸的盐皮质激素样作用研究进展

甘草酸在体内水解成甘草次酸,甘草次酸的化学结构类似于甾体激素,因此甘草酸是甘草次酸的前体药物.甘草酸和甘草次酸是甾体激素代谢失活酶(尤其是Ⅱ型11β-羟化甾体脱氢酶)抑制剂,可提高内源性和外源性皮质激素的活性.甘草酸和甘草次酸又可作为配体,与皮质激素受体结合呈现出糖皮质激素、盐皮质激素样作用.因此长期使用甘草或甘草酸类...     

Δ6-6-甲基皮质酮乙酸酯的肾上腺皮质激素样作用

△⁶-6-甲基皮质酮乙酸酯为我国化学家合成的一种皮质激素同型物,我们研究了其肾上腺皮质激素样作用。结果表明,此同型物对大鼠棉球肉芽肿和后足炎性水肿及胸腺组织的抑制作用与同剂量皮质酮大致相似;其肝糖原堆积作用约为皮质酮的4—5倍,对垂体ACTH条件反射性分泌的抑制作用亦较皮质酮强;对水盐代谢的影响则与皮质酮及脱氧皮质甾酮不同,不但不引起水分和钠储留,反而有明显利尿作用。     

甘草次酸衍生物的抗炎活性及水钠潴留作用的研究

目的 对合成的系列甘草次酸衍生物进行抗炎活性,水钠潴留作用的评价.方法 构建了急性及慢性炎症模型,评价合成的6个甘草次酸衍生物的抗炎活性及水钠潴留作用.结果 脱氧甘草次酸、脱氧甘草次酸甲酯、甘草次酸甲酯-3-O-乙酸酯及甘草次酸甲酯均表现出较好的急性炎症拮抗活性,甘草次酸乙酯-3-O-乙酸酯及甘草次酸也具有一定的活性.脱氧甘草次酸、脱氧甘草次酸甲酯、甘草次酸甲酯-3-O-乙酸酯及甘草次酸甲酯对棉球肉芽肿模型大鼠24 h尿量、尿钾离子含量、血清钠离子含量和钾离子含量均未见明显影响.结论 脱氧甘草次酸、脱氧甘草次酸甲酯、甘草次酸甲酯-3-O-乙酸酯及甘草次酸甲酯对急性炎症(渗出反应为主)有明显的拮抗作用,甘草次酸乙酯-3-O-乙酸酯及甘草次酸对急性炎症也有一定抑制作用.4种具有显著急性炎症拮抗作用的衍生物未表现出明显水钠潴留作用.     

Δ~6-6-甲基皮质酮乙酸酯的肾上腺皮质激素样作用

△~6-6-甲基皮质酮乙酸酯为我国化学家合成的一种皮质激素同型物,我们研究了其肾上腺皮质激素样作用。结果表明,此同型物对大鼠棉球肉芽肿和后足炎性水肿及胸腺组织的抑制作用与同剂量皮质酮大致相似;其肝糖原堆积作用约为皮质酮的4—5倍,对垂体ACTH条件反射性分泌的抑制作用亦较皮质酮强;对水盐代谢的影响则与皮质酮及脱氧皮质甾酮不同,不但不引起水分和钠储留,反而有明显利尿作用。     

复方甘草酸苷临床应用新进展

复方甘草酸苷是由甘草酸苷、盐酸半胱氨酸和甘氨酸组成的复方制剂,其主要成分为甘草中的活性物质甘草酸．甘草酸在人体内被葡萄糖甘酸酶水解后形成两个非对映异构体18α体和18β体甘草次酸。β-甘草酸在化学结构上与肾上腺皮质激素相似,对肝的类固醇激素代谢（△5—β-还原酶）具有强亲和力,抑制可的松和醛固酮在体内的灭活,减缓类固醇的代谢速度．发挥固醇样作用,因此具有抗炎和类盐皮质激素的作用,     

