• The Korean Journal of Physiology and Pharmacology
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• 제2권1호
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• pp.49-54
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• 1998

$Mg^{2+}$ is an important regulator of many cardiac functions. However, regulation of intracellular $Mg^{2+}$ activity in the heart is not well characterized. To assess the effect of histamine $H_2$-receptor stimulation on intracellular $Mg^{2+}$ regulation, changes in extracellular $Mg^{2+}$ concentration were examined under a variety of conditions in perfused guinea pig hearts. $Mg^{2+}$ in the cardiac perfusate was measured by atomic absorbance spectrophotometry. The histamine ($10^{-6}$ M) inuced a marked $Mg^{2+}$ efflux from the heart. The $H_2$-receptor antagonists, cimetidine ($10^{-6}$ M), ranitidined ($10^{-5}$ M), but not a H1-receptor antagonist, diphenhydramine ($3{\times}10^{-6}$ M), completely blocked the histamine-induced $Mg^{2+}$ efflux. The $Mg^{2+}$ efflux could also be induced by forskolin ($3{\times}10^{-6}$ M), 8-Cl-cAMP ($2{\times}10^{-4}$ M), permeable cAMP analogue, or dimaprit, ($10^{-5}$ M). However, the carbachol ($10^{-5}$ M) considerably decreased the efflux of $Mg^{2+}$. In the presence of papaverine ($10^{-5}$ M), a phosphodiesterase inhibitor, dimaprit-induced $Mg^{2+}$ efflux was potentiated. These results suggest that a significant $Mg^{2+}$ efflux from perfused guinea pig heart by histamine can be induced by the histamine $H_2$-receptor stimulation and it is suggested that cytosolic cAMP may be linked.

• 대한의생명과학회지
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• 제12권4호
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• pp.329-335
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• 2006

Echinostoma hortense (E. hortense) is an intestinal trematode with the highest infection rate in South Korea. However, the immune response against E. hortense infection has not been explained well. In the present study, we investigated the effect of treatment with cyclosporin A (CsA) and histamine receptor antagonists on the cytokine expression and mucosal goblet cells in E. hortense-infected C3H/HeN mice. The alteration of cytokine mRNA expression ($TNF-{\alpha},\;IL-l{\beta},\;IL-4\;and\;IL-5$), intestinal worm recovery rate and goblet cell responses were measured weekly from 0 to 5 weeks post-infection (P.I.) in the control and the following three drug-treated groups: CsA, hydroxyzine and cimetidine. Compared with the control group, the expression of $TNF-{\alpha}$, IL-4 and IL-5 mRNAs decreased in the CsA- and hydroxyzine-treated groups, but only IL-4 mRNA expression did in the cimetidine-treated group. Worm recovery rate was significantly increased in the drug-treated groups. Mucosal goblet cells and their mucin response significantly decreased in the CsA-treated group (P<0.01), but significantly increased in the cimetidine- (P<0.05) and hydroxyzine- (P<0.01) treated groups. These data suggest that CsA treatment inhibits production of Th1- and Th2-type cytokines which are necessary for the worm expulsion. Histamine receptor increases goblet cells and their mucin activation, although it remains to be elucidated whether it directly affects the worm expulsion period of E. hortense in C3H/HeN mice.

• 통합자연과학논문집
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• 제10권2호
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• pp.85-94
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• 2017

Fibroblast growth factor receptor (FGFR) belongs to the family of receptor tyrosine kinase. They play important roles in cell proliferation, differentiation, development, migration, survival, wound healing, haematopoiesis and tumorigenesis. FGFRs are reported to cause several types of cancers in humans which make it an important drug target. In the current study, HQSAR analysis was performed on a series of recently reported 1H-Pyrazolo [3,4-b]pyridine derivatives as FGFR antagonists. The model was developed with Atom (A) and bond (B) connection (C), chirality (Ch), hydrogen (H) and donor/acceptor (DA) parameters and with different set of atom counts to improve the model. A reasonable HQSAR model ($q^2=0.701$, SDEP=0.654, NOC=5, $r^2=0.926$, SEE=0.325, BHL=71) was generated which showed good predictive ability. The contribution map depicted the atom contribution in inhibitory effect. A contribution map for the most active compound (compound 24) indicated that hydrogen and nitrogen atoms in the side chains of ring B as well as hydrogen atoms in the side chain of ring C and the nitrogen atom in the ring D contributed positively to the activity in inhibitory effect whereas, the lowest active compound (compound 04) showed negative contribution to inhibitory effect. Thus results of our study can provide insights in the designing potent and selective FGFR kinase inhibitors.

