H_1 and H_2 receptors in the locus ceruleus are involved in the intracere-broventricular histamine-induced carotid sinus baroreceptor reflex reset-ting in rats

Objective To investigate the role of H1 and H2 receptors in the locus ceruleus （LC） in carotid sinus baroreceptor reflex （CSR） resetting induced by intracerebroventricular （i.c.v.） injection of histamine （HA）. Methods The left and right carotid sinus regions were isolated from the systemic circulation in 18 male Sprague-Dawley rats anesthetized with pentobarbital sodium. The intracarotid sinus pressure （ISP） was altered in a stepwise manner in vivo. ISP-mean arterial pressure （MAP） relationship curve and its characteristic parameters were constructed by fitting to the logistic function with five parameters. The changes in CSR performance induced by i.c.v. HA and the effects of pretreatment with H1 or H2 receptors selective antagonist, chlorpheniramine （CHL） or cimetidine （CIM） into the LC, on the responses of CSR to HA were examined. Results I.c.v. HA （100 ng in 5 μl） significantly shifted the ISP-MAP relationship curve upwards （P 〈 0.05） and obviously decreased the value of the reflex parameters such as MAP range and maximum gain （P 〈 0.05）, but increased the threshold pressure, saturation pressure and ISP at maximum gain （P 〈 0.05）. The pretreatment with CHL （0.5 μg in 1 μl） or CIM （1.5 μg in 1 μl） into the LC could obviously attenuate the changes mentioned above in CSR performance induced by HA, but the alleviative effect of CIM was less remarkable than that of CHL （P 〈 0.05）. Respective microinjection of CHL or CIM alone into the LC with the corresponding dose and volume did not change CSR performance significantly （P 〉 0.05）. Conclusion Intracerebroventricular administration of HA results in a rapid resetting of CSR and a decrease in reflex sensitivity, and the responses of CSR to HA may be mediated, at least in part, by H1 and H2 receptors activities in the LC, especially by H1 receptors. Moreover, the effects of the central HA on CSR might be related to a histaminergic descending pathway from the hypothalamus to LC.

Stimulation by nizatidine,a histamine H_2-receptor antagonist,of duodenal HCO_3^-secretion in rats:relation to anti-cholinesterase activity

AIM To examine whether nizatidine stimulates duodenal HCO_3^- secretion in rats by inhibiting AChE activity. METHODS Under pentobarbital anesthesia,a proximal duodenal loop was perfused with saline,and the HCO_3 secretion was measured at pH 7.0 using a pH-stat method and by adding 10mM HCI.Nizatidine,neostigmine,carbachol or famotidine was administered i.v.as a single injection. RESULTS Intravenous administration of nizatidine(3-30 mg/kg)dose-dependently increased duodenal HCO_3^- secretion,and the effect at 10mg/kg was equivalent to that obtained by carbachol at 0.01 mg/kg.This nizatidine action was observed at the same dose range that inhibited acid secretion and enhanced gastric motility,mimicked by i.v.injection of neostigmine(0.03 mg/kg),and significantly attenuated by bilateral vagotomy and prior s.c. administration of atropine but not by indomethacin,a cyclooxygenase inhibitor,or N^G-nitro-L-arginine methyl ester,a NO synthase inhibitor.The HCO_3^- secretory response to acetylcholine(0.001 mg/kg)was significantly potentiated by the concurrent administration of nizatidine(3mg/kg,i.v.).The IC_(50)of nizatidine for AChE of rat erythrocytes was 1.4×10^(-6)M,about 12 times higher than that of neostigmine.Neither famotidine(>10^(-3)M, 30mg/kg,i.v.)nor cisapride(> 10^(-3)M, 3mg/kg,i.v.)had any influence on AChE activity or duodenal HCO_3^- secretion.Duodenal damage induced by acid perfusion(100 mM HCI for 4 h)in the presence of indomethacin was significantly prevented by nizatidine and neostigmine,at the doses that increased the HCO_3^- secretion. CONCLUSION Nizatidine stimulates duodenal HCO_3^- secretion,in both vagal-dependent and atropine-sensitive manners,and the action is associated with the anti-AChE activity of this agent.

