• The Korean Journal of Pharmacology
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• v.32 no.2
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• pp.139-150
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• 1996

The effects of adenosine analogues on the electrically-evoked norepinephrine(NE) release and the influence of ischemia on the effects were studied in the rat hippocampus. Slices from the rat hippocampus were equilibrated with $0.1{\mu}M$ $[^3H]-norepinephrine$ and the release of the labelled product, $[^3H]-NE$, was evoked by electrical stimulation(3 Hz, 2 ms, 5 $VCm^{-1}$ and rectangular pulses for 90 sec), and the influence of various agents on the evoked tritium-outflow was investigated. Ischemia(15min with 95% $N_2$ +5% $CO_2$) increased both the basal and evoked NE release. These increases were abolished by addition of glucose into the superfused medium, and they were significantly inhibited either by $0.3\;{\mu}M$ tetrodotoxin pretreatment or by removing $Ca^{++}$ in the medium. MK-801$(1{sim}10\;{\mu}M)$, a specific NMDA receptor antagonist, and glibenclamide $(1\;{\mu}M)$, a $K^+-channel$ inhibitor, neither alter the evoked NE release nor affected the Ischemia-Induced increases in NE release. However, polymyxin B(0.03 mg), a specific protein kinase C inhibitor, inhibited the effect of ischemia on the evoked NE release. Adenosine and $N^6-cyclopentyladenosine$ decreased the NE release in a dose-dependent manner in ischemic condition, though the magnitude of inhibition was far less than those in normal (normoxic) condition. Also the treatment with $5{\mu}M$ DPCPX, a potent $A_1-adenosine$ receptor antagonist did not affect the ischemia-effect. These results suggest that the evoked-NE release is potentiated by ischemia, and this process being most probably mediated by protein kinase C, and that the decrease of NE release mediated through $A_1-adenosine$ receptor is significantly inhibited in ischemic state.

• YAKHAK HOEJI
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• v.34 no.4
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• pp.224-237
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• 1990

A single uniform population of specific, saturable, high affinity binding site of $[^3H]QNB$ guinuclidinyl benzilate(QNB) was identified in the rat cerebral microsomes. The Kd value(37.2 pM) for $[^3H]QNB$ calculated from the kinetically derived rate constants was in agreement with the Kd value(48.9 pM) determined by analysis of saturation isotherms at various receptor concentrations. Dimenhydrinate(DMH), histamine $H_1-blocker$, increased Kd value for $[^3H]QNB$ QNB without affecting the binding site concentrations and this effect resulted from the ability of DMH to slow $[^3H]QNB-receptor$ association. Pirenzepine inhibition curve of $[^3H]QNB$ binding was shallow(nH = 0.52) indicating the presence of two receptor subtypes with high ($M_1-site$) and low($M_2-site$) affinity for pirenzepine. Analysis of these inhibition curves yielded that 68% of the total receptor populations were of the $M_1-subtype$ and the remaining 32% of the $M_2-subtype$. Ki values for the $M_1-$ and $M_2-subtypes$ were 2.42 nM and 629.3 nM, respectively. Ki values for $H_1-blockers$ that inhibited $[^3H]QNB$ binding varied with a wide range ($0.02-2.5\;{\mu}M$). The Pseudo-Hill coefficients for inhibition of $[^3H]QNB$ binding by most of $H_1-blockers$ examined except for oxomemazine inhibition of $[^3H]QNB$ binding were close to one. The inhibition curve for oxomemazine in competition with $[^3H]QNB$ was shallow(nH = 0.74) indicating the presence of two receptor populations with different affinities for this drug. The proportion of high and low affinity was 33:67. The Ki values for oxomemazine were $0.045{\pm}0.016\;{\mu}M$ for high affinity and $1.145{\pm}0.232\;{\mu}M$ for low affinity sites. These data indicate that muscarinic receptor blocking potency of $H_1-blockers$ varies widely between different drugs and that most of $H_1-blockers$ examined are nonselective antagonist for the muscarinic receptor subtypes, whereas oxomemazine might be capable of distinguishing between subclasses of muscarinic receptor.

