The S1P1 regulator IMMH002 and its therapeutic effect and mechanism on autoimmune hepatitis / 药学学报

This study assessed and explored the pharmacological effects and mechanisms of action of IMMH002 {2-amino-2-(2-(4ʹ-(2-ethyloxazol-4-yl)-[1,1ʹ-biphenyl]-4-yl)ethyl)propane-1,3-dio}, a selective sphingosine-1-phosphate receptor subtype 1 (S1P1) modulator, in a concanavalin A (ConA)-induced autoimmune hepatitis (AIH) mouse model. The experimental protocol strictly adhered to the guidelines of the Ethics Committee for Animal Research of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College (Approval No.: 00004046). Male ICR mice were pre-treated with the drug for four days, followed by induction of AIH through tail vein injection of ConA protein. Liver function, hepatic tissue pathology, peripheral blood parameters, as well as immunoglobulin G (IgG), inflammatory cytokines, T cell distribution, and inflammatory pathways were evaluated in mice. Results demonstrated that IMMH002 significantly reduced liver function indicators such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alleviated hepatic tissue inflammation and necrotic damage, decreased serum IgG levels, and lowered the expression of inflammatory mediators including interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interferon γ (IFN-γ). Additionally, it facilitated T lymphocyte homing, downregulated the phosphorylation of nuclear factor kappa-B (NF-κB), IκB kinase β (IKKβ) and nuclear factor inhibitor protein-α (IκBα) proteins in hepatic tissue and cellular inflammation models. Collectively, IMMH002 effectively ameliorated ConA-induced autoimmune hepatitis in mice, exhibiting extensive anti-inflammatory and anti-necrotic effects, thereby laying a theoretical foundation for AIH clinical treatment.

Discovery of exogenous ligands for orphan receptor BRS-3 from Chinese herbs / 中国中药杂志

Bombesin receptor subtype-3(BRS-3) is an orphan receptor in the bombesin receptor family. Its signal transduction mechanism and biological function have attracted much attention. Seeking the ligand for BRS-3 is of great significance for exploring its function. Considering the fact that the activation of BRS-3 receptor can induce the change in intracellular Ca~(2+) concentration, the fluo-rometric imaging plate reader(FLIPR) was utilized for ligand screening at the cellular level. Among more than 400 monomeric compounds isolated from Chinese herbs, yuanhunine from Corydalis Rhizoma and sophoraisoflavanone A and licoriphenone from Glycyrrhizae Radix et Rhizoma antagonized BRS-3 to varying degrees. It was confirmed in HEK293 cells expressing BRS-3 that yuanhunine, sophoraisoflavanone A, and licoriphenone inhibited the calcium current response after the activation of BRS-3 by [D-Phe~6,β-Ala~(11),Phe~(13),Nle~(14)]bombesin-(6-14) in a dose-dependent manner with the IC_(50) values being 8.58, 4.10, and 2.04 μmol·L~(-1), respectively. Further study indicated that yuanhunine and sophoraisoflavanone A exhibited good selectivity for BRS-3. In this study, it was found for the first time that monomers derived from Chinese herbs had antagonistic activity against orphan receptor BRS-3, which has provided a tool for further study of BRS-3 and also the potential lead compounds for new drug discovery. At the same time, it provides reference for the research and development of innovative drugs based on the active ingredients of Chinese herbs.

The Interaction Between CAL and mGluR1 Alleviates Cytotoxicity Induced by mGluR1 Overactivation / 中国生物化学与分子生物学报

Glutamate excitotoxicity mediated by metabotropic glutamate receptor 1 (mGluR1) overexpression or overactivation plays an important role in the development of Parkinson's disease (PD). Although clinical trials support the therapeutic potential of certain mGluR negative allosteric modulators (NAMs), there are still some limitations of precise modulation of mGluR using NAMs. Thus, the identification of small molecules or endogenous genes that facilitate mGluR1 modulation might be potentially beneficial for PD treatment. We determined the role of interacting partner cystic fibrosis transmembrane conductance regulator-associated ligand (CAL) in overactivated mGluR1-mediated cell apoptosis and signaling pathway in vitro and in vivo. HEK293 cells were used as an experimental tool to directly examine the interaction between CAL and mGluR1. We found that agonist of mGluR1 significantly enhanced the interaction between CAL and mGluR1 (P< 0. 05). Furthermore, CAL suppressed overactivated mGluR1-induced cell apoptosis and the activation of mGluR1 downstream signaling pathways. CAL overexpression relieved rotenone-induced neuron death (P< 0. 001) by inhibiting the activation of mGluR1-mediated signaling pathways in rotenone-induced rat model of PD. This study may reveal a new mechanism of mGluR1 activity regulation, and hopefully provide a novel molecular mechanism for the nervous system related diseases.

