• 제목/요약/키워드: DPCPX

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허혈전처치의 허혈심장 보호과정에서 Adenosine 및 Protein Kinase C의 역할 (Role of Adenosine and Protein Kinase C in the Anti-ischemic Process of Ischemic Preconditioning in Rat Heart)

  • 유호진;박종완;김명석
    • 대한약리학회지
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    • 제32권1호
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    • pp.31-37
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    • 1996
  • 허혈전처치(IP)의 히혈-재관류손상에 대한 심근 보호작용의 기전을 규명하기 위한 일환으로 denosine에 의한 PKC자극이 허혈전처치의 주요 기전으로 작용할 가능성을 조사하였다. 흰쥐 적출심장의 Langendorff 관류 표본에서 실험적인 허혈(30분)-재관류(20분)손상을 유도하였고, 허혈전처치는 허혈-재관류 손상 유도 전에 5분 허혈-5분 재관류를 3회 반복하여 시행하였다. 심근 손상의 지표로 심수축기능, 세포질효소 유출을 측정하였다. Adenosine이 허혈전처치의 심보호 효과에 관여하는지를 관찰하기 위하여 adenosine수용체 억제제인 8-(p-sulfophenyl)-theophylline(SPT), Xanthine amine congener(XAC) 및 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)을 허혈전처치 유도 전에 투여하였다. 또한 PKC가 허혈전처치의 세포내 매개인자로 관여 할 가능성을 관찰하기 위하여 PKC활성 억제제인 polymyxin B 및 chelerythrine과 PKC translocation 억제제인 colchicine을 허혈전처치 유도 전에 투여하였다. 연구성적은 다음과 같다. 1) 허혈전처치는 허혈재관류 심장의 심기능의 저하를 현저히 회복시켜 심기능 회복률은 75%에 달하였다. 2) 허혈-재관류 심장에서 lactate dehydrogenase유출증가는 허혈전처치에 의해 현저히 저하되었다. 3) Adenosine 비선택적 차단제인 SPT와 Al 선택적 차단제인 DPCPX 및 XAC의 투여가 허혈전처치에 의한 심기능회복 및 LDH 유출 감소에 영향을 미치지 않았다. 4) PKC활성 억제제인 polymyxin B 와 chelerythrine을 처치시 히혈전처치 심장의 심기능 회복률이 현저히 감소되었으며 LHD 유출 역시 대조군 심장의 수준으로 증가하였다. 5) PKC translocation을 방해하는 colchicine도 허혈전처치의 심보호 효과를 억제시켰다. 이상의 결과들로부터 adenosine은 흰쥐 심장에서 허혈전처치의 심보호효과에 중요한 세포외 매개물질로 작용할 가능성이 희박하며, PKC는 흰쥐 심장에서 허혈전처치시 세포내 매개 인자로 관여하여 허혈전처치에 의한 심보호효과에 중요한 역할을 할 수 있으리라 사료된다.

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Involvement of Adenosine in Cardioprotective Effect of Catecholamine Preconditioning in Ischemia-Reperfused Heart of Rat

  • Kim, Young-Hoon;Kim, Chan-Hyung;Kim, Gi-Tae;Kim, In-Kyu;Park, Jong-Wan;Kim, Myung-Suk
    • The Korean Journal of Physiology and Pharmacology
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    • 제2권6호
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    • pp.753-761
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    • 1998
  • Preconditioning of a heart with small doses of catecholamines induces a tolerance against the subsequent lethal ischemia. The present study was performed to find a specific receptor pathway involved with the catecholamine preconditioning and to test if adenosine plays a role in this cardioprotective effect. Isolated rat hearts, pretreated with small doses of ${\alpha}-\;or\;{\beta}-adrenergic$ agonists/antagonists, were subjected to 20 minutes ischemia and 20 minutes reperfusion by Langendorff perfusion method. Cardiac mechanical functions, lactate dehydrogenase and adenosine release from the hearts were measured before and after the drug treatments and ischemia. In another series of experiments, adenosine $A_1\;or\;A_2$ receptor blockers were treated prior to administration of adrenergic agonists. Pretreatments of a ${\beta}-agonist,\;isoproterenol(10^{-9}{\sim}10^{-7}\;M)$ markedly improved the post-ischemic mechanical function and reduced the lactate dehydrogenase release. Similar cardioprotective effect was observed with an ?-agonist, phenylephrine pretreatment, but much higher $concentration(10^{-4}\;M)$ was needed to achieve the same degree of cardioprotection. The cardioprotective effects of isoproterenol and phenylephrine pretreatments were blocked by a ${\beta}_1-adrenergic$ receptor antagonist, atenolol, but not by an ${\alpha}_1-antagonist,$ prazosin. Adenosine release from the heart was increased by isoproterenol, and the increase was also blocked by atenolol, but not by prazosin. A selective $A_1-adenosine$ receptor antagonist, 1,3-dipropyl-8-cyclopentyl xanthine (DPCPX) blocked the cardioprotection by isoproterenol pretreatment. These results suggest that catecholamine pretreatment protects rat myocardium against ischemia and reperfusion injury by mediation of ${\beta}_1-adrenergic$ receptor pathway, and that adenosine is involved in this cardioprotective effect.