In vivo immunomodulatory profile of histamine receptors(H1,H2,H3 and H4):a comparative antagonists study

Objective:To delineate the comparative immunomodulatory roles of H1R-H4R in antibody generation profile in rabbit model.Methods:The cohort comprised of eight groups containing 18(9 male and 9 female) rabbits in each group.GroupⅠremained non-immunized and received only vehicle(sterile distilled water,1 mL/kg×b.i.d.) intramuscularly.GroupⅡreceived vehicle (1 mL/kg×b.i.d.) while GroupsⅢ-Ⅶ(drugs-treated) received subcutaneous histamine (100μg/kg×b.i.d.),and intramuscular H1R-antagonist(pheniramine,10 mg/kg×b.i.d.), H2R-antagonist(ranitidine,10 mg/kg×b.i.d.),H3R-antagonist(iodophenpropit,1μg/kg×b.i.d.) and H4R-antagonist(JNJ 7777120,10μg/kg×b.i.d.),and GroupⅧDMSO(1 mL/kg×b.i.d.),respectively for 10 days(starting from day 1).They were subsequendy immunized with intravenous injection of sheep red blood cells(SRBC) at day 3.The estimation of serum Igs,IgM and IgG were done by ELISA,and observed at day 0(pre-immunization),and 7,14,21,28 and 58(post-immunization).Results:It was shown that histamine and HRs-antagonists could influence a detectable antibody response to SRBC as early as day 7-post-immunization(post-Ⅰ), which lasted until day 58 post-Ⅰ.The results were found statistically significant(P【0.05,). Conclusions:This study suggests that histamine receptors play important roles in modulation of antibody generation in which H1R,H2R and H4R have immunosuppressive roles and conversely, H3R playes an immune enhancing role.The findings of this study may have clinical significance and provide the baseline information for future study.

Histamine H2 receptor deletion in glutamatergic neurons causes schizophrenia-like pheno⁃ types

OBJECTIVE Genetic variation in histamine H2 receptor(H2R)and H2R ligands are linked to schizophrenia,however little is known about how H2R contributes to pathogenesis of schizophrenia.Here,we detected a decreased expression of H2R in medial prefrontal cortex(mPFC)glutamatergic neurons in schizophrenia patients.METHODS AND RESULTS Selective knockout of H2R gene(Hrh2)in glutamatergic neurons induced schizophrenia-like behaviors including sensorimotor gating deficit,increased locomotor activity,social withdrawal and anhedo⁃nia in behavior tests,as well as reduced sponta⁃neous firing of mPFC glutamatergic neurons in electrophysiological tests.Selective deletion of the Hrh2 in mPFC glutamatergic neurons but not hippocampus glutamatergic neurons also induced such schizophrenia-like behaviors.Patch-clamp electrophysiology establishes that H2R deficiency reduced the intrinsic excitability of glutamatergic neurons by up-regulation of hyperpolarization activated cyclic nucleotide-gated channels.Fur⁃thermore,either overexpression of H2R in gluta⁃matergic neurons or activation of H2R in the mPFC reversed the MK-801-induced schizophrenia-like symptoms.CONCLUSION H2R can serve as a novel drug target given that functional deficiency of this receptor in mPFC glutamatergic neurons may be crucial for the pathogenesis of schizo⁃phrenia.H2R agonists can be viewed as drug candidates for the treatment of schizophrenia.

Histamine_2-receptor antagonists: Rapid development of tachyphylaxis with repeat dosing

Histamine_2-receptor antagonists(H_2RAs) are availableover-the-counter (OTC) for the treatment and prevention of heartburn, but more than occasional, singledose use can lead to rapid development of tachyphylaxis. The aim of this review is to assess the publishedevidence regarding the development of tachyphylaxiswith repeat usage of H_2RAs. PubMed and SCOPUS were searched across all years to identify clinical studies thatexamined the development of tachyphylaxis with repeated dosing of H_2RAs. Although a single (first) doseof an H_2RA can be effective for controlling gastric acidand preventing or relieving food-related heartburn, numerous studies confirm that tachyphylaxis, also knownas tolerance, is consistently detected at the first timepoint assessed after the first dose, including the second day and/or second dose. Even if symptom relief isachieved with an H_2RA, it may be due to desensitizationof the esophagus to acid exposure, potentially providingsymptom relief without significantly decreasing esophageal acid exposure. When recommending OTC drugsfor treatment of frequent heartburn, clinicians shouldbe aware of the potential for rapid development oftachyphylaxis in patients who use H_2RAs for 2 or more consecutive days. Even if symptom relief is achieved, it may be due to desensitization of the esophagus to acid by the H_2RA, potentially providing symptom relief without significantly decreasing esophageal acid exposure. Other strategies, such as an OTC proton pump inhibitor, may be needed to optimize management of frequent heartburn.

