• The Korean Journal of Physiology and Pharmacology
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• 제4권3호
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• pp.185-195
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• 2000

Vascular diseases are significant complications of diabetes mellitus (DM), and the endothelial cells may play a pivotal role in the development of vascular disease in DM. Endothelin-1 (ET-1) released from endothelium is a potent vasoconstrictor peptide and circulating level of ET-1 is increased in a variety of disease states. The purpose of this study was to determine the changes of responsiveness to ET-1 in DM, and we experimented on the changes in the ET-1-induced contraction, levels of nitrite and lipid peroxidation, and ET-1 immunoreactivity in aorta from streptozotocin-induced DM rats. DM was induced by single injection of streptozotocin (55 mg/kg, i.p.). The immunoreactive ET-1 levels in endothelial layer of thoracic aorta were much higher in DM rats than control rats. Nitrite in tissue homogenate was decreased and plasma nitrite was increased in DM rats. Malondialdehyde (MDA) was significantly increased in DM rats and cGMP was not significantly different between control and DM rats. ET-1 produced concentration- dependent contractile responses that are significantly attenuated in DM rats compared to controls. In the presence of selective $ET_A$ receptor antagonist BQ610, the maximum contraction was decreased and the concentration ratios for BQ610 yielded $pA_2$ values of 7.3 (slope, 0.65) in control rats, whereas BQ610 had no antagonistic effect on ET-1-induced contraction in DM rats. However, pretreatment with BQ788, an $ET_B$ receptor antagonist, maximum response was decreased and the dose-response curves for ET-1 were shifted to the right in both groups and $pA_2$ values were 7.9 and 7.7 (slope, 1.05 in control and DM rats), respectively. IRL 1620 and sarafotoxin S6c, $ET_B$ agonists, induced relaxation in control rats but not in DM rats. These results indicate that endothelial cell dysfunction and enhanced immunoreactivity of ET-1 have been found in DM rat and ET-1-induced contraction was attenuated in DM rat. These attenuated responses might be at least in part caused by the alteration of $ET_A$ receptor properties (e.g. desensitization), and partly related with an alteration in intracellular mechanism for contraction to ET-1.

• 한국임상약학회지
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• 제8권2호
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• pp.113-121
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• 1998

To clarify whether nizatidine, a $H_2$ receptor antagonist, has the cholinergic activity, the effects of nizatidine on the guinea pig ileum and on the acetylcholinesterase in human serum were studied. And, the mechanism of excitatory effect of nizatidine on the cholinergic system in ileum was also studied. Nizatidine caused a concentration-dependent contractile response by the guinea pig ileum. The $EC_{50}\;was\;53\;{\mu}M$ and the maximum response was at $300\;{\mu}M$. Ranitidine also caused a contractile response by the guinea pig ileum, but cimetidine and famotidine did not. The pretreatment with $H_1$ receptor antagonist did not affect the actions of nizatidine on the guinea pig ileum, but the pretreatment with atropine completely blocked them. Nizatidine significantly enhanced the acetylcholine-induced response of the guinea pig ileum, but not the pilocarpine-induced response. Nizatidine did not affect the histamine-induced response of the guinea pig ileum. Nizatidine still exerted the small excitatory effect on the guinea pig ileum pretreated with the high concentration of physostigmine. Nizatidine significantly inhibited the acetylcholinesterase in human serum. These results suggest that nizatidine exerts an excitatory effect on guinea pig ileum which seems to be associated with the cholinergic system, probably through an indirect mechanism, inhibition of acetylcholinesterase and/or increased release of acetylcholine.

• The Korean Journal of Physiology
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• 제21권1호
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• pp.67-77
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• 1987

Effect of intravenously injected clonidine on the flexion reflex was studied in 15 decerebrated and spinalized cats. The flexion reflex was elicited by electrical stimulation of the tibial nerve or the common peroneal nerve and it was recorded as single unit activity from filaments of the L6 or L7 ventral roots. In order to obtain the late flexion reflex discharges, $A{\delta}$ and C afferent fibers were stimulated with single or train electrical pulses respectively. The flexion reflex, especially the late component, was markedly inhibited after intravenous administration of clonidine. The clonidine-induced inhibition of the flexion reflex was compared before and after treatment of the animals respectively with yohimbine and naloxone. The inhibitory effect on the flexion reflex of clonidine was not altered by naloxone, a ${\mu}-opioid$ receptor blocker, whereas it was completely blocked by yohimbine, an ${\alpha}_2-adrenergic$ antagonist. These results indicate that clonidine inhibits the flexion reflex through excitation of ${\alpha}_2-adrenoceptors$ even at the spinal cord level.