长期服用甘草合剂引起低血钾症一例

甘草合剂为一中草药复方制剂,具有润肺止咳之功效,常用于治疗气管炎。有关文献报道,甘草次酸有糖皮质激素、盐皮质激素等样作用。甘草常与樟脑酊等药物配合制     

胍乙啶对大白鼠肾上腺皮质活动的影响

正常大白鼠腹腔注射胍乙啶每周3次,每次15—30毫克/公斤,共3周后,血压无明显变化。DOCA型高血压大白鼠给同剂量的胍乙啶组与对照组,在继续给DOCA的情况下,“浄升、降压面积百分比”分别为-1%和9%。两者相差10%,说明对DOCA型高血压大白鼠血压的继续上升,胍乙啶趋于抑制,腹腔注射20毫克/公斤的胍乙啶可使大白鼠的嗜酸性白血球和肾上腺中的抗环血酸含量在0.5—6小时内降低,但肾上腺内胆固酵含量的减低尚不明显。以上结果说明胍乙啶稍能影响腎上腺皮质的活动。     

甘草次酸差向异构体单独和联合给药后在大鼠体内的药动学研究

本文建立了大鼠血浆中甘草次酸差向异构体的高效液相测定方法, 用于研究甘草次酸差向异构体在单独与混合灌胃给药后大鼠的药物代谢动力学过程。本研究分别对大鼠灌胃给予甘草次酸α异构体、β异构体和两者的混合物, 于给药后不同时间点采集血样, 样品经液液萃取后, 用高效液相色谱法测定甘草次酸差向异构体的血药浓度。色谱柱为Kromasil C₁₈ (150 mm × 4.6 mm, 5 µm); 流动相为乙腈–4 mmol·L⁻¹醋酸铵水溶液 (46∶54, v/v); 流速为1.0 mL·min⁻¹; 检测波长为250 nm; 采用DAS 2.0软件计算药动学参数。结果显示, 大鼠单独给予单体后, α-甘草次酸的AUC_0−t为 (11.30 ± 1.53) μg·h·mL⁻¹, C_max为 (2.36 ± 0.58) μg·mL⁻¹; β-甘草次酸的AUC_0−t为 (9.79 ± 0.98) μg·h·mL⁻¹, C_max为 (2.09 ± 0.41) μg·mL⁻¹。两单体混合给药后, α-甘草次酸的AUC_0−t为 (13.04 ± 2.63) μg·h·mL⁻¹, C_max为 (2.72 ± 0.50) μg·mL⁻¹; β-甘草次酸的AUC_0−t为 (7.46 ± 1.77) μg·h·mL⁻¹, C_max为 (1.90 ± 0.31) μg·mL⁻¹。本研究所建立的高效液相色谱法专属性强、灵敏度高, 可用于甘草次酸差向异构体的体内药动学研究。α-甘草次酸与β-甘草次酸混合给药时, 主要药动学参数存在显著性差异 (P < 0.05); 单独给药时, α-甘草次酸与β-甘草次酸的主要药动学参数无显著性差异。对各差向异构体单独给药与混合给药时的主要药动学参数进一步进行统计分析, α-甘草次酸在两种给药方式时无显著性差异, 而β-甘草次酸的AUC_0−t与AUC_0−∞存在显著性差异。     

甘草次酸在人细胞色素CYP450中体外代谢研究(英)

甘草根是中医临床常用解毒草药, 其活性成分甘草次酸主要是通过肝脏代谢。本文研究了人肝微粒体以及人源性CYP450s对甘草次酸的体外代谢影响, 以及甘草次酸对几种CYP450酶活性的影响。实验结果表明, 甘草次酸体外主要代谢酶为CYP3A4。体外药代动力学参数K_m, V_max和CL_int分别为18.6 μmol·L⁻¹, 4.4 nmol·mg⁻¹(protein)·min⁻¹和0.237 mL·mg⁻¹(protein)·min⁻¹。体外抑制试验显示, 50 μmol·L⁻¹甘草次酸可以抑制CYP2C19、CYP2C9、CYP3A4酶的活性, 其抑制率可高达50%以上。     

