• Biomolecules & Therapeutics
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• 제16권4호
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• pp.299-305
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• 2008

Active cardiovascular anaphylactic response was induced in ovalbumin-sensitized, pithed Sprague-Dawley and Wistar rats. On intravenous administration of the antigen, ovalbumin, marked tachycardia and pressor responses were immediately elicited. Thereafter, a delayed long-lasting severe hypotensive response was observed. These anaphylactic cardiovascular responses were maximal 2-3 weeks after the sensitization, and the response was slightly diminished 6 weeks after sensitization. The immediate pressor response was blocked by a non-selective serotonin antagonist methysergide at a dose-dependent manner, but not by histamine receptor antagonists mepyramine (pyrilamine) or cimetidine. The delayed hypotension was reduced either by histamine $H_1$ receptor antagonist mepyramine or $H_2$ receptor antagonist cimetidine, both in a dose-dependent manner. The tachycardic response was not influenced by serotonin or histamine receptor antagonists examined in this study. Differently from the cardiovascular responses, there was no observable bronchial contraction in Sprague-Dawley rat trachea in contrast to Wistar rat where the trachea contracted to in vitro antigen challenge. The cardiovascular anaphylactic model seems to be useful for studying cardiovascular events that occur exclusively in peripheral heart-blood vessel systems. The involvement of two major anaphylactic mediators, serotonin and histamine, is partially demonstrated.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 1994년도 춘계학술대회 and 제3회 신약개발 연구발표회
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• pp.305-305
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• 1994

It has been shown that there are several subtypes of $\kappa$ opioid receptor, We have evaluated the properties of non-${\mu}$, non-$\delta$ binding of 〔$^3$H〕DIP, a nonselective opioid antagonist, in rat cortex membranes. Binding to ${\mu}$ and $\delta$ sites was inhibited by the use of an excess of competing selective agonists (DAMGO, DPDPE) for these sites. (-)Ethylketocyclazocine(EKC) inhibited 〔$^3$H〕DIP binding with Ki. of 70 nM. However, arylacetamides (U69593 and U50488H) gave little inhibition. Also, we have examined the opioid modulation of K$\^$+/(30 mM)-induced histamine release in rat frontal cortex slices labeled with 1-〔$^3$H〕histidine. The 〔$^3$H〕histamine release from cortex slices was inhibited by EKC, a $\kappa$$_1$-and $\kappa$$_2$-agonist, in a concentration-dependent manner(10 to 10,000 nM). The IC$\sub$50/ of EKC was 107 ${\pm}$ 6 nM. However, the $\delta$ receptor selective agonists, DPDPE and deltorphine II, ${\mu}$ receptor agonists, DAMGO and TAPS, $\kappa$$_1$-agonists, U69593 and U50488H, and $\varepsilon$-agonist, ${\beta}$-endorphin, did not inhibit histamine release even in micromoiar dose, indicating that ${\mu}$, $\delta$ or $\kappa$$_1$ receptors are not involved. The concentration-response curve of EKC was shifted to right in the presence of naloxone (300 nM), a ${\mu}$ preferential antagonist, norbinaltorphimine(300 nM), a $\kappa$$_1$ preferential antagonist and bremazocine(1 nM), a $\kappa$$_1$-agonist and $\kappa$$_2$-antagonist. These results suggest that $\kappa$$_2$ opioid receptor regulates histamine release in the frontal cortex of the rat.

• 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.

• 대한수의학회지
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• 제34권3호
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• pp.471-478
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• 1994

Effects of histamine on the ruminal smooth muscle motility of cattle were investigated in the longitudinal and circular smooth muscle strips. In order to these experiments, specimens were obtained from 35 korean native cattles, 3-4 years old, in Kwang-ju area slaughterhouse. Smooth muscle strips of rumen were made from sample, and then measured the isometric contraction with physiograph in $37{^{\circ}C}$ organ bath. The results were as follows : 1. Histamine caused two different types of response(a contraction or a relaxation) on the smooth muscle of cattle rumen. These responses increased in dose dependant manner. 2. Pyrilamine($H_1$-receptor antagonist) completely blocked contraction in all the preparation and converted the response into relaxation. 3. Cimetidine($H_2$-receptor antagonist) completely blocked relaxation in all the preparation and converted the response into contraction. 4. The contraction induced by histamine($10^{-3}M$) was not Mocked by cholinergic, adrenergic blocker or hexamethonium. 5. The contraction induced by histamine($10^{-3}M$) was markedly inhibited in the $Ca^{2+}$ free(or EDTA 2Na) Kreb's solution and by verapamil.