• 동의신경정신과학회지
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• 제24권3호
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• pp.271-280
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• 2013

Objectives : The development of natural drugs with antidepressant effects is important and needed. This study was performed to investigate the antidepressant-like effects of the distilled water extract of Portulaca oleracea L. (POL) in a mouse model and to investigate the role of ${\alpha}$-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors in producing these antidepressant-like effects. Methods : The forced swim test (FST) and tail suspension test (TST) were used to investigate the behavioral anti-depressive-like effects of POL in mice. Additional behavioral experiments with 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione, an AMPA receptor antagonist, were undertaken to determine the involvement of the antidepressant-like properties of POL in AMPA receptor throughput. Results : Oral administration of the POL extract (100 mg/kg) 1 h prior to testing significantly reduced the immobility times in the FST and TST. The antidepressant-like effects of the POL extract were not increased in a dose-dependent manner. Pre-treatment with NBQX significantly attenuated the reduction in immobility time induced by the POL extract in the FST. Conclusions : The distilled water extract of POL has antidepressant-like effects, which may be related to AMPA receptor. Pre-treatment with NBQX significantly attenuates the reduction in immobility time induced by the POL extract in the FST.

• Bulletin of the Korean Chemical Society
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• 제34권8호
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• pp.2305-2310
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• 2013

A novel series of 2-heteroaryl substituted benzimidazole derivatives, containing the piperidinylphenyl acetamide group at the 1-position, were synthesized and evaluated as MCH-R1 antagonists. Extensive SAR investigation probing the effects of C-2 heteroaryl group led to the identification of 2-[2-(pyridin-3-yl)ethyl] analog 3o, which exhibits highly potent MCH-R1 binding activity with an $IC_{50}$ value of 1 nM. This substance 3o also has low hERG binding activity, good metabolic stability, and favorable pharmacokinetic properties.

• The Korean Journal of Pain
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• 제19권1호
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• pp.22-32
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• 2006

Background: This study was conducted to investigate the roles of the spinal and peripheral ${\gamma}$-aminobutyric acid (GABA)- ergic systems for the mechanical hypersensitivity produced by chronic compression of the dorsal root ganglion (CCD). Methods: CCD was performed at the left 5th lumbar dorsal root ganglion. The paw withdrawal threshold (PWT) to von Frey stimuli was measured. The mechanical responsiveness of the lumbar dorsal horn neurons was examined. GABAergic drugs were delivered with intrathecal (i.t.) or intraplantar (i.pl.) injection or by topical application onto the spinal cord. Results: CCD produced mechanical hypersensitivity, which was evidenced by the decrease of the PWT, and it lasting for 10 weeks. For the rats showing mechanical hypersensitivity, the mechanical responsiveness of the lumbar dorsal horn neurons was enhanced. A similar increase was observed with the normal lumbar dorsal horn neurons when the GABA-A receptor antagonist bicuculline was topically applied. An i.t. injection of GABA-A or GABA-B receptor agonist, muscimol or baclofen, alleviated the CCD-induced hypersensitivity. Topical application of same drugs attenuated the CCD-induced enhanced mechanical responsiveness of the lumbar dorsal horn neurons. CCD-induced hypersensitivity was also improved by low-dose muscimol applied (i.pl.) into the affected hind paw, whereas no effects could be observed with high-dose muscimol or baclofen. Conclusions: The results suggest that the neuropathic pain associated with compression of the dorsal root ganglion is caused by hyperexcitability of the dorsal horn neurons due to a loss of spinal GABAergic inhibition. Peripheral application of low-dose GABA-A receptor agonist can be useful to treat this pain.

• The Korean Journal of Physiology
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• 제17권2호
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• pp.103-107
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• 1983

This experiment was undertaken to see whether dopamine has any effect on a uterine function and whether the uterus has a dopamine receptor. We used 14 female rats in the diestrus state which was identified by a vaginal smear. Under ether anesthesia, 3 pieces(1 cm length) from each side of the uterus were dissected out and mounted in 3 tissue chambers (4 cm diameter, 10 cm height) that contained Krebs-Ringer solution. The solution was continuously aerated with 95% $O_2$ containing 5% $CO_2$ and kept $37^{\circ}C$ consistantly during the whole experimental period. The spontaneous contractile activity of the isolated uterus was recorded using a force transducer. After a recovery period of 15 min in the chamber, the following experiments were carried out. In 7 rats, each piece of the uterus was received dopamine at concentrations of $10^{-4}$, $10^{-5}$ or $10^{-6}\;M$ for 10 min and then followed by domperidone at a concentration of $10^{-5}\;M$. In another 7 rats, each piece was received domperidone, a specific peripheral dopamine receptor antagonist, was administered at a concentration of $10^{-5}\;M$ for 5 min prior to dopamine at concentrations of $10^{-4}$, $10^{-5}$, or $10^{-6}\;M$. Dopamine inhibited the spontaneous uterine contraction dose-dependently (r=0.99, p<.01). The inhibited contractility by dopomine was significantly (P<.05) resumed by post-treatment of domperidone. Pre-treatment of domperidone also blocked significantly(p<.05) the inhibitory effect of dopamine. It is concluded from these results that dopamine has inhibitory role upon the spontaneous uterine contraction of the rat in the diestrus state and domperidone antagonized the inhibitory effect of dopamine. These results suggest strongly that dopamine may exert the inhibitory effect via the dopamine receptor in the rat uterus.