瑞舒伐他汀与去氧皮质酮-盐诱导的心肌纤维化

目的通过研究瑞舒伐他汀(ROS)对去氧皮质酮(DOCA)-盐联合诱导的大鼠心肌纤维化的干预效应,探索瑞舒伐他汀抑制盐皮质激素致心肌纤维化过程的可能机制。方法 60只雄性SD大鼠行右肾切除术,术后给予1%Nacl、0.2%Kcl饮水4周并随机分为对照组(CON组),DOCA组和DOCA+ROS组。苦味酸-天狼猩红染色观察大鼠心肌间质胶原容积分数(CVF)和心肌血管周围胶原面积比(PVCA),苏木精染色观察心肌间质炎症反应程度,免疫组化法观察心肌组织单核巨噬细胞抗原(ED-1)表达,免疫印迹法检测腱糖蛋白-C表达。结果第28 d DOCA组出现明显纤维化,其CVF和PVCA指标显著高于DOCA+ROS组(P=0.02),DOCA+ROS组与CON组的CVF及PVCA差异无统计学意义(P=0.07)。与CON组相比,DOCA组、DOCA+ROS组心肌间质可见明显炎症渗出及单核巨噬细胞浸润。CON组和DOCA+ROS组腱糖蛋白-C表达差异无统计学意义(P=0.08),但均明显低于DOCA组(P=0.01)。结论盐皮质激素致心肌纤维化与心肌组织的炎症反应有关,ROS具备抑制DOCA-盐诱导的大鼠心肌纤维化作用,其机制可能与其抑制了盐皮质激素致心肌组织的炎症反应过程、减少心肌纤维化指标的表达相关。     

A method for screening diuretic agents in the mouse: an investigation of sexual differences.

Acetazolamide, aminophyline, frusemide, ethacrynic acid and triamterene were tested for diuretic action at dosages of 3, 10 and 30 mg kg-1 (s.c.) in male and female mice. Each drug significantly raised sodium excretion and all but acetazolamide elevated urine volume and chloride excretion. Potassium excretion was significantly raised by acetazolamide and frusemide. Acetazolamide and triamterene evoked urinary alkalinization whereas frusemide and ethacrynic acid reduced urinary pH. Female mice were markedly more sensitive than males to the diuretic, natriuretic, chloruretic and urinary acidfying actions of ethacrynic acid.     

EFFECT OF CAPTOPRIL ON BRAIN CONVERTING ENZYME IN THE SPONTANEOUSLY HYPERTENSIVE RAT

The effect of oral captopril (30 mg/kg per day) on the blood pressure, plasma aldosterone concentration, urinary electrolytes and brain angiotensin-converting enzyme activity of spontaneously hypertensive rats of the Okamoto strain was examined. Over a seven day period, captopril caused a progressive fall in blood pressure with increased sodium excretion and urine volume and a significant fall in plasma aldosterone concentration. Following captopril, angiotensin converting enzyme activity increased significantly in the midbrain and medulla oblongata; the pituitary level of angiotensin converting enzyme activity was significantly decreased. The hypotensive action of captopril in the spontaneously hypertensive rat is associated with changes in body sodium, water and plasma aldosterone concentration. The alterations in brain angiotensin-converting enzyme activity following captopril treatment suggest that, with chronic administration, captopril can alter the activity of the brain renin-angiotensin system.     

Effects of subchronic parathion administration on sodium salicylate excretion kinetics in female rats

Organophosphorus (OP) pesticides are considered to be environmental contaminants, and chronic exposure to low levels through the diet may affect drug action. To study this possible interaction, ethyl parathion was administered by intubation to female rats for 35 consecutive days at a dose of 0.05 or 0.2 mg/kg of body weight per day. At 7, 21 and 35 days after parathion was initiated, rats were administered a single dose of 20 mg/kg sodium salicylate intraperitoneally. Total salicylates, salicylic acid (SA), salicyluric acid (SU) and gentisic acid (GA) were determined in urine. At 7 days, parathion treatment slowed the excretion of total salicylates. This effect was more evident at longer treatment times. Total excretion of SA was increased at the expense of GA at 7 days. However, this effect was reversed at 21 and 35 days. Excretion of SU was drastically diminished after 21 days of treatment with parathion. The results suggest that subchronic oral administration of parathion to female rats changes the excretion kinetics of sodium salicylate through combined effects on renal excretion mechanisms and biotransformation processes. Thus, exposure to low concentrations of environmental contaminants may produce important changes in drug action.     