Effect of Serum on Cultured Astrocytes Morphology and Expression of Aquaporin-4 in Rats / 中国康复理论与实践

Objective To explore the effect of blood-brain barrier disruption on expression of AQP-4,through comparing the cell morphology and the expression of aquaporin-4(AQP-4)of cultured astrocytes in medium with and without fetal bovine serum(FBS). Methods Cerebral cortical astrocytes from female Wistar rats were cultured in serum free medium,DMEM supplement-ed with 10% FBS,and serum free medium supplemented with 10% FBS.Phase contrast microscope was used to detect the cell morphology and cell size. Immunofluorescence staining and reverse real-time quantitative poly-merase chain reaction(RT-qPCR)were used to examine the expression of glial fibrillary acidic protein(GFAP), AQP-4 and metabotropic glutamate receptor 5(mGluR5). Results Astrocytes in serum free medium showed extensive process bearing morphology,small body and nucleus,and high refractivity.In contrast,in two kinds of 10% FBS-containing medium,astrocytes were flat with large body and nucleus,weak refractivity,as well as short process.Analysis of immunofluorescence staining and RT-qPCR revealed a down-regulation of GFAP and AQP-4 protein and mRNA expression in two kinds of 10% FBS-con-taining medium, compared with that in serum free medium (P<0.001), however, there was no difference in mGluR5 protein and mRNA expression(P>0.05). Conclusion FBS changed astrocyte morphology and down-regulated the expression of GFAP and AQP-4.

Activation of transient receptor potential vanilloid subtype 1 serves as a novel path-way to modulate secretion in submandibular gland / 北京大学学报(医学版)

SUMMARY Our work focused on the studies on the expression and function of transient receptor poten -tial vanilloid subtype 1 ( TRPV1) in the submandibular gland .By using reverse transcription-polymerase chain reaction ( RT-PCR ) , Western blotting , and immunofluorescence , our data demonstrated the expression and distribution characteristics of TRPV 1 in rabbit and human submandibular glands , as well as rat submandibular gland cell line SMG-C6.Furthermore, the possible intracellular signal molecules involved in the TRPV1-modulated saliva secretion were explored .Activation of TRPV1 increased the intracellular Ca2+concentration, upregulated the expression of aquaporin 5 (AQP5), the main transpor-ter that mediate water secretion through transcellular pathway , and led to AQP5 redistribution .Extracel-lular signal-regulated kinase 1/2 ( ERK1/2 ) was involved in the TRPV1-regulated AQP5 content. Besides, TRPV1 activation also modulated the expression , distribution, and function of tight junction protein, and increased paracellular permeability .ERK1/2 and myosin light chain 2 ( MLC2 ) were responsible for the regulation of TRPV1on tight junction properties.Taken together, our work suggested that TRPV1 was a potential target to promote saliva secretion , and activation of TRPV1 might provide a new and safe therapeutic strategy to ameliorate submandibular gland hypofunction .

The Importance of the RAS Interacting with the HGF/C-Met Receptor System in Hypertensive Type 2 Diabetes Mellitus.

The classic renin-angiotensin system (RAS) is described as a circulating hormone system with primary roles in the regulation of blood pressure, body water balance and thirst and control over vasopressin and aldosterone release. Recently local tissue RASs have been identified with regulatory physiological functions and also with pathophysiological processes including fibrosis, inflammation and dysfunctional cell proliferation. There is a strong correlation between organs vulnerable to diabetic–induced hyperglycemic injury (eg. kidney and retina) and the over activation of local RASs. Increased angiotensin II concentrations in these tissues promotes hypertension and end-organ damage in at least two ways: 1) By activating AT1 receptor proteins thus inducing changes in local blood flow and tissue hydration and 2) Exacerbating hyperglycemic-induced oxidative stress, elevated polyol and hexosamine pathway variability and facilitating glycation end-products. Thus, inhibition of the RAS has become an important treatment approach to control diabetic related hypertension, nephropathy and to a lesser extent retinopathy. The present review emphasizes the recently established importance of the hepatocyte growth factor (HGF)/c-Met receptor system interacting with the RAS in Type 2 diabetes and their likely contribution to end-organ damage. A hypothesis is offered concerning how the pancreatic RAS may affect dimerization of HGF and in turn activation of the c-Met receptor to promote β cell proliferation and insulin synthesis. We conclude with details concerning the development of an AngIV-based small molecule HGF mimetic designed to act as an insulinotropic factor.

