麻醉剂量羟甲芬太尼对大鼠脑内单胺递质及其代谢物含量的影响

麻醉剂量羟甲芬太尼对大鼠脑内单胺递质及其代谢物含量的影响金昔陆１唐琴梅金文桥周德和李桂芬池志强（中国科学院上海药物研究所，上海２０００３１）羟甲芬太尼（ｏｈｍｅｆｅｎｔａｎｙｌ，ＯＭＦ）是一种新的高选择性高亲和力μ阿片受体激动剂，在动物中能产生麻醉作...     

羟甲芬太尼对映异构体的镇痛活性及对阿片受体的选择性

羟甲芬太尼对映异构体的镇痛活性及对阿片受体的选择性金文桥，王智贤，陈洁，陈新建，池志强（中国科学院上海药物研究所，上海２０００３１，中国）关键词羟甲芬太尼；立体异构体；痛测定；μ阿片受体；δ阿片受体；放射配位体测定；结构活性关系目的：研究羟甲芬太尼...     

高效镇痛剂羟甲芬太尼药效构象的系统分析

本文用合理简化的系统搜索方法研究了柔性化合物羟甲芬太尼的构象性质，使用分子力学ＭＭＰ２程序，以（３Ｒ，４Ｓ，２０Ｒ）－羟甲芬太尼的Ｘ－射线晶体参数作为起始结构，通过能量优化得到该化合物的六个最低能量构象；在此基础上进一步研究了活性最高异构体（３Ｒ，４Ｓ，２０Ｓ）－羟甲芬太尼的低能构象。对比二者的低能构象推测出羟甲芬太尼两个可能的活性构象，（３Ｒ，４Ｓ，２０Ｒ）－羟甲芬太尼晶体中呈现的构象可能并不是该化合物的活性构象。依据所推测的活性构象和药效基团，可进一步设计新化合物分子，以提高药物的药效强度和选择性，     

新的高强度高选择性阿片μ受体激动剂［~11C］－羟甲芬太尼的合成

羟甲芬太尼（Ｉ）是一个新的高强度高选择性阿片μ受体激动剂。本文用ｃｉｓ－Ａ－Ｎ－［１－（２－羟基－２－苯乙基）－３－甲基－４－哌啶基］－苯胺（ＩＩ）或ｃｉｓ－Ｎ－［１－（苯甲酰甲基）－３－甲基－４－哌啶基］－苯胺（ＩＩＩ）作为前体合成了［１１Ｃ］－羟甲芬太尼，以便用正电子发射断层扫描（ＰＥＴ）来观察μ受体。通过水解ｃｉｓ－Ａ－羟甲芬太尼（Ｉ）和ｃｉｓ－Ｎ－［１－（苯甲酰甲基）－３－甲基－４－哌啶］－Ｎ－苯基丙酰胺（ｃｉｓ－ＩＶ）的４－Ｎ－丙酰基分别获得ＩＩ和ＩＩＩ。溴乙烷的格氏试剂与回旋加速器产生的［１１Ｃ］－二氧化碳反应后继而直接加入邻苯二甲酸二酰氯和２，６－二叔丁基吡啶生成同位素标记中间体［１１Ｃ］－丙酰氯。［１１Ｃ］－丙酰氯与ＯＨ－前体（ＩＩ）反应后再经ＨＰＬＣ分离纯化直接得［１１Ｃ］－羟甲芬太尼；［１１Ｃ］－丙酰氯与酮－前体（ＩＩＩ）反应后，再用硼氢化钠甲醇溶液处理，然后进行ＨＰＬＣ分离纯化得［１１Ｃ］－羟甲芬太尼。两种方法均可获得ｌｌ．１～１４．８ＧＢｑ／μｍｏｌ的特异性放射化学纯［１１Ｃ］－羟甲芬太尼。总共耗时为４０～５０ｍｉｎ（ＥＯＢ）。     

羟甲芬太尼的精神依赖性系统评价

羟甲芬太尼是一种强效镇痛药，本实验采用３种动物、３种药物精神依赖性评价方法对其精神依赖性潜力进行系统评价，结果表明羟甲芬太尼存在着一定的精神依赖性潜力，但等效剂量的羟甲芬太尼的精神依赖性潜力低于吗啡，同时对其依赖性机理进行初步探讨推测其药物强化效应可能是通过阿片μ－受体起作用的。     

