Effect of novel agonist of soluble guanylate cyclase sGC 003 on endothelin-1-induced cardiomyocyte hypertrophy / 中国药理学与毒理学杂志

OBJECTIVE To investigate the protective effect of sGC003,a novel agonist of soluble guanylate cyclase,on endothelin-1(ET-1)-induced cardiomyocyte hypertrophy. METHODS Cardiomy?ocytes were isolated from neonatal Sprague-Dawley rats using serial enzymatic digestion and then incubated with ET-1 10 nmol·L-1 in the absence or presence of sGC003 0.01,0.1 and 1.0μmol·L-1. Hyper?trophic responses including the cardiomyocyte area(Image-Pro Plus 6.0),the expression of atrial natri?uretic peptide gene(ANP)mRNA(RT-PCR method)and total protein content(BCA method)were detect?ed. RESULTS After 48 h stimulation with ET-1 10 nmol·L-1,the cardiomyocyte area increased by 80%(P<0.01),the total protein content increased by 120%(P<0.01) and the expression of ANP mRNA up-regulated by 140%(P<0.01). sGC003 0.01,0.1 and 1.0μmol · L-1 elicited antihypertrophic actions, including inhibition of ET-1-mediated increase in the cardiomyocyte area(P<0.01),raised total protein content(P<0.05)and upregulation of ANP mRNA(P<0.05). CONCLUSION sGC003 has protective,car?diomyocyte-selective antihypertrophic effects in vitro.

Role of histamine H3 receptor in regulation of hypoxia / 中国药理学与毒理学杂志

Hypoxia refers to the reduction in tissue oxygen supply or utilization. It occurs in various pathological symptoms like embolism,anthracemia,and chronic obstructive sleep. At high altitude, lower partial pressure of oxygen compromises the supply of adequate oxygen to the tissues and leads to many clinical syndromes,such as acute mountain sickness,high-altitude cerebral edema,and high-altitude pulmonary edema. Histamine H3 receptor, primarily as a presynaptic receptor, is widely expressed in the central and peripheral systems. Histamine,dopamine,acetylcholine and many other neurotransmitters are regulated by histamine H3 receptor. Studies have shown that histamine H3 receptor is involved in the hypoxic response of the respiratory network. In addition,histamine,espe?cially histamine H3 receptor,participates in the regulation of cerebral ischemia in the central nervous system. In this paper,we reviewed the structure and functions of histamine H3 receptor and explained its role in the regulation of hypoxia so as to evaluate the possibility of histamine H3 receptor as a drug target for the therapy of hypoxia-induced injuries.

Inhibitors of vesicular glutamate transporter:research advances / 国际药学研究杂志

Vesicular glutamate transporter(VGLUT), located on the vesicular membrane, is a highly specific marker of glut-amatergic neurons. VGLUT selectively transports glutamate in the cytoplasm into vesicles. VGLUT1, VGLUT2 and VGLUT3 are three subtypes of VGLUT. The VGLUT can influence the glutamatergic synaptic transmission through mediating sequestration, storage and release of glutamate. The number and activity of VGLUT can change the level of glutamate in synapse cleft through mediating sequestration,storage and release of glutamate,then influence the glutamatergic synaptic transmission. To improve this pathological situation and maintain glutamate at the physiologically relevant concentration, VGLUT inhibition is required. Several classes of competitive VGLUT inhibitors have emerged including azo dyes, substituted quinolines, fatty acids and alkaloids. This article provides a brief review on the structure and function of these potential VGLUT inhibitors.

Primary investigation on heterodimerization of kappa-opioid receptor and ORL1 receptor / 药学学报

This study investigates whether kappa-opioid receptor and ORL1 receptor may interact to form a heterodimer. In immunofluorescence and co-immunoprecipitation experiments, differentially epitope-tagged receptors, colocalization and heterodimerization of kappa-opioid receptor and ORL1 receptor were used and examined in primary culturing rat neurons, Chinese hamster ovary (CHO) or human embryonic kidney 293 (HEK293) cells. The results show that fluorescence of both kappa-opioid receptor and ORL1 receptor were overlapping in primary culturing hippocampal and cortical neurons. Similarly in co-expressing CHO or HEK293 cells, HA-KOR and Myc-ORL1 were almost exclusively confined to the membranes, revealing extensive colocalization. When Flag-KOR and Myc-ORL1 were co-expressing in CHO cells, heterodimerization was identified to have the ability to co-immunoprecipitate ORL1-receptors with kappa-opioid receptor and vice versa. In the current study, further evidence was provided for the direct interaction of two subtypes of opioid receptors, kappa-opioid receptor and ORL1-receptor, to form the heterodimerization. The finding represents the novel pharmacological mechanism for modulation of opioid receptor function as well as diversity of G protein-coupled receptors.

Antinociception of omega-conotoxin ω-SO3 in rat formalin test after acute or chronic intrathecal administration / 中国药理学通报

Aim To evaluate the antinociception of ω-SO3,a novel Omega-superfamily conotoxin,in rat formalin test.Methods Potency and duration of ω-SO3 antinociception compared with morphine were investigated in rat formalin test after acute intrathecal administration.Development of tolerance or cross tolerance to analgesia of ω-SO3 and morphine was tested in formalin test after chronic intrathecal administration.Locomotor activity of rat after acute intrathecal administration was tested to evaluate possible central side effects.Results In rat formalin test after intrathecal bolus injection,ω-SO3 produced dose-and time-dependent antinociception by suppressing acute(ED_(50),1.79 ng·g~(-1))and tonic phases(ED_(50),0.41 ng·g~(-1)),which was approximately 10-fold potency and twice longer-acting of morphine in blocking tonic phase responses.After repeated intrathecal injections twice daily for 5 consecutive days,ω-SO3 produced analgesia without loss of potency whereas morphine produced analgesia tolerance in rat formalin test;further,ω-SO3 still produced potent analgesia in morphine-tolerant rats.No changes in motor function were seen in rats receiving above antinociceptive doses.Conclusion sNovel ω-SO3 produces potent and long-acting spinal antinociception without observable motor dysfunction and after chronic intrathecal administration.ω-SO3 produces neither tolerance nor cross-tolerance to morphine analgesia.