• 한국동물학회지
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• 제37권3호
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• pp.377-384
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• 1994

The present study examines the inhibitow effect of progesterone (P) on luteinizing hormone $(LH)\beta$ subunit gene expression in anterior pituitary of ovariectomized, estradiol-treated adult rats. A single injection of P (1mg) further decreased the estradiol-Induced decrease in $LH\beta$ mRNA levels in ovariectomTzed rats in a time-dependent manner. p suppressed UIP mRNA levels at lower doses (0.1 and 1mg), but increased $LH\beta$ mRNA levels 81 a high dose (toms). The inhibitor action of P on $Uf\beta$ mRNA was restored when Ru486, a P receptor antagonist, was administered 1h before P treatment. These data clearly indicate that P inhibits gene expression of $LH\beta$ in the rift pituitary in a swersic manner with estrogen.

• Natural Product Sciences
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• 제25권1호
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• pp.28-33
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• 2019

A popular approach for the study of estrogen receptor ${\alpha}$ inhibition is to investigate the protein-protein interaction between the estrogen receptor (ER) and the coactivator surface. In our study, we investigated phytochemicals from Rubus coreanus that were able to disrupt $ER{\alpha}$ and coactivator interaction with an $ER{\alpha}$ antagonist. The E-screen assay and molecular docking analysis were performed to evaluate the effects of the estrogenic activity of R. coreanus extract and its constituents on the MCF-7 human breast cancer cell line. At $100{\mu}g/mL$, R. coreanus extract significantly stimulated cell proliferation ($574.57{\pm}8.56%$). Sanguiin H6, which was isolated from R. coreanus, demonstrated the strongest affinity for the $ER{\alpha}$ coactivator-binding site in molecular docking analysis, with a binding energy of -250.149. The initial results of the study indicated that sanguiin H6 contributed to the estrogenic activity of R. coreanus through the activation of the $ER{\alpha}$ coactivator-binding site.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1998년도 Proceedings of UNESCO-internetwork Cooperative Regional Seminar and Workshop on Bioassay Guided Isolation of Bioactive Substances from Natural Products and Microbial Products
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• pp.170-170
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• 1998

In order to discover new types of 5-hydroxytryptamine antagonists, we have devoted our attention to investigating naturally occurring compounds having anti-5HT activity in vitro. Recently, ${\gamma}$-mangostin [1,3,6,7-tetrahydroxy-2,8-bis(3-methyl-2-bytenyl)-9H-xanthen-9-one] from the fruit hull of Garcinia mangostana Linn has been shown to be a selective antagonist for 5-hydroxytryptamine$_{2A}$ receptors in smooth muscle and platelets. It is of interesting that y-mangostin which does not have a nitrogen atom, possesses marked 5-$HT_{2A}$ receptor blocking activity. The present study was undertaken to investigate the effects of ${\gamma}$-mangostin on central 5-HT receptors by using animal behavioural models. Intracerebronventricular injection of ${\gamma}$-mangostin (10-40n mol/mouse) inhibited 5-fluoro-${\alpha}$-methyltryptamin (5-FMT) (45 mg kg$^{-1}$, i.p.)-induced head-twitch response in mice in the presence or absence of citalopram (5-HT-uptake inhibitor). Neither the 5-FMT- nor the 8-hydroxy-2-( di-n-propylamino )tetralin (5-HT$_{1A}$-agonist)-induced 5-HT syndrome (head weaving and hindlimb abduction) was affected by ${\gamma}$-mangostin. The locomotor activity stimulated by 5-FMT through the activation of at-adrenoceptors did not alter in the presence of ${\gamma}$-mangostin. 5-HT-induced inositol phosphates accumulation in mouse brain slices was abolished by ketanserin. ${\gamma}$-Mangostin caused a concentration-dependent inhibition of the inositol phosphates accumulation and the binding of [$^3H$]-spiperone, a specific 5-$HT_{2A}$ receptor antagonist, to mouse brain membranes. Kinetic analysis of the [$^H3$]-spiperone binding revealed that ${\gamma}$-mangostin increased the $_{d}$ value without affecting the $B_{max}$ value, indicating the mode of the competitive nature of the inhibition by ${\gamma}$-mangostin. These results suggest that ${\gamma}$-mangostin inhibits 5-FMT-induced head-twitch response in mice by blocking 5-$HT_{2A}$ receptors not by blocking the release of 5-HT from the central neurone. ${\gamma}$-Mangostin is a promising 5-$HT_{2A}$ receptors antagonist in the central nervous system.m.