Role of glutamate receptor subtypes in cardiac nociception in nucleus tractus solitarius in rats / 吉林大学学报(医学版)

Objective To study the role of glutamate receptor subtypes in nucleus tractus solitarius(NTS)in cardiac-somatic motor reflex (CMR)induced by intrapericardial administration of capsaicin,and to clarify the modulation mechanism of NTS to cardiac nociceptoion.Methods 60 SD rats were randomly divided into ibotenic (IBO)group, glutamate group, MK-801 group, MCGP group, MK-801 + MCPG group and DNQX group. The NTS microinjected with 130 mmol·L-1 IBO 100 nL,100,200,500 mmol·L-1 L-glutamate 100 nL,NMDA receptor antagonist 40 and 60 mmol · L-1 MK-801 100 nL, metabotropic glutamate receptors antagonist 25 and 50 mmol·L-1 MCPG 100 nL,25 mmol· L-1 MCPG 50 nL plus 40 mmol· L-1 MK-801 50 nL,non-NMDA receptor antagonist 20 and 50 mmol·L-1 DNQX 100 nL,respectively.The changes of CMR of the rats in various groups were observed.Results Compared with control group,the CMR of the rats in IBO group was decreased (P0.05).Conclusion NTS play an facilictory role in cardiac nociception,and the NMDA receptors and mGluRs receptors mediate this facilitory modulation.

Characteristics of New Drugs as Ligands of G-Protein Coupled Receptor and Time-Dependent Changes of the New Drug Approvals over Three Decades from 1980 to 2009 in Japan / 医薬品情報学

<b>Objective: </b>We analyzed the characteristics of ligands of G-protein coupled receptor (GPCR) of new drugs approved, and the time dependent changes of these new drug approvals over three decades from 1980 to 2009 in Japan.<br><b>Methods: </b>The receptor therapeutic targets of 185 new drugs were distributed 20 receptor families of GPCR.  Most of new drugs which targeted GPCR were the ligands of class A receptors.  Among the class A receptors, the receptors of amine family, such as adrenaline, dopamine, histamine, serotonin and muscarinic receptor were the targets of new drugs.  One hundred and ten of 185 new drugs were the antagonist and other 75 were the agonist of GPCR.  Whether the new drug is agonist or antagonist depended on the receptor subtype.  The time dependent changes of new drug approval were different among the drugs depending on which GPCR was targeted.  Approval of new drugs which targeted some GPCR decreased time dependently.  In contrast, approval of new drugs which targeted other GPCR increased time dependently or continuously retained.<br><b>Results: </b>The results obtained in this study indicated characteristics of targeted GPCR, and time dependent changes of new drugs approvals, and suggest the future aspect of new drugs.

Endophenotypes and serotonergic polymorphisms associated with treatment response in obsessive-compulsive disorder

OBJECTIVES: Approximately 40-60% of obsessive-compulsive disorder patients are nonresponsive to serotonin reuptake inhibitors. Genetic markers associated with treatment response remain largely unknown. We aimed (1) to investigate a possible association of serotonergic polymorphisms in obsessive-compulsive disorder patients and therapeutic response to selective serotonin reuptake inhibitors and (2) to examine the relationship between these polymorphisms and endocrine response to intravenous citalopram challenge in responders and non-responders to serotonin reuptake inhibitors and in healthy volunteers. METHODS: Patients with obsessive-compulsive disorder were classified as either responders or non-responders after long-term treatment with serotonin reuptake inhibitors, and both groups were compared with a control group of healthy volunteers. The investigated genetic markers were the G861C polymorphism of the serotonin receptor 1Dβ gene and the T102C and C516T polymorphisms of the serotonin receptor subtype 2A gene. RESULTS: The T allele of the serotonin receptor subtype 2A T102C polymorphism was more frequent among obsessive-compulsive disorder patients (responders and non-responders) than in the controls (p<0.01). The CC genotype of the serotonin receptor subtype 2A C516T polymorphism was more frequent among the non-responders than in the responders (p<0.01). The CC genotype of the serotonin receptor subtype 1Dβ G681C polymorphism was associated with higher cortisol and prolactin responses to citalopram (p<0.01 and p<0.001, respectively) and with a higher platelet-rich plasma serotonin concentration among the controls (p<0.05). However, this pattern was not observed in the non-responders with the same CC genotype after chronic treatment with serotonin reuptake inhibitors. This CC homozygosity was not observed in the responders.