Proton pump inhibitors therapy vs H_2 receptor antagonists therapy for upper gastrointestinal bleeding after endoscopy: A meta-analysis

AIM: To compare the therapeutic effects of proton pump inhibitors vs H2 receptor antagonists for upper gastrointestinal bleeding in patients after successful endoscopy.METHODS: We searched the Cochrane library, MEDLINE, EMBASE and Pub Med for randomized controlled trials until July 2014 for this study. The risk of bias was evaluated by the Cochrane Collaboration's tool and all of the studies had acceptable quality. The main outcomes included mortality, re-bleeding, received surgery rate, blood transfusion units and hospital stay time. These outcomes were estimated using odds ratios(OR) and mean difference with 95% confidence interval(CI). Rev Man 5.3.3 software and Stata 12.0 software were used for data analyses. RESULTS: Ten randomized controlled trials involving 1283 patients were included in this review; 678 subjects were in the proton pump inhibitors(PPI) group and the remaining 605 subjects were in the H2 receptor antagonists(H2RA) group. The meta-analysis results revealed that after successful endoscopic therapy, compared with H2 RA, PPI therapy had statistically significantly decreased the recurrent bleeding rate(OR = 0.36; 95%CI: 0.25-0.51) and receiving surgery rate(OR = 0.29; 95%CI: 0.09-0.96). There were no statistically significant differences in mortality(OR = 0.46; 95%CI: 0.17-1.23). However, significant heterogeneity was present in both the numbers of patients requiring blood transfusion after treatment [weighted mean difference(WMD),-0.70 unit; 95%CI:-1.64- 0.25] and the time that patients remained hospitalized [WMD,-0.77 d; 95%CI:-1.87- 0.34]. The Begg's test(P = 0.283) and Egger's test(P = 0.339) demonstrated that there was no publication bias in our meta-analysis.CONCLUSION: In patients with upper gastrointestinal bleeding after successful endoscopic therapy, compared with H2 RA, PPI may be a more effective therapy.

Stronger inhibition of gastric acid secretion by lafutidine, a novel H_2 receptor antagonist, than by the proton pump inhibitor lansoprazole

AIM: To compare the antisecretory activity and plasma drug concentrations of a single oral dose of 10 mg lafutidine, a novel H2 receptor antagonist, with those of the proton pump inhibitor lansoprazole (LPZ) 30 mg. METHODS: Ten volunteers without H pylori infection participated in this crossover study comparing lafutidine 10 mg with LPZ 30 mg. Intragastric pH was monitored for 6 h in all participants, and blood samples were collected from four randomly selected individuals after single-dose administration of each drug. RESULTS: The median intragastric pH was significantly higher in individuals who received lafutidine 10 mg than in those who received LPZ 30 mg 2, 3, 4, 5, and 6 h after administration. Maximal plasma drug concentration was reached more promptly with lafutidine 10 mg than with LPZ 30 mg. CONCLUSION: In H pylori-negative individuals, gastric acid secretion is more markedly inhibited by lafutidinethan by LPZ.

Changes in hippocampal histamine receptors in rats after treatment with Trimeresurus albolabris venom