A study of the β-adrenergic receptors in rat kidneys

Dichloroisoprenaline (1 mg), injected intramuscularly into the rat, retarded the elimination of water and retained sodium, depressing both glomerular filtration rate and renal blood flow. A dose of 4 mg had a similar but more intense action. These actions of dichloroisoprenaline resembled those of 2 or 4 μg of (±)-isoprenaline given subcutaneously. Dichloroisoprenaline and (±)-isoprenaline summed in salt retaining effect but competed in renal vascular action. 2-Isopropylamino-1-naphth-2'-ylethanol hydrochloride (nethalide, 1 mg intramuscularly) was without action during water diuresis. A dose of 4 mg inhibited solely the excretion of water. Nethalide (1 mg) completely antagonized the antidiuretic and vascular actions of 2 μg of (±)-isoprenaline; antagonism of the salt retention caused by (±)-isoprenaline was less complete. A dose of 4 mg of nethalide antagonized both the salt retaining and the vascular actions of 4 μg of (±)-isoprenaline.     

Inhibition of kinin degradation on the luminal side of renal tubules reduces high blood pressure in deoxycorticosterone acetate salt-treated rats

1. To determine whether the antihypertensive response in deoxycorticosterone acetate (DOCA) salt-treated rats was mediated by kinins on the luminal side of renal tubules or in the circulation, selective urinary kininase inhibitors were administered to normal Brown Norway Kitasato (BN-Ki) rats and kininogen-deficient Brown Norway Katholiek (BN-Ka) rats. 2. Kinins were degraded by neutral endopeptidase (NEP) and carboxypeptidase Y-like kininase (CPY) in urine, but were inactivated mainly by angiotensin-converting enzyme (ACE) in the plasma. 3. Ebelactone B inhibited CPY, while poststatin inhibited CPY and NEP. 4. Daily administration of poststatin (5 mg/kg per day, s.c.) for 3 days reduced blood pressure (BP) in DOCA salt-treated BN-Ki rats, but not in BN-Ka rats. 5. Ebelactone B (5 mg/kg per day, s.c.) also reduced BP in BN-Ki rats, which was accompanied by increased urinary sodium excretion, but had no effect on BP in BN-Ka rats. 6. Lisinopril (5 mg/kg per day, s.c.) had no effect on BP in either rat strain. 7. Arterial kinin levels in BN-Ki rats increased significantly (2.2-4.6 pg/mL) with captopril (10 mg/kg, s.c.). However, arterial kinin levels that induced hypotension following the infusion of bradykinin (1000 ng/kg per min, i.v.) were 110-fold higher than endogenous arterial kinin levels attained following captopril. 8. These results suggest that inhibition of kinin degradation on the luminal side of the renal tubules may effectively attenuate hypertension.     

EFFECTS OF OPIATES ON SODIUM EXCRETION IN THE ISOLATED PERFUSED RAT KIDNEY

1. A rat isolated perfused kidney preparation was utilized to define clearly a renal site of action. The variables measured were perfusate pressure and flow, glomerular filtration rate, urine volume, sodium excretion and potassium excretion. 2. Dextromethorphan (3 nmol/L) and dextrorphan (10 nmol/L) reduced sodium excretion in kidneys from rats on either control or high K+ diet, in the absence of any other measured renal effects. Dextromethorphan (10 nmol/L) produced a decrease in glomerular filtration rate as well as a decrease in sodium excretion. Naloxone (1 mumol/L) inhibited the effect of dextromethorphan on sodium excretion but had no effect when administered alone. 3. The levorotatory opiates levorphanol and levomethorphan, the kappa agonist ketocyclazocine and a range of other opiates had no effect on sodium excretion. 4. The results suggest a renal action specific for dextrorotatory opiates. This renal action is consistent with earlier binding studies suggesting preferential recognition of dextrorotatory opiates.     