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The change of signaling pathway on the electrical stimulated contraction in streptozotocin-induced bladder dysfunction of rats

  • Han, Jong Soo;Min, Young Sil;Kim, Gil Hyung;Chae, Sang-hyun;Nam, Yoonjin;Lee, Jaehwi;Lee, Seok-Yong;Sohn, Uy Dong
    • The Korean Journal of Physiology and Pharmacology
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    • 제22권5호
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    • pp.577-584
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    • 2018
  • Bladder dysfunction is a common complication of diabetes mellitus (DM). However, there have been a few studies evaluating bladder smooth muscle contraction in DM in the presence of pharmacological inhibitors. In the present study, we compared the contractility of bladder smooth muscle from normal rats and DM rats. Furthermore, we utilized pharmacological inhibitors to delineate the mechanisms underlying bladder muscle differences between normal and DM rats. DM was established in 14 days after using a single injection of streptozotocin (65 mg/kg, intraperitoneal) in Sprague-Dawley rats. Bladder smooth muscle contraction was induced electrically using electrical field stimulation consisting of pulse trains at an amplitude of 40 V and pulse duration of 1 ms at frequencies of 2-10 Hz. In this study, the pharmacological inhibitors atropine (muscarinic receptor antagonist), U73122 (phospholipase C inhibitor), DPCPX (adenosine $A_1$ receptor antagonist), udenafil (PDE5 inhibitor), prazosin (${\alpha}_1$-receptor antagonist), verapamil (calcium channel blocker), and chelerythrine (protein kinase C inhibitor) were used to pretreat bladder smooth muscles. It was found that the contractility of bladder smooth muscles from DM rats was lower than that of normal rats. In addition, there were significant differences in percent change of contractility between normal and DM rats following pretreatment with prazosin, udenafil, verapamil, and U73122. In conclusion, we suggest that the decreased bladder muscle contractility in DM rats was a result of perturbations in $PLC/IP_3$-mediated intracellular $Ca^{2+}$ release and PDE5 activity.

The Altered Signaling on EFS-Induced Colon Contractility in Diabetic Rats

  • Thein, Wynn;Po, Wah Wah;Kim, Dong Min;Sohn, Uy Dong
    • Biomolecules & Therapeutics
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    • 제28권4호
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    • pp.328-336
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    • 2020
  • Diabetes mellitus affects the colonic motility developing gastrointestinal symptoms, such as constipation. The aim of the study was to examine the role of intracellular signaling pathways contributing to colonic dysmotility in diabetes mellitus. To generate diabetes mellitus, the rats were injected by a single high dose of streptozotocin (65 mg/kg) intraperitoneally. The proximal colons from both normal and diabetic rats were contracted by applying an electrical field stimulation with pulse voltage of 40 V in amplitude and pulse duration of 1 ms at frequencies of 1, 2, 4, and 6 Hz. The muscle strips from both normal rats and rats with diabetes mellitus were pretreated with different antagonists and inhibitors. Rats with diabetes mellitus had lower motility than the control group. There were significant differences in the percentage of inhibition of contraction between normal rats and rats with diabetes mellitus after the incubation of tetrodotoxin (neuronal blocker), atropine (muscarinic receptor antagonist), prazosin (α1 adrenergic receptor antagonist), DPCPX (adenosine A1 receptor antagonist), verapamil (L-type Ca2+ channel blocker), U73122 (PLC inhibitor), ML-9 (MLCK inhibitor), udenafil (PDE5 inhibitor), and methylene blue (guanylate cyclase inhibitor). The protein expression of p-MLC and PDE5 were decreased in the diabetic group compared to the normal group. These results showed that the reduced colonic contractility resulted from the impaired neuronal conduction and decreased muscarinic receptor sensitivity, which resulted in decreased phosphorylation of MLC via MLCK, and cGMP activity through PDE5.

허혈이 유발된 흰쥐 해마에서 Norepinephrine 유리에 미치는 Adenosine 수용체의 역할 (The Role of Adenosine Receptor on Norepinephrine Release from Ischemic-Induced Rat Hippocampus)

  • 정종훈;최봉규
    • 대한약리학회지
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    • 제32권2호
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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.