BACKGROUND： It has been demonstrated that histamine and its receptors in the hippocampus play an important role in memory and/or learning behaviors.OBJECTIVE： To investigate the expression levels of the histamine receptor gene and protein in the hippocampi of rats prior to and after administration of Trimeresurus albolabris venom using reverse transcription-polymerase chain reaction （RT-PCR） and Western blot techniques. DESIGN, TIME AND SETTING： A controlled observation based on cellular protein level was performed in the College of Life Sciences, Chongqing Normal University between March 2005 and April 2007. MATERIALS： Eighty adult male Sprague-Dawley rats were provided by the Laboratory Animal Center of the Third Military Medical University of Chinese PLA. The lyophilized powder of Trimeresurus albolabris venom was collected from Jin-Hu-Shan in Chongqing, China. METHODS： Twenty rats were randomly and evenly divided into an experimental group and a control group The experimental group was subcutaneously injected with 0.65 mg/mL Trimeresurus albolabris venom, 0.5 mL for each rat. The control group was subcutaneously injected with an equal amount of 0.9% physiological saline. Prior to and after injection, rats from these two groups were placed in the Morris Water Maze for recording of path length and escape latency. The remaining 60 rats were randomly allocated to another experimental group （n = 50） and another control group （n = 10）. Rats were correspondingly injected as described above. At different time points （0.1, 0.5, 1, 2, and 3 hours after injection）, rats were decapitated and bilateral hippocampal tissues were dissociated （approximately 100 mg for each sample）. Then, the acquired hippocampal tissue was immediately preserved at -70 ℃ for subsequent experiments. MAIN OUTCOME MEASURES： （1） The levels of histamine receptor （including H1R, H2R, and H3R） mRNA and protein in the hippocampi of rats were measured prior to and after injection of Trimeresurus albolabris venom using RT-PCR and Western Blot techniques. （2） Escape latency （namely, time to reach a platform） and path length were examined by Morris Water Maze testing. RESULTS： All 80 rats were included in the final analysis. In the experimental group, the level of mRNA for H3R receptor in rat hippocampi was just slightly changed, but the level of H3R receptor protein was significantly down-regulated compared with that in the control group （P 〈 0.05）. Both mRNA and protein levels for H1R receptor were initially downregulated and then recovered to normal levels. Expression of H2R receptor mRNA was initially upregulated, then downregulated, and finally restored to the control level. The level of H2R receptor protein showed a tendency for downregulation. In the Morris Water Maze testing, escape latency and path length were significantly longer in the experimental group than in the control group （P 〈 0.05）. CONCLUSION： Within three hours of injection with Trimeresurus albolabris venom, mRNA and protein levels of most histamine receptors in rat hippocampi were downregulated. Such changes possibly contribute to an impairment of memory and/or learning behaviors in rats following injection of Trimeresurus albolabris venom.

Role of Histamine H1 Receptors in Vestibular Nucleus in Motion Sickness

Objectives To investigate the expression of histamine H1 receptors （H1R） in the vestibular nucleus of brainstem in rats and the role of H1R in motion sickness （MS）. Methods A total of 24 healthy Sprague-Dawley rats were divided randomly into four groups （n=6 each） which determined if the animals would receive induction of MS or drug （promethazine） treatment： MS （ - ）/Drug （ - ）; MS（＋）/Drug （ - ）; MS （ - ）/Drug （ ＋ at 0.25 mg）; and MS （ ＋ ）/ Drug（＋）. MS was induced by complex motion stimulation and the conditioned taste aversion was used as a behavioral indicator of MS. The volume of 0.15% sodium saccharin solution （SS） intake within 45 minutes after motion stimulation was measured. H1R in the vestibular nucleus was examined by immunofluorescence staining. The expression of H 1R protein in brainstem tissue at vestibular nucleus level was detected by western blot. Results The mean SS intake volume in the MS （ ＋ ）/Drug （ - ） group （8.8 ml） was significantly less than that of the MS （ - ）/Drug （ - ） group （15.1 ml） （P 〈 0.01）. The mean SS intake volume of the MS （-）/Drug （＋） group （14.8 ml） was similar to that of the MS（-）/Drug（-） group. The mean SS intake volume （9.6 ml） of the MS（＋）/Drug（＋） group was more than that of the MS（＋）/Drug（-）group （P〈0.01）, but less than that of the MS（-）/Drug（-） group or MS（-）/Drug（＋） group （P 〈 0.01）. Immunofluorescence staining showed positive expression of H1R in the vestibular nucleus of brainstem and the expression was enhanced by motion stimulation. Western blot analysis showed that H1R protein expressed in the brainstem tissue at vestibular nucleus level and the expression also increased significantly after motion stimulation. The MS-induced increase of H1R was not affected significantly by promethazine. Conclusions H1Rs exist in the vestibular nucleus in rats and H 1R expression is up-regulated by motion stimulation, but not affected by promethazine. The findings indicate that the histaminergic system is involved in MS. Promethazine, as an H1R blocker, may play its anti-MS role by competing the binding site on H1Rs with histamine rather than inhibiting H1R expression.