Changes in the Muscarinic Receptors on the Colonic Smooth Muscles of Rats with Spinal Cord Injury

OBJECTIVE: To investigate changes in (1) the colonic response to acetylcholine (Ach), (2) the muscarinic (M) receptors in the colon, and (3) the levels of colonic contraction-related proteins after a spinal cord injury (SCI). METHOD: We divided 16 Sprague-Dawley rats into 2 groups: the control group and the SCI group. A spinal cord transection was performed surgically at the T10 vertebral level. After 1 week, the entire colon was divided into 2 segments, the proximal and distal colon. Each segment was mounted in a longitudinal or circular muscle direction in a 10-ml organ bath. We determined the intergroup differences as percentage changes in contractility after Ach treatment alone, Ach treatment with M2 receptor antagonist (AQ-RA741) pretreatment, and Ach treatment with M3 receptor antagonist (4-DAMP) pretreatment. Western blot analyses were performed to determine the expression level of RhoA, and heat shock protein 27 (HSP27). RESULTS: Compared to the control rats, the SCI rats showed an increased response to Ach along both the directions in the proximal colon (p<0.05). Compared to the control group, in the SCI group, the Ach response was significantly different in the proximal segment under AQ-RA741 pretreatment (p<0.05) and in the distal segment under 4-DAMP pretreatment (p<0.05). Findings of the western blot analyses showed a significant decrease in the level of protein gene product 9.5 in the proximal and distal colon and a significant increase in the level of RhoA and HSP27 in the proximal colon of the SCI rats. CONCLUSION: Our results suggest that changes in colonic contractility after SCI are partly attributable to changes in the M receptor subtypes.

Roles of Opioid Receptor Subtype in the Spinal Antinociception of Selective Cyclooxygenase 2 Inhibitor

BACKGROUND: Selective inhibitors of cyclooxygenase (COX)-2 are commonly used analgesics in various pain conditions. Although their actions are largely thought to be mediated by the blockade of prostaglandin (PG) biosynthesis, evidences suggesting endogenous opioid peptide link in spinal antinociception of COX inhibitor have been reported. We investigated the roles of opioid receptor subtypes in the spinal antinociception of selective COX-2 inhibitor. METHODS: To examine the antinociception of a selective COX-2 inhibitor, DUP-697 was delivered through an intrathecal catheter, 10 minutes before the formalin test in male Sprague-Dawley rats. Then, the effect of intrathecal pretreatment with CTOP, naltrindole and GNTI, which are micro, delta and kappa opioid receptor antagonist, respectively, on the analgesia induced by DUP-697 was assessed. RESULTS: Intrathecal DUP-697 reduced the flinching response evoked by formalin injection during phase 1 and 2. Naltrindole and GNTI attenuated the antinociceptive effect of intrathecal DUP-697 during both phases of the formalin test. CTOP reversed the antinociception of DUP-697 during phase 2, but not during phase 1. CONCLUSIONS: Intrathecal DUP-697, a selective COX-2 inhibitor, effectively relieved inflammatory pain in rats. The delta and kappa opioid receptors are involved in the activity of COX-2 inhibitor on the facilitated state as well as acute pain at the spinal level, whereas the micro opioid receptor is related only to facilitated pain.