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Sleep Promoting Effect of Luteolin in Mice via Adenosine A1 and A2A Receptors

  • Kim, Tae-Ho;Custodio, Raly James;Cheong, Jae Hoon;Kim, Hee Jin;Jung, Yi-Sook
    • Biomolecules & Therapeutics
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    • 제27권6호
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    • pp.584-590
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    • 2019
  • Luteolin, a widespread flavonoid, has been known to have neuroprotective activity against various neurologic diseases such as epilepsy, and Alzheimer's disease. However, little information is available regarding the hypnotic effect of luteolin. In this study, we evaluated the hypnotic effect of luteolin and its underlying mechanism. In pentobarbital-induced sleeping mice model, luteolin (1, and 3 mg/kg, p.o.) decreased sleep latency and increased the total sleep time. Through electroencephalogram (EEG) and electromyogram (EMG) recording, we demonstrated that luteolin increased non-rapid eye movement (NREM) sleep time and decreased wake time. To evaluate the underlying mechanism, we examined the effects of various pharmacological antagonists on the hypnotic effect of luteolin. The hypnotic effect of 3 mg/kg of luteolin was not affected by flumazenil, a GABAA receptorbenzodiazepine (GABAAR-BDZ) binding site antagonist, and bicuculine, a GABAAR-GABA binding site antagonist. On the other hand, the hypnotic effect of 3 mg/kg of luteolin was almost completely blocked by caffeine, an antagonist for both adenosine A1 and A2A receptor (A1R and A2AR), 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1R antagonist, and SCH-58261, an A2AR antagonist. From the binding affinity assay, we have found that luteolin significantly binds to not only A1R but also A2AR with $IC_{50}$ of 1.19, $0.84{\mu}g/kg$, respectively. However, luteolin did not bind to either BDZ-receptor or GABAAR. From these results, it has been suggested that luteolin has hypnotic efficacy through A1R and A2AR binding.

Cordycepin protects against β-amyloid and ibotenic acid-induced hippocampal CA1 pyramidal neuronal hyperactivity

  • Yao, Li-Hua;Wang, Jinxiu;Liu, Chao;Wei, Shanshan;Li, Guoyin;Wang, Songhua;Meng, Wei;Liu, Zhi-Bin;Huang, Li-Ping
    • The Korean Journal of Physiology and Pharmacology
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    • 제23권6호
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    • pp.483-491
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    • 2019
  • Cordycepin exerts neuroprotective effects against excitotoxic neuronal death. However, its direct electrophysiological evidence in Alzheimer's disease (AD) remains unclear. This study aimed to explore the electrophysiological mechanisms underlying the protective effect of cordycepin against the excitotoxic neuronal insult in AD using whole-cell patch clamp techniques. ${\beta}$-Amyloid ($A{\beta}$) and ibotenic acid (IBO)-induced injury model in cultured hippocampal neurons was used for the purpose. The results revealed that cordycepin significantly delayed $A{\beta}$ + IBO-induced excessive neuronal membrane depolarization. It increased the onset time/latency, extended the duration, and reduced the slope in both slow and rapid depolarization. Additionally, cordycepin reversed the neuronal hyperactivity in $A{\beta}$ + IBO-induced evoked action potential (AP) firing, including increase in repetitive firing frequency, shortening of evoked AP latency, decrease in the amplitude of fast afterhyperpolarization, and increase in membrane depolarization. Further, the suppressive effect of cordycepin against $A{\beta}$ + IBO-induced excessive neuronal membrane depolarization and neuronal hyperactivity was blocked by DPCPX (8-cyclopentyl-1,3-dipropylxanthine, an adenosine $A_1$ receptor-specific blocker). Collectively, these results revealed the suppressive effect of cordycepin against the $A{\beta}$ + IBO-induced excitotoxic neuronal insult by attenuating excessive neuronal activity and membrane depolarization, and the mechanism through the activation of $A_1R$ is strongly recommended, thus highlighting the therapeutic potential of cordycepin in AD.