甲砜霉素合成路线概述

甲砜霉素合成路线概述徐勤丰（上海第六制药厂，上海２００３３３）ＳＹＮＴＨＥＳＥＳＯＦＴＨＩＡＭＰＨＥＮＩＣＯＬ￥ＸＵＱｉｎ－Ｆｅｎｇ（ＳｈａｎｇｈａｉＮｏ．６ＰｈａｒｍａｃｅｕｔｉｃａｌＦａｃｔｏｒｙ，Ｓｈａｎｇｈａｉ２００３３３）甲砜霉素（ｔｈｉａ...     

羟甲芬太尼的精神依赖性系统评价

羟甲芬太尼是一种强效镇痛苦，本实验采用３种动物、３种药物精神依赖性评介方法对其精神依赖性潜力进行系统评价，结果表明羟甲芬太尼存在着一定的精神依赖性潜力，但等效剂量的羟甲芬太尼的精神依赖性潜力低于吗啡，同时对其依赖性机理进行初步探讨推测其药物强化效应可能是通过阿片μ－受体起作用的。     

脑室注射ACTH对抗羟甲芬太尼引起的镇痛

通常中枢注射促肾上腺皮质激素（ＡＣＴＨ）能够拮抗阿片的镇痛作用，然而其机制尚未阐明。本实验用辐射热─甩尾法测定痛阈，ｓｃｍｕ型阿片受体高选择性激动剂──羟甲芬太尼（０．８μｇ·ｋｇ－１），引起明显的镇痛效应，然后ｉｃｖＡＣＴＨ。发现小剂量的ＡＣＴＨ（１５．６～２５０ｎｇ）即可剂量依赖性抑制羟甲芬太尼的镇痛效应，其最大抑制率为７７．３％，半数有效量为１０７ｎｇ。单独注射ＡＣＴＨ２５０ｎｇ对基础病阈无影响。结果提示，ＡＣＴＨ在ｍｕ型阿片受体介导的镇痛中起重要作用。     

3—甲基芬太尼衍生物药效构象的研究

对芬太尼，３－甲基芬太尼的４个以及羟甲芬太尼的８个立体异构体进行了系统构象搜寻，并用比较分子力场分析方法研究其三维定量构效关系，从中得到６组与预测能力极高的ＣｏＭＦＡ模型相对应的可能活性构象。将上述６组可能活性构象分别对接到事先构建的μ阿片受体模型中，得到１组可能性最大的活性构象。     

羟甲芬太尼对慢性缺氧大鼠呼吸的影响

目的 探讨μ阿片受体激动剂对慢性缺氧模型呼吸功能的影响。方法 正常大鼠侧脑室注射羟甲芬太尼（Ｏｈｍｅｆｅｎｔａｎｙｌ，ＯＭＦ）后，观察记录呼吸频率（ＲＲ）；侧脑室微量注射阿片受体拮抗剂纳洛酮（ＮＬＸ）、ＯＭＦ，测定ＲＲ、潮气量（ＶＴ）及血气指标，并对每分通气量（ＭＶ）与ＰａＣＯ２作线性回归分析。结果 正常大鼠侧脑室注射ＯＭＦ后，ＲＲ显著下降（Ｐ＜０．０５）。慢性缺氧模型侧脑室注射ＯＭＦ后显著降低ＲＲ、ＶＴ以及中枢对ＣＯ２的敏感性（Ｐ＜０．０１）。电性缺氧模型侧脑室注射ＮＬＸ后，ＲＲ显著增高（Ｐ＜０．０５），并可增强中枢对ＣＯ２的敏感性。结论 μ阿片受体激动剂通过与中枢阿片受体结合降低ＲＲ、ＶＴ等呼吸指标以及中枢对ＣＯ２的敏感性，从而显著影响慢性缺氧模型的呼吸功能。     

Dietary zinc-deficiency and its recovery responses in rat liver cytosolic alcohol dehydrogenase activities