Clinicopathologic feature and PRA,PRB expressions of 17 cases uterine malignant mixed mesodermal tumor and their significannce / 中国癌症杂志

Background and purpose:MMMT is known as a rare malignancy in gynecological tumor. Because of its difficulty in diagnosis and treatment, the prognosis is extremely poor. This study was to discuss the clinicopathologic feature and PRA,PRB expressions of uterine MMMT. Methods:We analysed clinicopathologic data and the expressions of PRA,PRB by immunohistochemical staining on 17 cases of uterine MMMT, and 11 patients were followed up. Results:①The patients usually presented with abnormal vaginal bleeding with no specifi city clinically. ②The morphological changes were various and complicated, including epithelial and mesenchymal components and a variety of inter-permeated and transitional tissue elements.③The positive rate of PRA in stageⅠ and stageⅡ were 66.7% and 40%, and PRB in stage Ⅰ and stageⅡwere 55.6% and 20%, respectively. ④The mean survival time in stageⅠ,Ⅱ and Ⅲ were 43.8 months (32-59), 34.25 months (19~41) and 5 months, respectively. Conclusion:The diagnosis of uterine MMMT was mainly based on tissue morphology; the development of uterine MMMT might be related with the loss of PRA and PRB ; the clinical stage and the expression of PRA and PRB might be the prognostic factors for uterine MMMT.

Muscarinic M5 receptor subtype and its biologic characterizations / 中国药理学通报

The fifth muscarinic receptor (M5), the last one of the muscarinic receptor family to be cloned, has the same basic formation characterization as G-protein coupled receptor family. M5 transduces signals by coupling with G-proteins, which then modulate the activities of a number of effector enzymes and ion channels. As M5 also plays a variety of prominent physiological roles by regulating central transmitters NO and DA, it has been considered as a novel drug therapy target for drug addiction, dysfunction of dopamine-ergic nervous system, Alzheimers disease and cerebral ischemia.

Function and Significance of Very Low Density Lipoprotein Receptor Subtype Ⅱ / 华中科技大学学报（医学）（英德文版）

Summary: To explore the functions of very low density lipoprotein receptor (VLDL-R) subtype II in lipoprotein metabolism and foam cells formation, the recombinant plasmid with the two subtypes cDNA was constructed respectively, the ldl-A7 cell lines were transfected and two cell lines expressing VLDL-R were obtained: one stably expressing the VLDLR with the O-linked sugar region (type I VLDLR) and the other without the O-linked sugar region (type II VLDLR). In the study on binding of VLDLR to their nuclein labeled natural ligands (VLDL and β-VLDL), it was found that surface binding of 125I-VLDL or 125I-β-VLDL of ldl-A7 cells transfected with type I VLDLR recombinant (ldl-A7-VRI) was more higher than that of ldl-A7 cells transfected with type II VLDLR recombinant (ldl-A7-VRII). After being incubated with VLDL for different time, the contents of triglyceride and total cholesterol in cells were mensurated, and the formation of foam cells and accumulation of lipid in cells was observed by oil-red O staining. The results showed that the contents of triglyceride and total cholesterol in ldl-A7-VR I were much higher than those in ldl-A7-VR II, and ldl-A7-VR I could transform into foam cells notably. It was suggested that type I VLDLR binds with relative higher affinity to VLDL and β-VLDL, and internalizes much more lipoprotein into cells. As a result, we can conclude that type I VLDLR plays a more important role in lipoprotein metabolism and foam cells formation than type II VLDLR.

The Effect of Nerve Growth Factor and Vanilloid Receptor Subtype 1 on Bladder Function after Relief of Bladder Outlet Obstruction in Rats / 대한비뇨기과학회지

PURPOSE: This study was performed to investigate the changes in nerve growth factor (NGF), and vanilloid receptor subtype 1 (VR1), after the relief of bladder outlet obstruction, and to look at how these changes participate in functional changes of the bladder. MATERIALS AND METHODS: 50 Wistar male rats, weighing approximately 250-300g, were used for this study, and divided into two groups: 10 controls and 40 experimental. The control group consisted of sham operated animals. The experimental group was obstructed for 3 weeks by partial urethral ligation. After 3 weeks, the obstruction was relieved by urethral deligation. Cystometrograms (CMG) were performed 3 weeks after deligation. On the basis of CMG, the experimental group was subdivided into normalised, and unstable, bladder groups. The bladders of each group were dissected out, weighed and immunohistochemical staining for NGF and VR1 analysis, performed. RESULTS: Compared with the control group, bladder weights of the normalised, and unstable, bladder groups were increased (p<0.05). On CMG, there was no significant difference in contraction pressure among the 3 groups. The contraction interval of the unstable bladder group was markedly decreased compared with that of the control and normalised groups. On immunohistochemical staining, contrary to the control and normalised groups, the intensity of staining for NGF in the unstable bladder group increased in the basal layer, submucosa and interfascicular layers. VR1-immunoactive nerve fibre-like structures were seen in the basal and submucosal layers in the unstable bladder group, and there were no VR1-like structures in the muscle layer. However, there were no VR1-like structures any of the layers of the control and normalised groups. CONCLUSIONS: Increased NGF and VR1 may be related to persistent unstable bladder or bladder irritative symptoms after rectifying a bladder outlet obstruction.