• The Korean Journal of Physiology and Pharmacology
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• 제7권5호
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• pp.251-254
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• 2003

The present study was designed to examine whether the co-application of morphine with $Ca^{2+}$ channel antagonist $(Mn^{2+},\;verapamil)$, N-methyl-D-aspartate (NMDA) receptor antagonist (2-amino-5-phosphonopentanoic acid$[AP_5]$, $Mg^{2+}$) or protein kinase C inhibitor (H-7) causes the potentiation of morphine-induced antinociceptive action by using an in vivo electrophysiological technique. A single iontophoretic application of morphine or an antagonist alone induced weak inhibition of wide dynamic range (WDR) cell responses to iontophoretically applied NMDA and C-fiber stimulation. Although there was a little difference in the potentiating effects, the antinociceptive action of morphine was potentiated when morphine was iontophoretically applied together with $Mn^{2+}$, verapamil, $AP_5$, $Mg^{2+}$ or H-7. However, the potentiating action between morphine and each antagonist was not apparent, when the antinociceptive action evoked by morphine or the antagonist alone was too strong. These results suggest that the potentiating effect can be caused by the interaction between morphine and each antagonist in the spinal dorsal horn.

• 셀메드
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• 제2권4호
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• pp.38.1-38.6
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• 2012

The present study aimed to determine the possible mechanisms of the peripheral antinociception of the aqueous extracts of Dicranopteris linearis (AEDL), Melastoma malabathricum (AEMM) and Bauhinia purpurea (AEBP) leaves in mice. Briefly, the antinociceptive profile of each extract (300, 500, and 1000 mg/kg; subcutaneous (s.c.)), was established using the abdominal constriction test. A single dose (500 mg/kg) of each extract (s.c.) was pre-challenged for 10 min with various pain receptors' antagonists or pain mediators' blockers and 30 min later subjected to the antinociceptive assay to determine the possible mechanism(s) involved. Based on the results obtained, all extracts exerted significant (p < 0.05) antinociceptive activity with dose-dependent activity observed only with the AEMM. Furthermore, the antinociception of AEDL was attenuated by naloxone, atropine, yohimbine and theophylline; AEMM was reversed by yohimbine, theophylline, thioperamide, pindolol, reserpine, and 4-chloro-DL-phenylalanine methyl ester hydrochloride; and of AEBP was inhibited by naloxone, haloperidol, yohimbine and reserpine. In conclusion, the antinociceptive activity of those extracts possibly involved the activation of several pain receptors (i.e. opioids, muscarinic, ${\alpha}_2$-adrenergic and adenosine receptors, adenosine, H3-histaminergic and $5HT_{1A}$, dopaminergic receptors).

• Biomolecules & Therapeutics
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• 제3권1호
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• pp.21-27
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• 1995

The only compounds with antagonistic activity via AT$_1$receptor, one of two subtypes of angiotensin II (AII) receptor, have been demonstrated to block the vasoconstriction effects of AII and thereby provide therapeutic potential. This initiated the search for compounds with high specific affinity to AT$_1$receptor and their effective screening methods. The radioligand binding assay for the AII receptor is regarded as the primary method for the evaluation of AT$_1$receptor antagonists for their activity. In this paper, we characterized the liver AT$_1$receptor and describe the efficient method of the radioligand binding assay using rat liver as a source of AT$_1$receptor. Equilibrium binding studies with rat adrenal cortex, adrenal medulla, liver and bovine adrenal showed that the specific bindings of [$^3$H] AII were saturable in all tissues and the Scatchard plots of those data were linear, suggesting a single population of binding sites. Hill slopes were very near to the unity in all tissues. Kinetic studies of [$^3$H) AII binding in rat liver homogenates yielded two association rate constants, 4.10$\times$10$^{7}$ M$^{-1}$ min$^{-1}$ and 4.02$\times$10$^{9}$ M$^{-1}$ min$^{-1}$ , with a single dissociation rate constant, 7.07$\times$10$^{-3}$ min-$^{-1}$ , possibly due to the partial dissociation phenomenon. The rank order of inhibition potencies of [$^3$H] AII binding in rat liver was AII>Sarile>Losartan>PD 123177. Rat liver homogenates revealed to have very high density of homogeneous population of the AT$_1$receptor subtype, as the specifically bound [$^3$H] AII was not inhibited by PD 123177, the nonpeptide antagonist of AT$_2$. The results of this study demonstrated that the liver homogenates from rats could be the best receptor preparation for the AT$_1$receptor binding assay and provide an efficient system for the screening of newly synthesized candidate compounds of AT$_1$receptor antagonist.