Alpha adrenergic activity and renal function in two-kidney deoxycorticosterone-acetate hypertensive swine

To evaluate the role of alpha-adrenergic activity in deoxycorticosterone-acetate (DOCA) hypertensive swine, eight two-kidney Yucatan miniature swine were implanted with DOCA silicone strips (100 mg/kg) for 12–16 weeks. Mean arterial pressure (MAP) in these animals increased progressively from control values of approximately 1 15 mm Hg to 173 ± 5 mm Hg. Treatment of four conscious animals with phenoxybenzamine (POB) (1 mg/kg) resulted in a significant decrease in MAP from 190 ± 3 to 157 ± 5 mm Hg (P < 0.05). This decline was due to a 21% decrease in total peripheral resistance (TPR) (P < 0.05), while cardiac output (CO) and heart rate (HR) remained unchanged. Pentobarbital anesthesia caused a small insignificant decrease in MAP to 165 ± 5 mm Hg. While under anesthesia, infusion of POB into the left renal artery (0.04 μg/kg/min) caused a slight increase in left renal blood flow (P > 0.05), without affecting MAP, HR, TPR, or CO. Left kidney urine flow and sodium excretion also increased during intra-renal POB infusion. Potassium excretion was unchanged and GFR decreased slightly. When POB (1 mg/kg) was infused systemically during anesthesia, MAP decreased to 82 ± 6 mmHg (P < 0.05). This was due to a 34% and 14% decrease in TPR and CO, respectively (P < 0.05). Whole animal urine flow, sodium excretion, and GFR all decreased significantly with systemic POB. These findings suggest that alpha-adrenergic activity plays a role in the maintenance MAP and the determination of renal function in DOCA hypertensive swine.     

On the pharmacological actions of a diuretic,fenquizone, with particular reference to its site of action

The pharmacological actions of a diuretic drug, fenquizone have been investigated and its effects compared with well characterized diuretics in rats, mice and rabbits. Changes in sodium and potassium excretion and urine volume were similar in magnitude and duration to those of the thiazide diuretics over dose range 0·05–100 mg kg^?1. Free water clearance in rabbits was decreased indicating an action at the cortical diluting site in the nephron and since free water reabsorption was relatively unaffected it appears unlikely to have actions at other sites. Calcium and phosphate excretion studies also suggested that the predominant effects are those occurring at the cortical diluting segment of the nephron. Additional parameters not affected by the drug were blood flow to the cortex and medulla of the kidney (and other major organs), plasma glucose concentration and plasma urate concentration.     

The natriuresis following oral administration of the calcium antagonists--nifedipine and nitrendipine.

Ten healthy individuals received in random order placebo, nifedipine 10 mg, nifedipine 20 mg, nitrendipine 10 mg and nitrendipine 20 mg as single oral administrations at weekly intervals. On the day before each treatment placebo was administered. Urine was collected for 6 h and then for 18 h after each administration. There was a significant increase in urine volume and sodium excretion after the drugs, but no change in potassium excretion. The effect was most evident in the 6 h after drug administration. The effect was no greater at the higher doses of either drug. A natriuretic-diuretic action of nifedipine and nitrendipine has been confirmed in man. The mechanism of the effect remains unclear.     

Pharmacological and toxicological properties of the saluretic xipamide (4-chloro-5-sulfamoyl-2',6'-salicyloxylidide)]

Xipamide (4-chloro-5-sulfamoyl-2',6'-salicyloxylidide, Aquaphor), a new compound is a derivate of salicylic acid with marked sodium and water excreting potency. Its effect is dosage dependent. Dosages as low as 0.001 mg/kg p.o. in rats and 0.04 mg/kg p.o. in dogs lead to a statistically significant increase of sodium and water excretion. Potassium excretion was less affected and showed to be rather constant in a dosage range between 0.01 and 10.0 mg/kg. In rats a maximum of sodium and water excretion could be reached by a dose of 200 mg/kg duration of action in rats was approximately 10 h. In dogs a statistically significant sodium and chloride excretion could be detected after oral application of 0.04 mg/kg. Xipamide increased diuresis started with an oral dose of 0.1 mg/kg. Intravenous application of xipamide in a dose of 0.2 mg/kg in dogs accompanied by permanent infusion of 5 per cent mannit solution clearly showed the diuretic profile of the substance: increased diuresis started within 40 min. A peak was reached within 40-60 min post injectionem. Then excretion decreased slowly. Even 120 min post injectionem a diuretic action could be detected. Diuresis and sodium excretion could be demonstrated in rats with experimentally predamaged kidneys and with steroid dependent sodium retention. As could be demonstrated in hypertensive rats xipamide had a hypotensive effect, normotensive rats were not affected. In animal studies xipamide was excellently tolerated. The therapeutic range of the substance was high in single doses as well as when the drug administered over 6 weeks.