硝苯吡啶、阿斯匹林及两者并用对大鼠急性心肌缺血的保护作用

应用垂体后叶素所致大鼠急性心肌缺血模型观察了硝苯吡啶、阿斯匹林及两者并用抗心肌缺血作用。结果表明:20%乙醇(2 ml/kg)、硝苯吡啶(0.05mg/kg)、阿斯匹林(0.025mg/kg)对大鼠缺血性心电图各项指标均无明显影响。硝苯吡啶(0.1mg/kg)、阿斯匹林(0.05mg/kg)及阿斯匹林加硝苯吡啶(o.o25+o.05mg/kg)均能显著对抗垂体后叶素引起的大鼠心电图1、2期ST—T的改变、心率减慢及心律失常的发生。剂量与效应相关。两者并用呈明显的协同效应。     

SHORT-TERM INFLAMMATORY RESPONSES FOLLOWING INTRATRACHEAL INSTILLATION OF FINE AND ULTRAFINE CARBON BLACK IN RATS

Ultrafine carbon black (ufCB) 14 nm in diameter and fine carbon black (CB) 260 nm in diameter were instilled intratracheally in rats at mass of 125 mug, and the bronchoalveolar lavage (BAL) profile at 6 h was assessed. UfCB generated a 50% neutrophil alveolitis 6 h after intratracheal instillation compared to CB, which showed similar activity to the phosphate-buffered saline (PBS) vehicle control. UfCB instillation also produced a marked increase in lactate dehydrogenase (LDH) levels in BAL fluid, which was associated with increased epithelial permeability measured as total protein. In contrast, CB had much less of an effect in increasing BAL protein. Although both particle types caused a decrease in glutathione (GSH) in lung tissue compared to control, the greatest depletion was seen in ufCB-treated animals. To investigate time response, bronchoalveolar lavage was carried out at 6 h, 24 h, and 7 days after a single 125-mug instillation of ufCB. Neutrophil influx was relatively persistent and was still maintained 7 days later. Tumor necrosis factor (TNF) production by BAL leukocytes increased gradually post instillation, whereas NO production became significantly higher at 24 h after instillation and remained at raised levels up to 7 days. Higher doses of CB caused more inflammation than the ufCB. Thus, in the instillation model, a localized dose of particle over a certain level causes the particle mass to dominate the response, rather than the surface area. In contrast to the effect of CB, which showed a dose-related increasing inflammatory response, ufCB at the highest dose caused less of a neutrophil influx than at the lower dose. Six hours after intratracheal instillation, the threshold dose for neutrophil influx occurred at 50 mug. Calculation of surface area of particles instilled suggested that this was likely to be an overload-inducing dose of particles, as gauged from recent experiments with inhaled particles. In summary, this study provides evidence in a rat instillation model that ufCB has greater ability than CB to produce lung inflammation and oxidant stress at a relatively low dose of 125 mug. At high doses, however, BAL is not a reliable indicator of pulmonary response, since the overall response seems to scale to mass or volume of instilled particulate without an influence of surface area.     

新生牛肝细胞生长因子对大鼠急性肝衰竭影响的初步研究

参照Labrecque等提取肝细胞刺激物质(HSS)的方法,从新生牛肝脏中提取出分子量小于1.98万u的生物活性物质,动物试验表明,该物质对D-氨基半乳糖(D-Gal)所致的急性肝衰竭大鼠的存活率有明显的提高,并对大鼠肝细胞DNA合成有明显的促进作用。     

没食子酸丙脂对乙醇诱导鼠肝急性损伤的保护作用

本文研究没食子酸丙酯对乙醇塑造鼠急性肝损伤模型的影响。结果证实该化合物具有抑制肝组织脂质过氧化、维持鼠肝线粒体氧化磷酸化、保护其形态结构的完整性等作用。为阐明赤芍的生化药理作用提供资料。     

CARDIOVASCULAR RESPONSES TO ACUTE MYOCARDIAL ISCHAEMIA IN MORPHINE-DEPENDENT RATS

1. The cardiovascular responses to acute myocardial ischaemia were studied in opiate-dependent animals before and after 2 weeks morphine withdrawal. 2. Rats were treated with morphine sulphate in drinking water for 2, 3 or 5 weeks. The development of morphine tolerance and dependence was verified by the tailimmersion test for analgesia and the naloxone-precipitated withdrawal syndrome, respectively. 3. Acute left coronary artery ligation induced a decrease in blood pressure, a slight increase in heart rate and ventricular tachycardia or fibrillation in anaesthetized naive rats. 4. Chronic morphine treatment did not alter the haemodynamic responses to coronary artery ligation. However, a significantly lowered incidence, and prolonged time of onset, of ventricular arrhythmias was found in 3 and 5 week morphine-treated rats. This phenomenon did not occur in animals receiving morphine for 2 weeks and in a 3 week morphine-treated group which was subsequently withdrawn for 2 weeks. 5. It is suggested that the decreased occurrence of early ventricular arrhythmias resulting from acute myocardial ischaemia in chronic morphine-treated rats may be related to the degree of opiate tolerance and dependence.     