LOCALIZATION OF 5-HT1A RECEPTOR SUBTYPE IN THE RAT NERVOUS SYSTEM / 神经解剖学杂志

Immunocytochemical staining technique by using specific antibody against 5-HT1A receptor subtype (5-HT1AR) wasused to observe the distribution of 5-HT1AR immunoreactivity in the rat nervous system. The highest level of 5-HT1AR im-munoreactivity was observed in piriform cortex, septum, ventraldorsal thalamic nucleus, reticular thalamic nucleus, basolateralamygdaloid nucleus, Purkinje cell layer, red nucleus, facial nucleus and nucleus of the trapezoid body. Considerably weaker im-munoreactivity was detected in hippocampus, frontal cortex, mediodorsal thalamic nucleus, interpeduncular nucleus, mesen-cephalic trigeminal nucleus, dorsal raphe nucleus, spinal trigeminal nucleus, the superficial layers of the spinal dorsal horn, dor-sal root and trigeminal nerve ganglia, Very weak immunoreactivity was found in the olfactory bulb, caudate putamen,globus pal-lidus, nucleus diagonal band, bed nucleus stria terminalis, habenular nucleus, substantia nigra and superior olive. The presentresults indicate that 5-HT1AR immunoreactive structures are widely distributed in the rat nervous system and might play impor-tant role in mediating the multiple effects of 5-HT in the nervous system.

THE EXPRESSION OF THE VANILLOID RECEPTOR SUBTYPE 1 IN AFFERENT FIBERS OF THE RAT ESOPHAGUS / 解剖学报

Objective To study the expression of the capsaicin receptor,vanilloid receptor subtype 1(VR1) immunoreactivity,their morphology and distribution in afferent fibers of rat esophagus. Methods Laser scanning confocal microscope combined with immunohistochemical double labeling methods were used. Results VRl-like immunoreactivity was observed on nerve fibers and terminalis within mucosa,submucosa,muscle layer and surrounding blood vessel throughout esophagus.Their profiles were fine fibers with some spiny,possessing varicose-like swellings along their lengths.About(92.3?3.7)% VR1 positive fibers co-localized with CGRP immunoreactivity,which representing large majority of afferent fibers in the esophagus was extrinsic in origin with cell bodies located in dorsal root ganglia.In dorsal root ganglion,VR1 was expressed in small-and middle-sized cell bodies.About(41.5?4.5)% VRl-immunoreactive neurons co-stained with CGRP and(67.9?3.2)% CGRP positive neurons co-localized with VR1.In nodose ganglion,the expression of VR1 was similar with dorsal root ganglion,but CGRP immunoreactive neurons very few.Only(4.7?1.4)% VR1 positive neurons co-stained with CGRP.Conclusion These results suggest that VR1 is expressed in afferent fibers in the wall of the rat esophagus which is in origin in dorsal root ganglion.

Relationship between IP_3 and detrusor cell contraction mediated by M_3R / 中华泌尿外科杂志

Objective To study the relationship between IP 3 and detrusor cell contraction mediated by M 3R. Methods [3H]-IP contents of human cultured detrusor cells were detected after stimulated by carbachol,atropine,methoctramine and 4-DAMP respectively. Results [3H]-IP contents increased with carbachol concentration.On the different concentrations (10 -9、10 -8、10 -7、10 -6、10 -5、10 -4 mmol/L )of 4-DAMP,[3H]-IP contents were 3 926.57?273.29、2 780.52?211.09、2436.84?153.62、1 973.22?164.71、1 372.38?141.35 and 1 107.98?920.45 cpm respectively.On the some concertrations of Atropine,[3H]-IP contents were 3 602.69?280.17,2 891.31?207.45,1 983.97?145.74,1 269.57? 105.31,1 106.37?75.23,927.50?77.36/min,respectively.On the same concentrations of methoctramine, the [3H]-IP contents was 4 462.74?360.69、3 938.61?327.13、3 315.45?270.36、3 063.19? 246.79、2927.37?226.45 and 2 836.55?241.63 cpm.This donoted that 4-DAMP and atropine signficantly inhibited the effect of carbachol on PI decomposition(P0.05). Conclusions M 3R is much related to IP 3.