• The Korean Journal of Pain
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• 제37권3호
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• pp.218-232
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• 2024

Background: Cynara scolymus has bioactive constituents and has been used for therapeutic actions. The present study was undertaken to investigate the mechanisms underlying pain-relieving effects of the hydroethanolic extract of C. scolymus (HECS). Methods: The antinociceptive activity of HECS was assessed through formalin and acetic acid-induced writhing tests at doses of 50, 100 and 200 mg/kg intraperitoneally. Additionally, naloxone (non-selective opioid receptors antagonist, 2 mg/kg), atropine (non-selective muscarinic receptors antagonist, 1 mg/kg), chlorpheniramine (histamine H₁-receptor antagonist, 20 mg/kg), cimetidine (histamine H₂-receptor antagonist, 12.5 mg/kg), flumazenil (GABA_A/BDZ receptor antagonist, 5 mg/kg) and cyproheptadine (serotonin receptor antagonist, 4 mg/kg) were used to determine the systems implicated in HECS-induced analgesia. Impact of HECS on locomotor activity was executed by open-field test. Determination of total phenolic content (TPC) and total flavonoid content (TFC) was done. Evaluation of antioxidant activity was conducted employing 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay. Results: HECS (50, 100 and 200 mg/kg) significantly indicated dose dependent antinociceptive activity against pain-related behavior induced by formalin and acetic acid (P < 0.001). Pretreatment with naloxone, atropine and flumazenil significantly reversed HECS-induced analgesia. Antinociceptive effect of HECS remained unaffected by chlorpheniramine, cimetidine and cyproheptadine. Locomotor activity was not affected by HECS. TPC and TFC of HECS were 59.49 ± 5.57 mgGAE/g dry extract and 93.39 ± 17.16 mgRE/g dry extract, respectively. DPPH free radical scavenging activity (IC₅₀) of HECS was 161.32 ± 0.03 ㎍/mL. Conclusions: HECS possesses antinociceptive activity which is mediated via opioidergic, cholinergic and GABAergic pathways.

• Bulletin of the Korean Chemical Society
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• 제34권2호
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• pp.549-552
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• 2013

An efficient and alternative synthesis of enantiomerically pure (+)-(S)-4-(4-((4-chlorophenyl)(pyrid-2-yl)methoxy]piperidin-1-yl)butanoic acid, bepotastine (1) is described. The key resolution of (R/S)-bepotastine l-menthyl ester (3) is achived via diastereomeric salt crystallization using N-benzyloxycarbonyl-L-aspartic acid (NCbzLAA) as the resolving agent to provide (S)-bepotastine l-menthyl ester (S)-3. Hydrolysis of (S)-bepotastine l-menthyl ester (S)-3 afforded the desired bepotastine (1) with good yields and enantiopurity (> 99%). Finally, bepotastine besilate (4) and bepotastine calcium (5) are achived by salt formation of bepotastine (1) with benzene sulfonic acid and calcium salt respectively. The reaction conditions were optimized to make suitable for commercial scale production.

• 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.

• 약학회지
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• 제35권5호
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• pp.368-371
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• 1991

For the development of new antiulcer agents 5, 6-dihydroimidazo[2, 1-b]- thiazoles substituted at the 3-position are sythesized. Thus, the reaction of 3-chloromethyl-5, 6-dihydroimidazo[2, 1-b]thiazole(2) with thiourea and subsequently with 3-chloro-propionitrile gives 3-[3-[5, 6-dihydroimidazo[2, 1-b]thiazolyl]methylthio]propionitrile(4), which by partial alcoholysis with methanol is converted into methyl-3-[3-[5, 6-dihydro-imidazo[2, 1-b]thiazoyl]methylthio]propionimidate(5) . This compound(5) is treated finally with sulfamide or sulfonamides. 3-[3-[5, 6-dihydroimidazo[2, 1-b]thiazoyl]methylthiol-N$^{2}$-sulfamoyl-propionamidine(6) inhibited gastric acid secretion (45%) when administered intraduodenally (100 mg/kg) to pylorus-ligated rats.