Roles of transient receptor potential channel 6 in glucose-induced cardiomyocyte injury

BACKGROUND Diabetic cardiomyopathy(DCM) is a serious complication of end-stage diabetes that presents symptoms such as cardiac hypertrophy and heart failure. The transient receptor potential channel 6(TRPC6) protein is a very important selective calcium channel that is closely related to the development of various cardiomyopathies.AIM To explore whether TRPC6 affects cardiomyocyte apoptosis and proliferation inhibition in DCM.METHODS We compared cardiac function and myocardial pathological changes in wild-type mice and mice injected with streptozotocin(STZ), in addition to comparing the expression of TRPC6 and P-calmodulin-dependent protein kinase Ⅱ(P-CaMKⅡ) in them. At the same time, we treated H9C2 cardiomyocytes with high glucose and then evaluated the effects of addition of SAR, a TRPC6 inhibitor, and KN-93, a CaMKⅡ inhibitor, to such H9C2 cells in a high-glucose environment.RESULTS We found that STZ-treated mice had DCM, decreased cardiac function, necrotic cardiomyocytes, and limited proliferation. Western blot and immunofluorescence were used to detect the expression levels of various appropriate proteins in the myocardial tissue of mice and H9C2 cells. Compared to those in the control group, the expression levels of the apoptosis-related proteins cleaved caspase 3 and Bax were significantly higher in the experimental group, while the expression of the proliferation-related proteins proliferating cell nuclear antigen(PCNA) and CyclinD1 was significantly lower. In vivo and in vitro, the expression of TRPC6 and P-CaMKⅡ increased in a high-glucose environment. However, addition of inhibitors to H9C2 cells in a high-glucose environment resulted in alleviation of both apoptosis and proliferation inhibition.CONCLUSION The inhibition of apoptosis and proliferation of cardiomyocytes in a high-glucose environment may be closely related to activation of the TRPC6/P-CaMKⅡ pathway.

Imetit Dihydrobromide and Thioperamide Medication in Cough Hypersensitivity Model—The Role of H3 Receptors

Chronic cough is a troublesome problem and it is frequently associated with diseases such as gastroesophageal reflux, asthma and upper airway diseases—so called diagnostic triade. The magnitude and severity of cough is strongly associated with the ongoing nasal inflammation in subjects with rhinosinusitis and treatment of nasal inflammation leads to the down regulation of pathologically up-regulated cough. Histamine plays a key role in the inflammation of the upper airways of different aetiologies;therefore histamine receptors seem to be promising targets. The aim of our study was to ascertain the effect of H3R agonist imetit and H3R antagonist thioperamide on cough and symptoms of allergic rhinitis (AR) in an animal model of upper airway cough syndrome in ovalbumin sensitized guinea pigs. OVA sensitized guinea pigs (n = 10) were repeatedly challenged with i.n. allergen-OVA to induce allergic rhinitis and to enhance cough reflex according to the validated model of experimental allergic rhinitis. Animals were pre-treated by i.p. administration of imetit (1 mg/kg and 2 mg/kg of body weight) and thioperamide 30 min. prior i.n. OVA administration. Rhinitis evaluation was based on the occurrence of typical symptoms. The effect on cough was assessed from the response to inhalation of citric acid (0.4 M, 10 min), final cough count and cough latency were analysed from the airflow traces, cough motor pattern and the cough sound. AR up-regulated the cough response from 9 ± 2 to 16 ± 1 cough per provocation, med ± IQR, p < 0.05 and shortened cough latency. Imetit (1 mg/kg) suppressed nasal symptoms and decreased number of cough from 16 ± 1 to 12 ± 1;however the data did not reach significance. Imetit (2 mg/kg) significantly suppressed the nasal symptoms, and number of coughs from 16 ± 1 to 6 ± 2, med ± IQR, p < 0.05. Thioperamide (5 mg/kg of body weight) did not have expected effects on tested parameters. H3R agonist imetit, unlike H3R antagonist thioperamide has antitussive potential and ability to suppress nasal symptoms in animal model of allergic rhinitis.

Histamine Excites Rat GABAergic Ventral Pallidum Neurons via Co-activation of H1 and H2 Receptors

The ventral pallidum(VP) is a crucial component of the limbic loop of the basal ganglia and participates in the regulation of reward, motivation, and emotion.Although the VP receives afferent inputs from the central histaminergic system, little is known about the effect of histamine on the VP and the underlying receptor mechanism. Here, we showed that histamine, a hypothalamicderived neuromodulator, directly depolarized and excited the GABAergic VP neurons which comprise a major cell type in the VP and are responsible for encoding cues of incentive salience and reward hedonics. Both postsynaptic histamine H1 and H2 receptors were found to be expressed in the GABAergic VP neurons and co-mediate the excitatory effect of histamine. These results suggested that the central histaminergic system may actively participate in VP-mediated motivational and emotional behaviors via direct modulation of the GABAergic VP neurons. Our findings also have implications for the role of histamine and the central histaminergic system in psychiatric disorders.