Effects of Long-term Atenolol Treatment on Cardiac Adrenoreceptors in Rats / 中国药房

PURPOSE: To know whether the cardiac function of the patients with heart disease is impaired or improved after long-term taking ?-AR antagonists. METHODS: After giving the rats ?-AR selective antagonist, atenolol, for 12wk, the method of radioligand binding assay and the experiment of isolated left-atrium contractive function were carried out to observe the quantity and distribution of ?-AR, its subtypes, ?-AR, and the change of left - atrium contractive function. RESULTS: After long-term administration of atenolol, there were no any obvious changes in ?-AR, the density of the total ?-AR, ?1-AR, and the proportion of ?2-AR in tota1 amount of ?-AR, but the con centrat ion - response cu rves shi fted l e ftwa rd s si gn ifi cant ly as compared with control group- The PA2 value of isoprotenol(ISO) - induced positive inotropic effect after antagonized by ?1-AR selective antagonist CGP20712A in atenolol group was increased significantly as compared with control group. But the PKB value after antagonized by ICI 118511 showed no obvious difference between two groups. HPLC detection showed that the level of plasma atenolol was 3. 5pmol/L in atenolol group and the leveIs of plasma norepinephrine had no significant difference between two groups. But the level of plasma adrenaline in atenolol group was obviously lower than that in control group. CONCLUSIO- N: The long-term administration of ?l-AR antagonist will cause significant increase of the sensitivity of heart ?-AR, especially ?1-AR to excitant ISO. But the number of ?-AR and its subtypes did not change significantly. Besides, after the long-term administration of ?1-AR antagonist atenolol, the level of plasma adrenaline in rats was much lower than that in control group.

Molecular Biologic Study on the Changes of Glutamate Receptor (mGluR5) in Rat Hippocampus after Brain Ischemia / 대한구급학회지

BACKGROUND: Metabotropic glutamate receptors (mGluRs) participate in the induction of synaptic plasticity phenomena, such as long-term potentiation and long-term depression that are thought to be at the origin of learning and memory. They are also likely to play a role in modulating glutamate-induced neurotoxicity. It will become apparent that mGluRs are excellent targets for the development of drugs that modulate excitatory synaptic transmission. But there were several controversies about the exact role of group 1 mGluRs subtype 5 (mGluR5). This study was designed for evaluation of the neuroprotective role of mGluR5. METHODS: Fifty male Sprague-Dawley rats were divided into three groups, control, MK-801 and lamotrigine. The hippocampus and basal ganglia were removed at 6 hours and 3 days after the one hour transient middle cerebral artery occlusion. The gene expression of mRNA of the brain samples were evaluated by using reverse transcriptase polymerase chain reaction technique. RESULTS: The gene expression of mGluR5 mRNA in hippocampus was increased by 101.96 +/- 18.45% at 6 hours after ischemia and decreased by 50.70 +/- 15.73% at 3 days after ischemia (p<0.01). MK-801 and lamotrigine attenuated the ischemia-induced increases of gene expression of mGluR5 mRNA. In MK-801 group, the expression in basal ganglia was increased by only 0.23 +/- 5.41% at 6 hours after ischemia and decreased by 9.82 +/- 4.35% at 3 days after ischemia. In MK-801 group, the expression in hippocampus was decreased by 3.45 +/- 8.24% and 9.35 5.69% at 6 hours and 3 days after ischemia. In lamotrigine group, the expressions in hippocampus and basal ganglia were decreased by 26.66 +/- 9.85% and 9.45 +/- 5.22% at 6 hours after ischemia. CONCLUSIONS: From these results, the role of mGluR5 was defined as a mediator for neuronal damage after transient focal cerebral ischemia in hippocampus and basal ganglia.