• 약학회지
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• 제39권2호
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• pp.153-160
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• 1995

Receptor binding study was carried out as an in vitro assay to test the anti-ulcer effect for newly synthesized test compounds(IY-80843 and IY-80845) which were reported to have a strong anti-secretory effect in Shay-ligated rats. The histamine H$_{2}$-receptor fraction was prepared from the membranes of the isolated gastric glands in guinea pigs and $^{3}$H-cimetidine was used as a radioligand. The binding of $^{3}$H-cimetidine to the membranes of the isolated gastric glands was found to be time dependent, saturable and confined to a single population of binding sites with $K_{D}$ value of 0.13$\pm$0.03 $\mu{M}$ and B$_{max}$ value of 52.5$\pm$1.5 pmol/mg. From the competition experiments, both IY-80843 and IY-80845 were shown to have a strong blocking effect against binding of $^{3}$H-cimetidine to the histamine H$_{2}$-receptor. The IC$_{50}$, Ki, and Hill coefficient(nH) values for IY-80843 were 0.18$\pm$0.02 $\mu{M}$, 0.16$\pm$0.02 $\mu{M}$, and 0.97$\pm$0.15, respectively and those values for IY-80845 were 0.27$\pm$0.02 $\mu{M}$, 0.24$\pm$0.02 $\mu{M}$, and 0.82$\pm$0.13, respectively. The results demonstrated that the blocking effects of IY-80843 and IY-80845 were 7 and 5 times stronger than that of cimetidine, respectively. Therefore, the newly synthesized compounds, IY-80843 and IY-80845, appeared to be the highly potent competitive inhibitors of histamine on the H$_{2}$-receptor.

• 대한수의학회지
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• 제34권3호
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• pp.493-500
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• 1994

The purpose of this study was to investigate the effects of neurotransmitters and the source of $Ca^{2+}$ in the effects of neurotransmitters on the motility of pig oviductal isthmic smooth muscle. The motility of the isolated smooth muscle was recorded by using physiological recording system. The results were summarized as follows; Acetylcholine, norepinephrine, histamine and prostaglandin $F_{2{\alpha}}(PGF_{2{\alpha}})$ caused the contraction and the contractile responses were increased in a dose-dependent manner from the concentration of $10^{-7}$ to $10^{-4}M$. The maximum contractility of acetylcholine, norepinephrine, histamine and $PGF_{2{\alpha}}$ was 65.99, 28.66, 83.99 and 47.33% of 100 mM K contraction, respectively. The contractile response induced by acetylcholine$(10^{-6}M)$ was completely blocked by the pretreatment with cholinergic receptor blocker, atropine$(10^{-6}M)$, the contractile response induced by norepinephrine$(10^{-5}M)$ was blocked by the pretreatment with ${\alpha}$-adrenergic receptor blocker, phentolamine$(10^{-6}M)$ but was not blocked and rather increased by the pretreatment with ${\beta}$-adrenergic receptor blocker. propranolol$(10^{-6}M)$, the contractile response induced by histamine$(10^{-6}M)$ was completely blocked by the pretreatment with $H_1$-histaminergic receptor blocker, pyrilamine$(10^{-6}M)$ but was increased by the pretreatment with $H_2$-histaminergic receptor blocker, cimetidine$(10^{-6}M)$. The contractile response induced by acetylcholine$(10^{-6}M)$, norepinephrine$(10^{-5}M)$ and histamine$(10^{-6}M)$ was weakly contracted response in $Ca^{2+}$-free medium, but the contractile response induced by $PGF_{2{\alpha}}(10^{-6}M)$ was disappeared. The contractile response induced by acetylcholine$(10^{-6}M)$, norepinephrine$(10^{-5}M)$ and histamine$(10^{-6}M)$ was powerfully depressed by the pretreatment with $Ca^{2+}$-channel blocker, verapamil$(10^{-5}M)$ but the contractile response induced by $PGF_{2{\alpha}}(10^{-6}M)$ was completely inhibited.