雷公藤多苷联合他克莫司及激素治疗难治性肾病综合征的效果及对血清sTNF-R1、IGFBP-2、CFH水平的影响

目的 探讨雷公藤多苷联合他克莫司及激素治疗难治性肾病综合征(RNS)的疗效对血清可溶性肿瘤坏死因子受体1(s TNF-R1)、胰岛素样生长因子结合蛋白-2(IGFBP-2)、补体因子H(CFH)水平的影响。方法 研究对象为2018年8月至2021年8月于江南大学附属医院治疗的RNS患者102例,以随机数字表法分为对照组(n=51,采取甲泼尼龙片加他克莫司胶囊治疗)和观察组(n=51,在对照组基础上给予雷公藤多苷片治疗)。评估两组的治疗效果、血清相关指标,统计两组的不良反应。结果 观察组治疗总有效率(96.08%)高于对照组(80.39%)(χ^(2)=6.044,P=0.014);治疗后,观察组患者血清白蛋白、CFH水平[分别为(36.54±8.11) g·L^(-1)、(586.20±100.72)μg·m L^(-1)],高于对照组[分别为(32.58±6.12) g·L^(-1)、(540.11±100.47)μg·m L^(-1)],差异均有统计学意义(t=2.783,P=0.006;t=2.314,P=0.023);观察组患者24 h尿蛋白、肌酐、s TNF-R1、IGFBP-2水平[分别为(2.67±0.69) g、(82.25±16.13)μmol·L^(-1)、(1.56±0.45) ng·m L^(-1)、(51.34±10.44) ng·m L^(-1)],低于对照组[分别为(3.24±1.02) g、(92.68±17.35)μmol·L^(-1)、(1.91±0.58) ng·m L^(-1)、(57.79±12.58) ng·m L^(-1)],差异均有统计学意义(t=3.306,P=0.001;t=3.135,P=0.002;t=3.405,P=0.001;t=2.820,P=0.005);观察组复发率(1.96%)低于对照组(13.73%)(χ^(2)=4.883,P=0.027)。结论 公藤多苷联合他克莫司及激素治疗RNS效果佳,降低复发率,改善肾功能,减轻炎症,有望作为辅助治疗RNS的药物。

Effects of splice sites on the intron retention in histamine H_3 receptors from rats and mice

In the alternative splicing, intron retention, of histamine H3 receptors in rats and mice, the short transcript isoforms that are excised alternatively spliced introns are easily detected in a very low level in rats and are undetectable in mice using the regular PCR protocol. The retained introns have common 5＇ splice site and different 3＇ splice sites. The detailed mechanism for the special alternative splicing remains largely unclear. In this study, we developed a minigene splicing system to recapitulate natural alternative splicing of the receptors and investigated the effects of 5＇ and 3＇ splice sites on intron retention in HeLa cells. Mutating weak 5＇ and 3＇ splice sites of the alternatively spliced introns toward the canonical consensus sequences promoted the splicing of the corresponding introns in rat and mouse minigenes. The effect of splice site strength was context-dependent and much more sigiaificant for the 3＇ splice site of the longer alternative intron than for the 3＇ splice site of the shorter alternative intron and the common 5＇ splice sites; it was also more significant in the rat minigene than in the mouse minigene. Mutating the 3＇ splice site of the longer alternative intron resulted in almost complete splicing of the intron and made the corresponding isoform to become the nearly exclusive transcript in the rat minigene.