The purpose of the present study was to elucidate the effects of dietary zinc-deficient feeding and its recovery on liver cytosolic alcohol dehydrogenase (ADH; alcohol: NAD(+) oxidoreductase, EC1.1.1.1) activities and plasma zinc levels in rats. The weaned male Sprague Dawley rats were randomly divided into the zinc-deficient diet (ZDF: 1.9 mg zinc/kg diet) group and the control diet (53.5 mg zinc/kg diet) group, and were fed for 4 weeks. In the recovery periods, the rats of two groups were fed with the control diet for 3 weeks. Liver cytosolic protein content per body weight in the zinc-deficiency and its recovery period showed no significant changes between both groups. However, zinc-deficiency decreased significantly liver cytosolic ADH specific activity, total liver cytosolic ADH activity and total liver cytosolic ADH activity/body weight by 50%, 76% and 53%, respectively, as compared with the control diet group. Zinc-deficiency also decreased significantly plasma zinc concentration by 84%, as compared with the control diet group. On the contrary, no significant changes in liver cytosolic ADH specific activity, total liver cytosolic ADH activity and total liver cytosolic ADH activity/body weight in the recovery period were observed between both groups. Plasma zinc concentration in the recovery period was almost recovered to the control level. These results suggest that rat liver cytosolic ADH activity was clearly related to dietary zinc intake levels.     

Effects of shrimp (Macrobracium rosenbergii)-derived chitosan on plasma lipid profile and liver lipid peroxide levels in normo- and hypercholesterolaemic rats

1. The effects of chitosan (CS) derived from the exoskeleton of the shrimp Macrobracium rosenbergii on bodyweight, plasma lipid profile, fatty acid composition, liver lipid peroxide (LPO) levels and plasma levels of glutamate pyruvate transaminase (GPT) were determined in normocholesterolaemic (NC) and hypercholesterolaemic (HC) Long Evans rats. 2. The NC rats were fed a diet containing 2% CS and the HC rats were fed a diet containing 2 and 4% CS for 8 weeks. Chitosan significantly reduced bodyweight gain only in HC + 4% CS rats compared with HC rats, but not in NC + 2% CS or HC + 2% CS rats. 3. Chitosan reduced plasma total cholesterol in the HC + 2% CS, HC + 4% CS and NC + 2% CS rats; however, low density lipoprotein-cholesterol decreased only in the first two groups. High-density lipoprotein-cholesterol (HDL-C) increased in the HC + 4% CS rats by 24% compared with the HC + 2% CS group and by 30% compared with HC rats; however, HDL-C did not increase in the NC + 2% CS group compared with NC rats. The level of plasma triglycerides decreased significantly only in HC + 2% CS rats compared with HC rats. 4. Chitosan significantly decreased plasma levels of arachidonic acid in the HC + 2% CS and HC + 4% CS groups, with a concurrent increase in the molar ratio of total unsaturated fatty acid (TUFA) to total saturated fatty acid (TSFA). 5. Moreover, CS increased liver LPO levels without affecting plasma levels of GPT. Liver LPO levels were positively correlated with the TUFA/TSFA molar ratio. 6. The present study suggests that dietary CS decreases the atherogenic lipid profiles of both NC and HC rats and reduces the bodyweight gain of HC rats.     

The renin and isorenin-angiotensin system in rats with hereditary hypothalamic diabetes insipidus

It is known that the active end product of the renin-angiotensin system, angiotensin II, will stimulate ADH release in the brain and corticosteroid release from the adrenal gland and it is possible that isorenin-angiotensin systems present in those tissues are important control mechanisms for that release. In these experiments plasma renin and adrenal gland and brain isorenin concentration (ISO-RC) measurements were made in rats of the Brattleboro strain with hereditary hypothalamic diabetes insipidus (DI) both with and without ADH substitution. Heterozygous DI rats have low storage levels of ADH but can maintain normal water balance. These animals had normal plasma renin concentrations and increased ISO-RC in the hypothalamus and neurohypophysis compared to Long-Evans control rats. Substitution with 100 mU ADH/day, given subcutaneously, decreased ISO-RC in both hypothalamic and neurohypophyseal tissues of heterozygous DI to control levels. In comparison with Long-Evans control rats, higher plasma renin concentrations and increased ISO-RC were found in adrenal gland and brain hypothalamus tissue of homozygous DI rats while no differences were observed in frontal cortex, medulla oblongata or choroid plexus. Substitution of homozygous DI rats with 100 mU ADH/day decreased plasma renin concentration but resulted in no correction of adrenal gland or brain ISO-RC. These results suggest the plasma renin-angiotensin system is altered by changes in fluid balance in the DI rat which can be corrected by ADH substitution. Changes in tissue ISO-RC in DI compared to controls are not related to fluid balance but may be correlated with brain ADH content.     