ACUTE AND SUBCHRONIC NEUROTOXICOLOGICAL EVALUATION OF TETRAHYDROFURAN BY INHALATION IN RATS

Groups of adult male and female rats received exposure to tetrahydrofuran (THF) vapor by inhalation in acute or subchronic exposure scenarios. Acute exposure concentrations were 0, 500, 2500, or 5000 ppm for 6 hr. Evaluations conducted immediately after exposure included clinical observations, motor activity assessments (MA), and a battery of functional tests (FOB) designed to reveal nervous system dysfunction. During exposure to 2500 and 5000 ppm, rats had a diminished or absent startle response to a punctate auditory alerting stimulus. Following exposure to 5000 ppm, male and female rats were lethargic, exhibited abnormal gait or mobility, and splayed rear feet. Lethargy and splayed rear feet were also observed in females esposed to 2500 ppm. During the subsequent FOB, males exposed to 5000 ppm had a lower incidence of palpebral closure, higher incidences of slow or absent righting reflex, and a biphasic pattern of reduced motor activity followed by increased motor activity. Females exposed to 5000 ppm had increased incidences of palpebral closure in the open field, increased incidences of slow or absent righting reflex, and decreased motor activity.

During the 14-week subchronic exposure series, daily THF exposure concentrations were 0, 500, 1500, or 3000 ppm, and neurobehavioral evaluations occurred on non-exposure days at approximately monthly intervals. Diminished startle responses to an auditory alerting stimulus were observed during exposure to 1500 or 3000 ppm; however, repeated exposures did not cause additional neurobehavioral or pathological effects. This pattern of effects is suggestive of transient sedation. Despite daily reinstatement of acute sedative effects during repeated exposure with up to 3000 ppm, THF did not produce any persistent or cumulative effects on nervous system structure or function. The demonstrated no-observed-effect level of THF for both acute and subchronic exposure was 500 ppm.     

ATRIAL AND BRAIN NATRIURETIC PEPTIDES: SECRETION DURING EXERCISE IN PATIENTS WITH ESSENTIAL HYPERTENSION AND MODULATION BY ACUTE ANGIOTENSIN-CONVERTING ENZYME INHIBITION

1. This study examined whether brain and atrial natriuretic peptides (BNP, ANP) are secreted together through the coronary sinus from the heart, and whether plasma concentrations of BNP and ANP were affected by ergometric exercise in patients with essential hypertension. The effects of temocapril, a potent angiotensin-converting enzyme (ACE) inhibitor, on plasma concentrations of these peptides was also examined. 2. The plasma concentrations of immunoreactive (ir) BNP and ir-ANP in the coronary sinus in seven patients with ischaemic heart disease during cardiac catheterization were far greater than values with plasma obtained at the same time from the femoral artery. 3. The plasma concentrations of ir-BNP and ir-ANP increased with exercise and were correlated with each other. Temocapril reduced the blood pressure and slightly (but significantly) decreased the levels of both peptides at rest and during exercise. 4. The results suggest that BNP and ANP were secreted together through the coronary sinus from the heart. The secretion was increased by exercise and suppressed by acute ACE inhibition. The increase in these peptides during exercise may reflect a compensatory mechanism against further elevation of blood pressure.     