• Journal of Life Science
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• v.20 no.7
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• pp.969-976
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• 2010

In vivo studies of KR-31125 (2-butyl-5-dimethoxymethyl-6-phenyl-7-methyl-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine) were performed in pithed rats, conscious angiotensin II (AII) challenged normotensive rats, renal hypertensive rats (RHRs) and furosemide-treated beagle dogs. KR-31125 induced a non-parallel right shift in the dose-pressor response curve to AII ($ID_{50}$: 0.095 mg/kg) with a dose-dependent reduction in the maximum responses in pithed rats. Compared to losartan, this antagonistic effect was about 18 times more potent, presenting competitive antagonism. Other agonists such as norepinephrine and vasopressin did not alter the responses induced by KR-31125. Orally administered KR-31125 had no agonistic effect and dose-dependently inhibited the pressor response to AII with a slightly weaker potency ($ID_{50}$: 0.25 and 0.47 mg/kg, respectively) in the AII-challenged normotensive rat model, but with a more rapid onset of action than losartan (time to $E_{max}$: 30 min for KR-31125 and 6 hr for losartan). KR-31125 produced a dose-dependent antihypertensive effect with a higher potency than losartan in RHRs, and these effects were confirmed in furosemide-treated dogs where they presented a dose-dependent and long-lasting (>8 hr) antihypertensive effect with a rapid onset of action (time to $E_{max}$: 2-4 hr), as well as a 20-fold greater potency than losartan. These results suggest that KR-31125 is a potent, orally active $AT_1$ receptor antagonist that can be applied to the development of new diagnostic and research tools as an added exploratory potential of $AT_1$ receptor antagonist.

• Archives of Pharmacal Research
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• v.18 no.1
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• pp.1-7
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• 1995

IY-80843, N[2-(2-methoxyphenyl)ethyl]-N'-[4-(lmidazole-4-yl)phenyl] formamidine, is a new potent $H_2-receptor$ anagonist. The potential secondary pharmacologic effects of this agent, on the central nervous and cardiovascular systems were studied. IY-80843 caused ptosis, suppression of locomotion, hypotehrmia, prolongation of sleeping time and hypotensive effects in mice, rats and dogs. These results suggest that IY-80843 affects the funcition of the central nervous and cardiovascular systems in a dose-dependent manner.

• The Korean Journal of Physiology and Pharmacology
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• v.2 no.1
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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.

• Archives of Pharmacal Research
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• v.18 no.3
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• pp.153-158
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• 1995

The levels of extracellualr glutamate, intracellular $Ca^{2+}\;([Ca2+]_i)$ and cGMP were determined for 1 h with the excitatory amino acids, N-methyl-D-aspartate (NMDA) or kainate in cultured cerebellar granule cells. Both NMDA and kainate produced a time-dependent release of glutamate, and kainate was more potent than NMDA in glutamate elevation. The elevation of extracellular glutamate was not purely governed by intracellular $Ca^{2+}$ concentration. However, in opposite to the time-dependent elevation of glutamate, the elevation of cGMP by NMDA and kainate were at maximum level in short-time (1 min) incubation then remarkably decreased with longer incubation times. Post-applications (30 min after agonist) of EAA antagonist did not block EAAs-induced glutamate elevation. However, NMDA antagonist, phencyclidine (PCP), blocked NMDA-induced cGMP elevation at pre- or post-application, but kainate antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), paradoxically augmented kainate-induced cGMP elevation for 1 h incubation. These results show that NMDA or kainate induces time-dependent elevations of extracellular glutamate, while the elevations of cGMP by these EAAs are remarkably decreased with longer incubation times. However, NMDA- arid kainate-indcued glutamate release was blocked by pre-application of each receptor antagonist but not by post-application while EAA-induced $[Ca^{2+}]_i$ was blocked by post-application of antagonist. These observations suggest that EAA-induced elevation of $[Ca^{2+}]_i$ is not parallel with elevation of glutamate release or cGMP.