The Inhibitory Mechanism on Acetylcholine-Induced Contraction of Bladder Smooth Muscle in the Streptozotocin-Induced Diabetic Rat

  • Han, Jong Soo;Kim, Su Jin;Nam, Yoonjin;Lee, Hak Yeong;Kim, Geon Min;Kim, Dong Min;Sohn, Uy Dong
    • Biomolecules & Therapeutics
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    • 제27권1호
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    • pp.101-106
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    • 2019
  • Most diabetic patients experience diabetic mellitus (DM) urinary bladder dysfunction. A number of studies evaluate bladder smooth muscle contraction in DM. In this study, we evaluated the change of bladder smooth muscle contraction between normal rats and DM rats. Furthermore, we used pharmacological inhibitors to determine the differences in the signaling pathways between normal and DM rats. Rats in the DM group received an intraperitoneal injection of 65 mg/kg streptozotocin and measured blood glucose level after 14 days to confirm DM. Bladder smooth muscle contraction was induced using acetylcholine (ACh, $10^{-4}M$). The materials such as, atropine (a muscarinic receptor antagonist), U73122 (a phospholipase C inhibitor), DPCPX (an adenosine $A_1$ receptor antagonist), udenafil (a PDE5 inhibitor), prazosin (an ${\alpha}_1$-receptor antagonist), papaverine (a smooth muscle relaxant), verapamil (a calcium channel blocker), and chelerythrine (a protein kinase C inhibitor) were pre-treated in bladder smooth muscle. We found that the DM rats had lower bladder smooth muscle contractility than normal rats. When prazosin, udenafil, verapamil, and U73122 were pre-treated, there were significant differences between normal and DM rats. Taken together, it was concluded that the change of intracellular $Ca^{2+}$ release mediated by PLC/IP3 and PDE5 activity were responsible for decreased bladder smooth muscle contractility in DM rats.

The Role of Adenosine Receptors on Acetylcholine Release in the Rat Striatum

  • Kim, Do-Kyung;Kim, Hyeon-A;Choi, Bong-Kyu
    • The Korean Journal of Physiology and Pharmacology
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    • 제1권1호
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    • pp.1-12
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    • 1997
  • As it has been reported that the depolarization induced acetylcholine (ACh) release is modulated by activation of presynaptic $A_1$ adenosine heteroreceptor and various evidence suggest that indicate the $A_2$ adenosine receptor is present in the striatum, this study was undertaken to delineate the role of adenosine receptors on the striatal ACh release. Slices from the rat striatum were equilibrated with $[^3H]$choline and then the release amount of the labelled product, $[^3H]$ACh, which was evoked by electrical stimulation (rectangular pulses, 3 Hz, 2 ms, 24 mA, $5\;Vcm^{-1}$, 2 min), was measured, and the influence of various agents on the evoked tritium outflow was investigated. And also, quantitative receptor autoradiography and drug-receptor binding assay were performed in order to confirm the presence and characteristics of $A_1$ and $A_2$ adenosine receptors in the rat striatum. Adenosine $(10{sim}100\;{mu}M)$ and $N^6$-cyclopentyladenosine (CPA, $1{sim}100\;{mu}M)$ decreased the $[^3H]$ACh release in a dose-dependent manner without changing the basal rate of release in the rat striatum. The reducing effects of ACh release by adenosine and CPA were abolished by 8-cyclopentyl-1,3-dipropy-Ixanthine (DPCPX, 2 ${mu}M$), a selective $A_1$, adenosine receptor antagonist, treatment. The effect of adenosine was potentiated markedly by 3,7-dimethyl-1-propargylxanthine (DMPX, 10 ${mu}M$), a specific $A_2$ adenosine receptor antagonist. 2-P-(2-carboxyethyl)phenethylamimo-5'-N- ethylcarboxamidoadenosine hydrochloride (CGS-21680C), in concentrations ranging from 0.01 to 10 ${mu}M$, a recently introduced potent $A_2$ adenosine receptor agonist, increased the $[^3H]$ACh release in a dose related fashion without changing the basal rate of release. These effects were completely abolished by DMPX $(10\;{mu}M)$. In autoradiograrhy experiments, $[^3H]$2-chloro-$N^6$-cyclopentyladenosine ($[^3H]$ CCPA) bindings were highly localized in the hippocampus and the cerebral cortex. Additionally, lower levels of binding were found in the striatum. However, $[^3H]$CGS-21680C bindings were highly localized in the striatal region with the greatest density of binding found in the caudate nucleus and putamen. Lower levels of binding were also found in the nucleus accumbens and olfactory tubercle. In drug-receptor binding assay, binding of $[^3H]$ CCPA to $A_1$ adenosine receptors of rat striatal membranes was inhibited by CPA ($K_i$ = 1.6 nM) and N-ethylcarboxamidoadenosine (NECA, $K_i$ = 12.9 nM), but not by CGS-21680C ($K_i$ = 2609.2 nM) and DMPX ($K_i$ = 19,386 nM). In contrast, $[^3H]$CGS-21680C binding to $A_2$ denosine receptors was inhibited by CGS-21680C ($K_i$ = 47.6 nM) and NECA ($K_i$ = 44.9 nM), but not by CPA ($K_i$ = 2099.2 nM) and DPCPX ($K_i$ = 19,207 nM). The results presented here suggest that both types of $A_1$ and $A_2$ adenosine heteroreceptors exist and play an important role in ACh release in the rat striatal cholinergic neurons.