COMPARISON OF MYCOBACTERIA-INDUCED CYTOTOXICITY AND INFLAMMATORY RESPONSES IN HUMAN AND MOUSE CELL LINES

Environmental mycobacteria, which are ubiquitous in nature, are also detected in moisture-damaged buildings. Their potential role inducing the adverse health effects associated with living in moisture damaged buildings requires clarification. To establish a model for these studies, we evaluated inflammatory responsiveness in different cell lines exposed to environmental mycobacterial species. Four mycobacterial isolates belonging to Mycobacterium avium complex and Mycobacterium terrae, recovered from the indoor air sampled when a moldy building was being demolished, were studied for their cytotoxicity and ability to stimulate the production of inflammatory mediators in mouse RAW264.7 and human 28SC macrophage cell lines, and human A549 lung epithelial cell line. Lipopolysaccharide (LPS) was used as a positive control. Production of cytokines (tumor necrosis factorα, TNF-α; interleukin 6, IL-6; and interleukinβ, IL-1β) was analyzed immunochemically, nitric oxide (NO) by the Griess method, expression of inducible NO synthase with Western blot analysis, and cytotoxicity with the MTT test. Both human and mouse cells produced NO and IL-6 after mycobacterial exposure. Mouse macrophages also showed production of TNF-α induced by both mycobacteria and LPS, whereas the human cell lines failed to produce TNF-α after mycobacterial exposure and the human epithelial cell line also failed to respond to LPS. Similarly, only mouse macrophages produced IL-1β. Mycobacterial exposure was not cytotoxic to human cells and was only slightly cytotoxic to mouse macrophages. The results indicate that environmental mycobacterial isolates from moldy buildings are capable of activating inflammatory mechanisms in both human and murine cells. The human and mouse cell lines, however, differ significantly in the grade and type of the responses.     

RENIN, PRORENIN, AND RENIN GENE EXPRESSION IN RATS WITH ACUTE NEPHROTIC SYNDROME

1. The concentration of total, active and inactive renin was analysed in plasma, urine and kidney from control (C), pair-fed (PF) and nephrotic (NS) rats, as well as renin mRNA levels in kidney, liver and brain. 2. Nephrotic syndrome were induced by a single subcutaneous injection of puromycin aminonucleoside (PAN) and determinations were made 6 days after PAN injection. 3. Plasma total renin did not change, active renin increased in NS rats with respect to PF and C groups and in PF rats with respect to C. In contrast, the inactive renin percentage decreased in NS rats with respect to PF and C groups and in PF animals with respect to C. Total, active and inactive renal renin content did not change and active and inactive renin were significantly excreted by urine with no changes in the prorenin percentage with respect to C and PF groups. 4. In both NS and PF groups, renin mRNA levels did not change in any of the tissues studied. In another group of rats, kidney renin mRNA levels were measured on days 1, 3, 5 and 7 after PAN injection and no time-course changes in its expression were found. 5. These results suggest that renin gene expression is not altered in acute nephrotic syndrome and that plasma renin concentration is regulated at the translational or post-translational level in this experimental model.     

舒必利对大鼠吗啡所致奖赏效应的影响

确定舒必利消除吗啡所致奖赏效应的作用.采用条件性位置偏爱实验方法对盐水组、吗啡组和吗啡加舒必利(5、10、20 mg/kg)三个组的50只大鼠进行观察.结果显示,吗啡加舒必利三个组及盐水组的大鼠,与用药前相比,并未对吗啡搭配箱体产生显著偏爱(P＞0.05),说明舒必利可拮抗吗啡的奖赏效应.     

POSTOPERATIVE ANALGESIA INDUCED BY INTRATHECAL NEOSTIGMINE OR BETHANECHOL IN RATS

• 1 Cholinergic agonists and acetylcholinesterase inhibitors, such as neostigmine, produce a muscarinic receptor‐mediated antinociception in several animal species that depends on activation of spinal cholinergic neurons. However, neostigmine causes antinociception in sheep only in the early, and not late, postoperative period.
• 2 In the present study, a model of postoperative pain was used to determine the antinociceptive effects of bethanechol (a muscarinic agonist) and neostigmine administered intrathecally 2, 24 or 48 h after a plantar incision in a rat hind paw. Changes in the threshold to punctate mechanical stimuli were evaluated using an automated electronic von Frey apparatus.
• 3 Mechanical hyperalgesia was obtained following plantar incision, the effect being stronger during the immediate (2 h) than the late post‐surgical period. Bethanechol (15–90 µg/5 µL) or neostigmine (1–3 µg/5 µL) reduced incision‐induced mechanical hyperalgesia, the effects of both drugs being more intense during the immediate (2 h) than the late post‐surgical period.
• 4 The ED₅₀ for bethanechol injected at 2, 24 and 48 h was 5.6, 51.9 and 82.5 µg/5 µL, respectively. The corresponding ED₅₀ for neostigmine was 1.62, 3.02 and 3.8 µg/5 µL, respectively.
• 5 The decline in the antinociceptive potency of neostigmine with postoperative time is interpreted as resulting from a reduction in pain‐induced activation of acetylcholine‐releasing descending pathways. However, the similar behaviour of bethanechol in the same model points to an additional mechanism involving intrinsic changes in spinal muscarinic receptors.