• Bulletin of the Korean Chemical Society
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• 제18권9호
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• pp.939-945
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• 1997

Several types of 4-substituted-quinoline-2-carboxylic acid derivatives possessing different substituents at C4-position such as sulfonyl, phosphonyl, carbonyl groups, or a flexible alkyl chain have been synthesized and evaluated for their in vitro antagonistic activity at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Of them, 5,7-dichloro-4-(tolylsulfonylamino)-quinoline-2-carboxylic acid 9 was found to have the best in vitro binding affinity with IC50 of 0.57 μM. On the other hand, in compounds 21 and 22 the introduction of flexible alkyl chains on C4 of the quinoline mother nuclei caused a significant decrease of the in vitro binding affinity. In addition, replacement of polar carboxylic acid group on C2 by neutral bioisosteres in compounds 23a-d also seems to be disadvantageous to in vitro activity. In the structure-activity relationship (SAR) study of the 4-substituted quinoline-2-carboxylic acid acid derivatives, it was realized that the substitution pattern on C4 significantly influences on the binding affinity for the glycine site of NMDA receptor and the binding affinity might be increased by the introduction of a suitable electron rich substituent at C4 which has the ability of H-bonding donor.

• 대한의생명과학회지
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• 제13권3호
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• pp.197-206
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• 2007

P2X receptors are membrane-bound ion channels that conduct $Na^+,\;K^+$, and $Ca^{2+}$ in response to ATP and its analogs. There are seven subunits identified so far ($P2X_1-P2X_7$). $P2X_2$ receptors are known to be expressed in a wide range of organs including brains and adrenal grands. PC12 cells are originated from adrenal grand and differentiated by nerve growth factor or pituitary adenylate cyclase activating poly peptide (PACAP). Previous studies indicate that $P2X_2$ receptor activation in PC12 cells couples to $Ca^{2+}-dependent$ release of catecholamine and ATP. It is known that acidic pH potentiates ATP currents at $P2X_2$ receptors. This leads to a hypothesis that $P2X_2$ receptors may play an important role in PC12 cell differentiation, one of the characteristics of which is neurite outgrowth, induced by the hormones under lower pH. In the present study, we isolated several clones which potentiate neurite outgrowth by PACAP in acidic pH (6.8), but not in alkaline pH (7.6). RT-PCR and electrophysiology data indicate that these clones express only functional $P2X_2$ receptors in the absence or presence of PACAP for 3 days. Potentiation of neurite outgrowth resulted from PACAP (100 nM) in acidic pH is inhibited by the two P2X receptor antagonists, suramin and PPADS ($100\;{\mu}M)$ each), and exogenous exprerssion of ATP-binding mutant $P2X_2$ receptor subunit ($P2X_2[K69A]$). However, acid sensing ion channels (ASICs) are not involved in PACAP-induced neurite outgrowth potentiation in lower pH since treatments of an inhibitor of ASICs, amyloride ($10\;{\mu}M$), did not give any effects to neurite extension. The vesicular proton pump ($H^+-ATPase$) inhibitor, bafilomycin (100 nM), reduced neurite extension indicating that ATP release resulted from $P2X_2$ receptor activation in PC12 cells is needed for neurite outgrowth. These were confirmed by activation of mitogen activated protein kinases, such as ERKs and p38. These results suggest roles of ATP and $P2X_2$ receptors in hormone-induced cell differentiation or neuronal synaptogenesis in local acidic environments.

• The Korean Journal of Physiology and Pharmacology
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• 제18권1호
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• pp.41-46
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• 2014