组胺H 1受体激动剂通过Akt/NF-κB通路抑制脂多糖诱导的星形胶质细胞炎症反应

目的探讨组胺H 1受体(histamine H 1 receptor,H 1R)对脂多糖(lipopolysaccharide,LPS)诱导的星形胶质细胞炎症反应的影响及其调控机制。方法采用LPS建立体外星形胶质细胞炎症模型,随机将大鼠原代星形胶质细胞分为对照组、LPS组、LPS+H 1R激动剂组(2-pyridylethlamine,Pyri)和H 1R激动剂组。对照组仅加入培养液,LPS+H 1R激动剂组提前在培养液中加入100μmol·L-1的Pyri,1 h后再加入终浓度为100μg·L-1的LPS。CCK-8法检测细胞活性;免疫荧光法检测活化标记物GFAP和H 1R的表达;倒置相差显微镜下观察星形胶质细胞的形态变化;ELISA法检测细胞上清中炎症因子TNF-α和IL-6水平;Western blot检测p-Akt、Akt、p-NF-κB p65、NF-κB p65的蛋白表达。结果与对照组比较,LPS组星形胶质细胞分支和辐射状突起减少,GFAP表达增加,细胞表面H 1R表达下调,上清液中TNF-α和IL-6含量增加,Akt和NF-κB p65的磷酸化水平明显增加;与LPS组相比,LPS+H 1R激动剂组激活态星形胶质细胞减少,GFAP表达降低,培养基上清中TNF-α和IL-6的含量明显下降,Akt和NF-κB p65的磷酸化表达明显降低。结论H 1R激动剂能够抑制LPS诱导的星形胶质细胞活化和炎症因子的表达,且Akt/NF-κB通路可能是H 1R参与星形胶质细胞免疫调节的重要途径。

紫外/过二硫酸盐对组胺H_(2)受体拮抗剂的降解特性及自由基模拟

研究了基于硫酸根的高级氧化技术UV/过二硫酸盐(UV/PDS)对水体中组胺H2受体拮抗剂(HRAs)的降解,并选取HRAs中的典型物质西咪替丁(CMTD)为目标污染物.采用竞争动力学方法得到了HRAs和·OH及SO_(4)^(−)反应的二级速率常数,k·OH/HRAs为(2.8—14.6)×10^(9)L·mol^(−1)·s^(−1),kSO_(4)^(−)/HRAs为(0.81—8.10)×10^(9)L·mol^(−1)·s^(−1).研究在实验基础上建立了UV/PDS的自由基拟稳态模型,模拟结果表明,UV/PDS对污染物的降解,其间接光解起主要作用,体系中·OH和SO_(4)^(−)是间接光解的主导自由基.在(0.1—0.5)mmol·L^(−1)PDS投加量下,·OH和SO_(4)^(−)的浓度分别为(3.85—5.16)×10^(−16)mol·L^(−1),(1.21—1.68)×10^(−13)mol·L^(−1),SO_(4)^(−)对污染物的降解起主导作用.酸性条件下自由基浓度相对更高,从而促进了CMTD的去除.水体基质(Cl^(−)、HCO_(3)^(−)和NOM)存在条件下,CMTD的降解受到一定的抑制,模拟结果表明自由基浓度显著降低;但是模拟结果与实验结果有一定偏差,主要是基质存在下生成了衍生自由基,由于衍生自由基的复杂性而未计入模型计算中导致.在实际水样中应用的研究表明,UV/PDS可以有效降解地表水(SW)和实际废水(WW)中的CMTD,具有良好的应用前景.

质子泵抑制剂和H_2受体阻滞剂预防应激性溃疡的系统评价再评价

目的对质子泵抑制剂和H_2受体阻滞剂预防应激性溃疡的有效性和安全性系统评价进行再评价。方法计算机检索Cochrane图书馆、Pub Med、Embase、Web of Sciene、中国知网(CNKI)、中国科技期刊全文数据库(VIP)、中国生物医学文献数据库(CBM)和万方医学数据库,检索时限均从建库至2016年5月。根据纳入排除标准,筛选符合纳入排除标准的系统评价和Meta分析,使用AMSTAR量表评价所纳入系统评价的方法学质量,Grade系统评价结局指标的证据质量,提取原始研究用Rev Man 5.3软件进行Meta分析。结果共纳入7个系统评价/Meta分析,方法学质量评分>7分者仅占41.86%;对21个单个结局指标分别进行质量评价,14个(67.77%)的证据质量均为低或极低。对36个研究(3 820例)数据进行再分析,PPI在预防应激性溃疡出血、临床大出血和显性出血方面优于H_2RA(P<0.001),但是在肺炎发生率、死亡率和ICU住院天数方面,PPI和H_2RA比较差异无统计学意义(P>0.05)。结论 PPI预防ICU的危重患者的应激性溃疡出血优于H_2RA,但原始研究质量不高,仍需后续更多的高质量、结局指标设计全面的前瞻性研究。