     

RELATIONSHIP BETWEEN GASTRIC MUCUS SYNTHESIS, SECRETION AND SURFACE GEL EROSION MEASURED IN AMPHIBIAN STOMACH IN VITRO

1. The layer of adherent mucus that protects the surface of the stomach reflects a dynamic balance between biosynthesis of glycoprotein, secretion of preformed mucus and erosion of the adherent gel layer. The present study is the first in which all these processes have been measured concomitantly and was undertaken to define interrelationships between the three parameters. 2. A chambered sac preparation of amphibian gastric mucosa is described. Biosynthesis was determined by specific incorporation of radiolabeled sugars into purified glycoprotein. Mucus secretion was determined by measuring the thickness of the adherent gel and erosion of the surface layer was assessed from the appearance of soluble mucin in the luminal solution. 3. 16,16-Dimethyl-prostaglandin (PG. E₂ stimulated glucosamine incorporation by 10-fold, but did not alter the rate of incorporation of galactose. There was a rapid two-fold increase in the thickness of the adherent mucus layer but no change in the rate of erosion. Dibutyryl-cAMP also stimulated mucus release but, unlike PG, increased glycoprotein labelling by galactose. 4. Both distention or the application of a cholinergic agonist increased adherent mucus thickness. Stimulation of mucus release in response to carbachol was accompanied by a decrease in glycoprotein labelling by galactose. In contrast, the adrenergic agent noradrenaline decreased secretion but did not influence labelling. 5. These results indicate that biosynthesis and secretion of gastric mucus are subject to differential regulation. Moreover, the profile of incorporation of sugars in response to secreta-gogues also differs, indicating the need for caution when interpreting effects on glycoprotein biosynthesis.     

INCREASED NALOXONE POTENCY INDUCED BY PRETREATMENT WITH MORPHINE AND NALBUPHINE IN MICE

1. Both morphine and nalbuphine were effective in suppressing the abdominal constriction response induced by intraperitoneal injection of acetic acid in mice. On a weight to weight basis, nalbuphine was more potent than morphine in this test. However, the effect of nalbuphine was more effectively blocked by naloxone. 2. Pretreatment with morphine 2.0 mg/kg subcutaneously did not alter the antinociceptive effect of either morphine or nalbuphine measured 3 h later. However, naloxone was about 1.4-fold more effective in antagonizing the antinociceptive effect of both drugs in morphine-pretreated mice than in saline-pretreated animals. 3. Pretreatment with nalbuphine (1.0–2.0 mg/kg s.c.) did not alter the antinociceptive effect of either morphine or nalbuphine measured 3 h later, while naloxone was more effective in antagonizing the antinociceptive actions of morphine and nalbuphine. 4. The increases in naloxone potency in antagonizing morphine after nalbuphine pretreatment were not dose-dependent on the amount of nalbuphine in the pretreatment and they were only marginally significant. In addition, these increases were much lower than that induced by morphine pretreatment. 5. On the other hand, the naloxone effectiveness against nalbuphine itself was enhanced to a greater extent than that induced by morphine pretreatment. Furthermore, these increases in naloxone potency showed a dose-dependent relationship to the amount of nalbuphine used in the pretreatment. 6. Based on these results, it was concluded that nalbuphine is an analgesic drug with properties in between those of the full agonist morphine and the partial agonist pentazocine.     

Malotilate对四氯化碳及D-半乳糖胺引起的小鼠急性肝损伤的影响

Malotilate(50或100mg/kg ig×3)可明显对抗四氯化碳(CCl_4)引起的小鼠血清转氨酶升高、肝糖元合成减少、肝脏蛋白质及血清蛋白质含量降低、肝脏甘油三酯蓄积以及肝匀浆细胞色素P-450含量降低,使之恢复或趋于正常水平。malotilate(50mg/kg ip×5)亦可明显对抗D-半乳糖胺引起的SGPT的升高和肝脏蛋白含量的降低。     