• Bulletin of the Korean Chemical Society
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• v.33 no.7
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• pp.2389-2392
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• 2012

• Proceedings of the PSK Conference
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• 2003.04a
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• pp.298.2-298.2
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• 2003

The insulinotropic hormone, glucagons-like peptide-1 (GLP-1), which has been proposed as a new potential therapeutics for type-II diabetes, but this is metabolized extremely rapidly by the ubiquitous enzyme, dipeptidyl peptidase IV (DPP IV), forming a metabolite, which acts as an antagonist at the GLP-1 receptor. (omitted)

• Journal of the Korean Society of Laryngology, Phoniatrics and Logopedics
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• v.18 no.2
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• pp.108-112
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• 2007

Otolaryngological manifestations of acid reflux include a wide range of pharyngeal and laryngeal symptoms ; and the constellation of symptoms has been called laryngopharyngeal reflux (LPR). In the absence of definite diagnostic criteria, LPR disease remains a subjective entity. A diagnosis of LPR is usually based on response of symptoms to empirical treatment. Investigative modalities such as pH monitoring and, more recently, impedance studies are generally reserved for treatment failures. LPR usually requires more aggressive and prolonged treatment to achieve regression of both symptoms and laryngeal findings. The suppression of gastric acid and secretion with anti-secretary agents has been the mainstay of medical treatment for patients with acid-related disorders. The suppression of gastric acid secretion achieved with Hz-receptor antagonist $(H_2RA)$ has proved suboptimal for relief of reflux symptoms. The rapid development of tolerance and rebound acid hypersecretion after the with-drawal of $H_2RA$ limit their clinical use. Proton pump inhibitors (PPI) have been proved to be very effective for suppressing intragastric acidity, but the optimal dose and duration is unknown. Current evidence indicates that pharmacologic intervention should include, at a minimum, a 3 month trial of twice daily PPI. Symptoms of LPR improve over 2 months of therapy. The physical findings of LPR resolve more slowly than the symptoms and this continues through out at least 6 months of treatment. For most patients with LPR, twice daily dosing with a PPI is usually recommended for an initial treatment for a period of no less than 6 months treatment, and lifetime treatment may be required.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.6
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• pp.769-774
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• 1997

Non-neuronal high affinity binding sites for benzodiazepines have been found in many peripheral tissues including cardiac muscle and vascular smooth muscle, and have been designated as 'peripheral benzodiazepine receptor'. Benzodiazepines have been shown to induce relaxation of the ileal, vesical, and uterine smooth muscles. However, it is still unclear about possible involvement of peripheral benzodiazepine receptor on the contractility of trachealis muscle. This study was performed to investigate the role of the peripheral benzodiazepine receptor on the contractility of canine trachealis muscle. Canine trachealis muscle strips of 15 mm long were suspended in an isolated organ bath containing 1 ml of physiological salt solution maintained at $37^{\circ}C$, and aerated with $95%\;O_2/5%\;CO_2$. Isometric myography was performed, and the results of the experiments were as follows: Ro5-4684, FGIN-1-27 and clonazepam reduced a basal tone of isolated canine trachealis muscle strip concentration dependently, relaxant actions of RoS-4684 and FGIN-1-27 were antagonized by PK11195, a peripheral benzodiazepine receptor antagonist. Flumazenil, a central type antagonist, did not antagonize the relaxant action of Peripheral type agonists. Saturation binding assay of [3H]Ro5-4864 showed a high affinity$(Kd=5.33{\pm}1.27nM,\;Bmax=\;867.3{\pm}147.2\;fmol/mg\;protein)$ binding site on the canine trachealis muscle. Ro 5-4684 suppressed the bethanechol-, 5-hydroxyoyptamine- and histamine- induced contractions. Platelet activating factor (PAF) exerted strong and prolonged contraction in trachealis muscle strip. Strong tonic contraction by PAE was attenuated by Ro 5-4684, but not by WEB 2086, a PAF antagonist. Based on these results, it is concluded that the peripheral benzodiazepine receptor mediates the inhibitory regulation of contractilty of canine trachealis muscle.