beta-adrenergic reactivity in conscious DOCA-salt hypertensive rats

The endocrine (plasma renin activity, insulin and ADH) and hemodynamic responses (heart rate and mean arterial pressure) to isoprenaline infusion were examined in conscious deoxycorticosterone-salt hypertensive rats (DS) and compared with uninephrectomized-salt control rats (US). A dose-related rise in plasma renin activity and plasma insulin values was found in US rats, while no change in either parameter was observed in DS rats after 30 min of isoprenaline infusion. ADH was not increased in US rats at any dose of isoprenaline infusion. However, in DS rats the largest dose (450 ng/kg/min) produced a significant rise. Isoprenaline infusion increased the heart rate in both groups, but the increases in the DS group were significantly lower than in the US group for the 200-ng/kg/min dose (p less than 0.01). The drop in mean arterial pressure was found to be more pronounced in DS rats than in US rats at 50, 100 and 200-ng/kg/min isoprenaline doses. Recovery of the mean arterial pressure to basal levels was also found in US rats with the various doses of isoprenaline administered. However, in DS rats the different doses of isoprenaline produced a progressive drop in mean arterial pressure with no recovery at the end of 30 min of isoprenaline infusion. The present results provide no evidence of subsensitivity to isoprenaline in the resistance vessels of conscious DS rats and suggest that the greater hypotensive response observed in these rats may be due to the inability of the renin-angiotensin system to adequately compensate the vasodilation produced by isoprenaline.     

Effect of substances influencing brain serotonergic transmission on plasma vasopressin levels in the rat

Studies were carried out in the rat to investigate whether serotonin (5-HT) is involved in the regulation of vasopressin (ADH) release. For this purpose plasma ADH levels were measured in rats treated with drugs enhancing 5-HT transmission, such as d-fenfluramine and quipazine and with 5-HT depleting drugs, p-chlorophenylalanine (PCPA) and 5,7-dihydroxytryptamine (5,7-DHT). Forebrain 5HT, noradrenaline (NA) and dopamine (DA) were also measured. d-Fenfluramine and quipazine induced dose-related increases in plasma ADH levels in normohydrated rats. The effects of quipazine and d-fenfluramine were prevented by PCPA, indicating that 5-HT transmission was required for the biologic response. 5,7-DHT and PCPA pretreatment decreased forebrain 5-HT content and prevented ADH increases involved by water deprivation, suggesting that 5HT is necessary for the hormonal response to osmotic stimuli. The results summarized imply that serotonin may have a role in the physiological release of ADH from neurohypophysis.     

THE MECHANISM OF POLYURIA IN RATS PRETREATED WITH LITHIUM STUDIES BY IN VITRO MICROPERFUSION

The collecting ducts in papillae taken from normal rats have a measurable increase in diffusional tritiated water (THO) permeability with ADH 5 μunit/ml and this increase is maximal with antidiuretic hormone (ADH) 100 μunit/ml added to the media. 2 The presence of plasma from rats pretreated with lithium to make them polyuric inhibited the response to ADH. The lowest concentration of ADH that caused a measurable increase in diffusional water permeability was 50 μunit/ml and the increase was maximal with ADH 2000 μunit/ml. 3 The maximum response to ADH did not differ whether plasma from control or lithium pretreated rats was used. However, the dose-response curve to ADH was shifted to the right by the plasma from lithium-pretreated rats. 4 Lithium added to the plasma from control rats did not alter the response to ADH. 5 It is proposed that lithium given to rats causes a circulatory factor to be produced that inhibits in a competitive fashion the response of the collecting duct to ADH. Such an effect would explain many features of the impairment of water excretion associated with lithium use.     