ACUTE INFLAMMATORY REACTION IN RATS AFTER INTRATRACHEAL INSTILLATION OF MATERIAL COLLECTED FROM A NYLON FLOCKING PLANT

Several cases of interstitial lung disease have been diagnosed among workers at a nylon flock plant, but the etiologic agent for the disease outbreak was unknown. The results of a medical survey and industrial hygiene study indicated that the dust present in the plant may be responsible. Thus, airborne dust collected at the plant was examined for its inflammatory potential in rat lungs. The endpoints measured were: (1) breathing rates, (2) differential cell counts of bronchoalveolar lavage cells, (3) alveolar macrophage (AM) chemiluminescence, (4) albumin concentration and matrix metalloprotease activities in the acellular fluid from the initial bronchoalveolar lavage, and (5) pulmonary histopathology. In the first study, rats received a single dose of the airborne dust sample (10 mg/kg body weight) by intratracheal (IT) instillation. At 1 d post-IT, all inflammatory endpoints were significantly increased versus controls, but by 29 d post-IT they did not differ significantly from controls. Histopathology demonstrated mild to moderate, multifocal, suppurative pneumonia, usually centered around bronchioles, at 1 d post-IT. At 29 d post-IT, pulmonary inflammation was minimal to mild and characterized by alveolar histocytosis usually restricted to the immediate area of retained birefringent fibers. In subsequent experiments, airborne dust was extracted with water and the dust (washed airborne dust) and water extract (soluble fraction) were separated by centrifugation for further study. Nylon tow dust was prepared in the laboratory by milling uncut nylon strands (called tow) that had not been treated with the finish or dyes that are commonly used in the flock plants. Rats were administered a single dose of a dust sample (10 mg/kg body weight) or the soluble fraction (1.3 ml/ kg body weight) by IT administration and the same endpoints were measured at 1 d post-IT. The dust samples caused significant increases in all of the inflammatory endpoints; however, the soluble fraction was much less active. Histological analysis of the lungs 1 d post-IT confirmed lung inflammation was occurring and tended to center around bronchioles. The results suggest that: (1) nylon flocking generates particles of respirable size that can interact with AM in the lung and can be detected in the lung 29 d after exposure, ( 2) the dust samples examined cause an inflammatory response, (3) water-extractable agent(s) from airborne dust contribute only minimally to the inflammatory response, and (4) the acute inflammatory response to these dusts is substantial when compared to other pathologic occupational dusts previously examined in our laboratory.     

EFFECTS OF VERAPAMIL ON PANCREATIC EXOCRINE SECRETION INDUCED BY DOPAMINE, SECRETIN AND PANCREOZYMIN IN THE DOG

1. The effects of verapamil on dopamine-, secretin- and pancreozymin-induced pancreatic secretion were investigated in the isolated, blood-perfused canine pancreas in vivo. 2. The volume of pancreatic secretion either in the resting state or induced by pancreozymin given intra-arterially (i.a.) was decreased by an infusion of 5 μg/min of verapamil; that induced by dopamine or secretin i.a. was also decreased but the changes were not statistically significant. 3. Protein concentration in pancreatic juice either in the resting state or in that of stimulated secretion by pancreozymin was decreased significantly, but protein concentration induced by dopamine or secretin was not affected, by verapamil treatment. 4. Verapamil had no effect on bicarbonate concentration in pancreatic juice secreted either in the resting state or when stimulated by these secretagogues. 5 These results suggest that verapamil, at least in part, may affect the secretory mechanisms of acinar cells but not that of the ductular cells.     

FACTORS INVOLVED IN HEPATIC GLUTATHIONE DEPLETION INDUCED BY ACUTE ETHANOL ADMINISTRATION

Factors implicated in changes of the hepatic glutathione concentration following acute ethanol administration were examined in rats. Adult female rats were treated with either ethanol (4 g/kg, po) or an isocaloric glucose solution. The hepatic reduced glutathione (GSH) concentration decreased rapidly after ethanol intake with a maximum diminution, approximately 50% of the control value, being observed at t = 6 h. The hepatic GSH concentration gradually increased, and finally rebounded at 24 h after ethanol ingestion. The dose of ethanol induced a transient increase in the oxidized glutathione (GSSG) and GSSG/GSH ratio, which was associated with a significant reduction in GSH rather than elevation in GSSG. The activity of g-glutamylcysteine synthetase (GCS), the rate-limiting enzyme for glutathione synthesis, and the cysteine concentration in liver were also measured. The GCS activity was depressed to approximately 80% of the control value at t = 2.5 h followed by rapid recovery, but no difference in the hepatic cysteine concentration between control and ethanol treated rats was observed for 24 h, suggesting that the reduction in glutathione synthesis may not play a major role in the significant depletion of this tripeptide in liver. The total glutathione concentration was measured both in prehepatic and posthepatic inferior vena cava blood. The glutathione concentration in posthepatic blood was approximately twice as high as that of prehepatic blood in control rats. Acute ethanol administration doubled the elevation of glutathione in posthepatic blood measured at t = 2.5 h. The sinusoidal efflux of glutathione estimated from the increase in blood glutathione concentration was greater than the total amount of its depletion in the liver of rats treated with ethanol. The results suggest that in the liver of rats treated acutely with ethanol, glutathione efflux plays the most important role in the reduction of this tripeptide, which would be aggravated by a transient decrease in glutathione synthesis and by increased consumption in association with its metabolism.