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니코틴의 마우스 소뇌과립세포내 칼슘의 항상성 조절기전 (Cellular Mechanism of Nicotine-mediated Intracellular Calcium Homeostasis in Primary Culture of Mouse Cerebellar Granule Cells)

  • 김원기;배영숙
    • 대한약리학회지
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    • 제32권1호
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    • pp.13-21
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    • 1996
  • 세포내 칼슘농도는 신경세포의 다양한 기능에 매우 중요한 역할을 하고 있다. 본 연구에서는 일차배양한 마우스 소뇌과립세포에서 니코틴성 아세틸콜린 수용체가 특정 발생단계에 발현되고 세포내 칼슘의 농도조절에 관여하는 것을 관찰하였다. 니코틴에 의한 세포내 칼슘농도의 변화는 $^{45}Ca^{2+}$나 fura-2를 사용하여 형광법으로 측정하였다. 니코틴은 마우스 소뇌과립세포내 칼슘의 농도를 최대한 증가시키는 것으로 보인다. 반면에 일차배양한 Glia 세포들에서는 $^{45}Ca^{2+}$ 농도를 증가시키지 않았다. 세포내 칼슘농도에 미치는 니코틴의 효과는 NMDA 수용체에 대한 길항제에 의하여 억제되었다. 또한 Glutamate pyruvate transminase (GPT)를 사용하여 배양액의 글루타민산을 제거하면 니코틴효과가 소실되는 것이 관찰되었다. 이러한 결과는 니코틴에 의한 세포내 칼슘농도의 변화가 세포에서 유리된 글루타민산에 의한 간접적인 효과임을 암시한다. Fura-2를 사용한 형광법으로 실험한 결과 니코틴은 two phase로 세포내 칼슘농도를 증가시키는 것을 보여주었다. NMDA 수용체 길항제와 GPT는 단지 후기 plateau상만 억제하였다. 따라서 본 연구결과는 니코틴이 직접 니코틴성 아세틸콜린 수용체를 자극하여 일시적으로 세포내 칼슘농도를 증가시키고 글루타민산을 유리하여 NMDA 수용체를 활성화시킴으로써 세포내 칼슘농도를 지속적으로 증가시키는 것으로 보여진다. 이러한 결과는 니코틴성 아세틸콜린 수용체가 특정한 발생과정에 발현되어 세포내 칼슘농도 조절에 관여함으로써 신경발생과정에서 중요한 역할을 할 수 있음을 보여주고 있다. state를 나타내는 것을 알 수 있다. 또한 $[^3H]DPCPX$를 이용한 competitive binding assay에서 0.1 mM GTP는 효현제인 PIA의 apparent affinity를 감소시켰으며, DPCPX의 apparent affinity는 증가시키고, CGS-15943에는 아무런 영향을 미치지 않았다. 이것은 상기의 $[^{35}S]GTP_{\gamma}S$ binding의 결과를 뒤받침해 주는 결과라고 생각된다.요한 역할을 할 수 있으리라 사료된다.X>$Ca^{2+}$에 의하여 활성화되는 $K^+$ 통로를 개방시킴으로 세포내 $Ca^{2+}$을 감소시켜 뇌 기저동맥의 이완반응을 매개하는 것으로 사료된다. 함량을 조정하므로, 흉선세포의 apoptosis에 억제적으로 작용할 수 있음을 시사하는 것으로 사료된다. 영양액에 의하여는 회복됨을 볼 수 있었으며 $Mg^{++}$ 증가 영양액에서는 억제, TTX 동시 투여시에는 완전히 소실되었다. 이상의 실험결과로 흰쥐 해마에서 $A_1-adenosine$ 수용체를 통한 adenosine의 NE 유리 감소는 TEA 및 4AP에 예민한 $K^+$-통로가 관여하고 여기에는 세포외액의 Ca^{++}의 농도가 중요한 인자의 하나로 관여 하는 것으로 사료된다. 영상의 질을 크게 향상 시켜 줌으로 비가역 3구획모델에서의 PGA방법을 대체할 새로운 파라메터 영상구성방법으로 적합할 것이다.관계되며, YH439는 중금속으로 유도된 조직독성에 방어효과가 있음을 지지한다.총 아미노산의 순은

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