组胺H_3受体对垂体瘤AtT-20细胞分泌ACTH的调节作用

目的 观察组胺受体激动剂对 At T- 2 0细胞分泌ACTH的影响 ,并探讨 G蛋白在组胺 H3受体信号转导机制中的作用 .方法 选用文献报道的高表达组胺 H3受体的垂体细胞瘤 At T- 2 0作为观察系统 ,用放免分析法测定给予组胺受体激动剂后各时间点细胞上清液中 ACTH分泌量的变化 ,并观察药物对细胞增殖的影响 .结果 组胺 H3受体激动剂R- (α) - Me HA(0 .1μmol· L- 1 )作用 8h能明显促进 ACTH的释放 ,释放量为 192 0 μg· L- 1 ,与同时间对照组 (780 μg·L- 1 )相比 ,明显增高 (P<0 .0 1) ;H1 和 H2 激动剂则无此作用 .且 R- (α) - Me HA引起 ACTH分泌的效应能被 H3受体特异性拮抗剂 thioperamide所拮抗 ,而 H1 受体和 H2 受体拮抗剂均不影响 R- (α) - Me HA的效应 .R- (α) - Me HA作用 8和 2 4h,对细胞增殖无明显影响 .用 G蛋白失活剂 NEM预先处理细胞后 ,取消了 R- (α) - Me HA增强 At T- 2 0细胞 ACTH分泌的效应 .结论 特异性激动组胺 H3受体后能引起兴奋 -分泌耦联过程 ,其信号转导过程中有 G蛋白的参与 .

Comparative study of therapeutic effects of PPI and H2RA on ulcers during continuous aspirin therapy

AIM:To compare the therapeutic effects of proton pump inhibitors(PPI) and histamine 2 receptor antagonists(H2RA) on gastroduodenal ulcers under continuous use of low-dose aspirin.METHODS:Sixty patients who had a gastroduodenal ulcer on screening endoscopy but required continuous use of low-dose aspirin were randomly assigned to receive PPI(lansoprazole 30 mg,n = 30) or H2RA(famotidine 40 mg or if famotidine had been administered before assignment,ranitidine 300 mg,n = 30).The therapeutic effects were evaluated by endoscopy after 8-wk treatment.The presence or absence of Helicobacter pylori(H.pylori) was determined by urea breath test before treatment.Abdominal symptoms were compared with the gastrointestinal symptom rating scale(GSRS) questionnaire before and after treatment.RESULTS:Twenty-six patients in the PPI group and 26 patients in the H2RA group,excluding dropouts,were analyzed.There were no significant differences in median age,sex,underlying disease,smoking status,H.pylori infection,prevalence of ulcers before treatment,and lesion site between the two groups.The therapeutic effects were endoscopically evaluated as healed in 23 patients(88.5%) and not healed in 3 patients in the PPI group and as healed in 22 patients(84.6%) and not healed in 4 patients in the H2RA group.Abdominal symptoms before treatment were uncommon in both groups;the GSRS scores were not significantly reduced after treatment as compared with before treatment.CONCLUSION:The healing rate of gastroduodenal ulcers during continuous use of low-dose aspirin was greater than 80% in both the PPI group and the H2RA group,with no significant difference between the two groups.

H_2受体拮抗剂用于抑制由化疗引起的恶心呕吐的临床研究

基于含铂或中度以上致呕肿瘤化疗方案 ,应用 5 HT3 受体拮抗剂为基础的止呕方法 ,对 12 6例病理学确诊为晚期恶性肿瘤患者按 2∶1信封法随机分组进行跟踪治疗 ,研究组加用H2 受体拮抗剂和安定 ,而对照组加用地塞米松 ,并从疗效、不良反应、耐受性及安全性等方面对两分组加以分析比较。研究组对抑制急性恶心呕吐有效率为91 2 % ( 73 / 80 ) ,迟缓性恶心呕吐有效率为 87 5 % ( 70 / 80 ) ,而对照组分别为 71 7% ( 3 3 / 46)及 60 9% ( 2 8/ 46) ,两分组相比差异有统计学意义 ,P值分别为 0 0 0 4及 0 0 0 1;加救援治疗后 ,研究组总完全控制率 10 0 % ( 80 / 80 ) ,对照组仅70 % ( 2 8/ 46) ,两组间差异也有统计学意义 ,P =0 0 0 0。初步研究结果提示 ,以 5 HT3 受体拮抗剂为基础加H2 受体拮抗剂和安定的止呕方法对由含铂或中度以上致呕肿瘤化疗方案所引起的恶心呕吐有明显的抑制作用 ,尤其是在迟缓性呕吐方面 ,有效率高 ,不良反应小 ,患者有良好的耐受性及安全性。