The possible roles of spinal histamine receptors in the regulation of the blood glucose level were studied in ICR mice. Mice were intrathecally (i.t.) treated with histamine 1 (H1) receptor agonist (2-pyridylethylamine) or antagonist (cetirizine), histamine 2 (H2) receptor agonist (dimaprit) or antagonist (ranitidine), histamine 3 (H3) receptor agonist (${\alpha}$-methylhistamine) or antagonist (carcinine) and histamine 4 (H4) receptor agonist (VUF 8430) or antagonist (JNJ 7777120), and the blood glucose level was measured at 30, 60 and 120 min after i.t. administration. The i.t. injection with ${\alpha}$-methylhistamine, but not carcinine slightly caused an elevation of the blood glucose level. In addition, histamine H1, H2, and H4 receptor agonists and antagonists did not affect the blood glucose level. In D-glucose-fed model, i.t. pretreatment with cetirizine enhanced the blood glucose level, whereas 2-pyridylethylamine did not affect. The i.t. pretreatment with dimaprit, but not ranitidine, enhanced the blood glucose level in D-glucose-fed model. In addition, ${\alpha}$-methylhistamine, but not carcinine, slightly but significantly enhanced the blood glucose level D-glucose-fed model. Finally, i.t. pretreatment with JNJ 7777120, but not VUF 8430, slightly but significantly increased the blood glucose level. Although histamine receptors themselves located at the spinal cord do not exert any effect on the regulation of the blood glucose level, our results suggest that the activation of spinal histamine H2 receptors and the blockade of spinal histamine H1 or H3 receptors may play modulatory roles for up-regulation and down-regulation, respectively, of the blood glucose level in D-glucose fed model.

• 대한약리학회지
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• 제23권2호
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• pp.101-111
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• 1987

중추신경계 특히 뇌내(腦內)의 무수카린성 콜린 수용체 (mAchR)에 대한 수용체 특성의 연구의 하나로, 물리 화학적 성상에 다른 두 종류의 콜린길항제를 사용하여 서로 다른 두 형태의 조직에서 약물의 작용양상 및 다른 약물과의 상호작용을 정초하였다. 실험동물로는 흰쥐를 일정기간 규정사료를 사육하였고, 사용한 Radioactive ligands는 $(^3H)$ QNB와 $(^3H)$ NMS였으며 그외에 다른 수종의 길항제 또는 효능제와의 치환작용을 brain homogenates와 intact brain cell aggregates에서 관찰하여 다음과 같은 결과를 얻었다. 1. $(^3H)$ QNB와 $(^3H)$ NMS는 모두 질량작용의 법칙에 비례하여 수용체와의 결합에서 높은 친화력과 포화를 보였으며 또한 높은 결합 능력을 나타내었다. 더욱이 homogenates 제제와 intact cell aggregates제제에서의 결과 사이에는 유사한 점이 많았다. 2. Homogenates제제를 사용한 실험에서, 제 3 급아민콜린길항제인 QNB, atropine과 scopolamine 또는 제 4 급 암모늄골린 길항제인 methylatropine과 methylscopolamine을 사용하여 위의 radioactive ligands와의 치환작용을 검토하였다. $(^3H)$ NMS 실험군에서는 제 3 급아민 및 제 4 급 암모늄길항제 모두가 구조의 구별없이 질량작용의 법칙에 따라 치환되었으나 $(^3H)$ QNB 실험군에서는 제 4급 암모늄콜린 길항제들을 단일성(unity)이 아닌 높고 낮은 두 종류의 친화도를 가진 결합부위의 양상을 나타내었다. 또 비특이성 콜린길항제인 pirenzepine을 사용한 실험군에서는 두 ligands을 모두 치환시켰고 서로 다른 결합부위가 있음을 보였다. 3. Intact cell aggregates 제제를 사용한 실험에서, $(^3H)$ NMS와 $(^3H)$ QNB 모두 homogenates 제제에서와 같은 양상의 반응을 보였다. 또 $(^3H)$ NMS를 radioligand로 하여 수종의 콜린길항제와 수종의 콜린 효능제를 사용하여 약물 상호작용으로 수용체의 성질을 검토하였다. 그 결과 콜린 길항제들은 질량작용의 법칙에 따라 치환되었으나 콜린 효능제 투여군에서는 높고 낮은 두 종류의 다른 친화력의 결항부위를 나타내었다. 4. 위의 실험의 결과로,(a) 친유성콜린 길항제인 $(^3H)$ QNB는 친수성 콜린길항제인 $(^3H)$ NMS보다 훨씬 높은 결합능력을 보였으며 이것으로 수용체 특히 mAchR의 존재 장소 또는 mAchR의 형상의 일부는 세포막 표면 뿐 아니라 세포막내의 어떤 부위와도 관계가 되는 것으로 간주되는데 이것이 $(^3H)$ QNB가 $(^3H)$ NMS보다 높은 최대 결합능력 $(B_{max})$을 나타낼 이유이다. (b) 두 종류의 다른 제제에서 우리는 같은 양상의 결과를 관찰하었기에 결점이 많은 homogenates 제제보다는 intact cell aggregates 제제를 수용체 연구에 대한 새로운 실험모형(experiment model)으로 사용할 수 있는 가능성을 제시하고자 한다.