Effects of different kinds of opiate receptor on oxycodone-induced hyperlococomotor and analgesia in mice / 中国药理学通报

Aim To investage the effects of ?、?、?-receptor on hyperlocomotor and analgesia in mice.Methods Locomotor activity experiment and hot-plate pain experiment were measured.Results Oxycodone dose-dependently enhanced locomotor response in mice.Naloxone,a unselective opioid receptor antagonists and naltrindole(?-selective opioid receptor antagonist)could attenuate the increase of locomotor acitivity induced by oxycodone,but naloxonazine,a ?-receptor antagonist had no such effect.?-receptor antagonist nor-Binltorphimine increased hyperlocomotion induced by oxycodone.In antinociceptive experiment,naloxonazine and naltrindole could not attenuate the that of oxycodone,but nor-Binaltorphimine could attenuate the antinociceptive effects of oxycodone.Conclusion Oxycodone-hyperlocomotor is probably mediated by ? opioid receptor,and antinocieptive effects of oxycodone is probably mediated by ? opioid receptor.

The function of C-terminal tail of opioid receptors and the proteins interaction with C-terminal tail of opioid receptors / 中国药理学通报

The C-terminal tail of opioid receptor is important for opioid receptor phosphorylation,desensitization and internalization after opioid agonists treatment.The C-terminal point mutant and truncated mutant of amino acid residues of ?opioid receptors such as T394A,T383A,T357A,S355A affect the function of the opioid receptor obviously.The identical results could be seen in the C-terminal point mutant S363A of ?opioid receptor and S369A of ?opioid receptor.It is well known that opioid receptor requires interaction with other proteins for function,regulation and trafficking.Although proteins such as PPL,FilaminA,PLD2,PKCI,GASP and EBP50/NHERF have been identified to interact with C-terminals of opioid receptors,the role of interaction of these proteins with opioid receptor in the dependence,tolerance and addiction of opioids is dubious.Therefore,looking for the proteins specifically interacting with the C-terminals of opioid receptor may be important to understand the mechanism of opioids addiction.

Pharmacokinetics of a naltrexone sustained release preparation in dog / 中国药理学与毒理学杂志

AIM To evaluate bioavailability, biocompa- tibility and biodegradability of an injectable microsphere sustained release preparation of naltrexone(NTX) in 4 dogs. METHODS Pharmacokinetic data of NTX and remained NTX in microspheres in injection site were studied using high performance liquid chromatography(HPLC)-electrochemical detection with naloxone(NLX) as internal standard. Biocompatibility of the microspheres was assayed by histological examination. RESULTSPharmacokinetics of NTX after an intramuscular dose of 0.5 or 1.0 mg*kg-1 NTX indicated a plasma clearance range of 0.66 to 0.73 L*min-1 and a t1/2β range of 60.0 to 67.2 min. After a 1-week washout period without medication, NTX microspheres injection period about 4 weeks followed. After injection of 1.0 g of microspheres containing (296.5±2.1)mg of NTX, mean blood concentrations of NTX exceeded 1 μg*L-1 for 26-28 d, and cmax per dose (mg*kg-1) was only 1% of that after NTX dosing. It was estimated that approximately (93.0±4.1)% of the administered dose was absorbed after microspheres injection in 4 dogs. There were no serious adverse effects other than light tissue irritation. CONCLUSIONThis NTX microspheres preparation provides a safe, complete and sustained release of the drug for about one month.

Endothelins system and myocardial hypertrophy / 中国药理学通报

Cardiac hypertrophy is a major adaptational mechanism in stresses such as pressure overload and neurohumoral stimulation.As powerful vasoconstrictor peptides in cardiovascular system,especially the vascular endothelium,smooth muscle cells and cardiocyte,ETs play important physiological roles in the regulation of normal cardiovascular function.Excessive generation of ETs in local cardiac muscle has been linked to myocardial hypertrophy.Endothelin-1(ET-1) in cardiac muscle exerts its actions in the development of myocardial hypertrophy through binding to specific receptors and interacting with other vasoactive substance of local tissues.ET-1 can induce the hypertrophy for cardiocytes and the proliferation for cardiac fibroblasts by ETA.ETB receptors are implicated both in initiating and maintaining myocardial hypertrophy.As a new target of drug,ET receptors have become the research focus,and great progress has been made on the development of the ET antagonists.

Expression of Cannabinoid receptor 2 in the CNS and pharmacology of its agonists / 中国药理学通报

Two types of cannabinoid receptors,named cannabinoid receptor 1(CB1) and cannabinoid receptor 2(CB2),have been cloned.CB2 receptors are expressed predominantly in the peripheral immune tissues,but accumulating evidence has revealed that CB2 receptors are also expressed in CNS.Previous studies showed that CB2 agonists can cure and suppress formation of inflammatory and neurophathic pain without central effects after chronic administration.Therefore,they will have good clinical applications in the treatment of pain and neurodegenerative diseases.In this paper,we will review the tissue distribution of CB2 in CNS and pharmacological characteristics of the CB2 agonists have been reviewed.