LACK OF PROLONGED EFFECT OF ANTIDIURETIC HORMONE ON THE RENIN-ALDOSTERONE SYSTEM IN THE DOG

1. The effects of maximally antidiuretic, subpressor antidiuretic hormone (ADH) administration on the renin-aldosterone system were studied in dogs during 4 days of continuous intravenous infusion of ADH at a rate of 0.067 mU/kg per min. Water intake was limited to 700 ml/day to avoid changes in fluid volume status. 2. At the conclusion of the four-day study, plasma sodium concentration had fallen from 140.3 ± 0.8 to 137.2 ± 2.0 mmol/l, plasma potassium concentration, ²²Na space, and mean arterial pressure remained within the control ranges. 3. Neither plasma renin activity nor plasma aldosterone concentration showed any tendency to change in response to the ADH infusion. 4. The results indicate that physiologic levels of ADH have no prolonged, direct effect on the renin-aldosterone system.     

Marked changes in erythrocyte antioxidants and lipid peroxidation levels of rats exposed to acute, repeated and chronic restraint stress

The aim of this study was to investigate the effects of acute, repeated and chronic restraint stress on the antioxidant status and lipid peroxidation. For this purpose, 48 male Wistar rats, aged three months were used in this study. Rats were separated into six groups as follows; control (C), acute stress (AS), restrained for 7 days (1 h/day) (RS), restrained for 21 days (1 h/day) (CS1), restrained for 28 days (1 h/day) (CS2) and restrained for 21 days (1 h/day) and allowed to recovery for 7 days (CS3). Copper, zinc-superoxide dismutase (Cu, Zn-SOD), catalase (CAT) and selenium-dependent glutathione peroxidase (Se-GSH-Px) activities, corticosterone, reduced glutathione (GSH) and thiobarbituric acid-reactive substances (TBARS) levels were measured in blood samples. Corticosterone levels of all groups were found to be elevated after stress compared to group C. Cu, Zn-SOD activity was lower in all stress groups than in group C. CAT and Se-GSH-Px activities were increased in all stress groups. All stress models decreased GSH levels except for the CS3 group. TBARS levels were higher in stress groups than in C group except for AS group. The highest corticosterone level, CAT and Se-GSH-Px activity and TBARS level were seen in group RS. The lowest Cu, Zn-SOD activity and GSH level were seen in group CS2. These results may have an important implication for impaired erythrocyte antioxidant enzyme activities and glutathione levels resulting from exposure to different stress models (acute, repeated and chronic restraint stress).     

Losartan may prevent the elevation of plasma glucose, corticosterone and catecholamine levels induced by chronic stress.

INTRODUCTION: Stress is a stimulus that activates the hypothalamic pituitary adrenal (HPA) axis and sympathetic nervous system (SNS). Increased activity of the SNS causes to increment or impairment in blood pressure, heart rate, body temperature and plasma glucose and adreno- corticotrophic hormone (ACTH) levels. Angiotensin II (Ang II), which is a product of the renin-angiotensin system (RAS), is an important factor affecting the activity of the SNS and responses to stress. We suggest that the blockade of Ang II may be worthwhile in the prevention and treatment of diabetes mellitus and cardiovascular diseases affected by stress. Therefore, we investigated the effects of immobilisation stress on blood glucose, norepinephrine (NE), epinephrine (E) and corticosterone levels and the effects of an Ang II receptor antagonist, losartan, on these parameters. MATERIALS AND METHODS: The rats were kept in small cylindrical cages for 60 min/day for 10 consecutive days to perform chronic immobilisation stress. Losartan (10 mg/kg) was given daily by gavage to Losartan (L) and Losartan + Chronic Stress (L+CS) groups. Control (C) and Chronic Stress (CS) groups received an equal volume of saline daily by gavage for 10 days. After the last stress regimen, blood samples were collected for plasma glucose, NE, E and corticosteroid measurements. RESULTS: Plasma glucose, NE, E and corticosterone levels in the CS Group increased significantly compared with the C group. In Group L+CS, the plasma glucose, NE, E and corticosterone levels decreased significantly vs. Group CS. In Group L there was no significant difference vs. Group C. CONCLUSION: It can be speculated that chronic blockade of RAS may decrease the excess sympathetic responses to stress in cardiovascular diseases and prevent the likely development of Type II diabetes mellitus.