• 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.

• Biomolecules & Therapeutics
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• 제25권2호
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• pp.149-157
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• 2017

The interleukin-1 receptor antagonist (IL-1RA) is a potential stroke treatment candidate. Intranasal delivery is a novel method thereby a therapeutic protein can be penetrated into the brain parenchyma by bypassing the blood-brain barrier. Thus, this study tested whether intranasal IL-1RA can provide neuroprotection and brain penetration in transient cerebral ischemia. In male Sprague-Dawley rats, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 1 h. The rats simultaneously received 50 mg/kg human IL-1RA through the intranasal (IN group) or intraperitoneal route (IP group). The other rats were given 0.5 mL/kg normal saline (EC group). Neurobehavioral function, infarct size, and the concentration of the administered human IL-1RA in the brain tissue were assessed. In addition, the cellular distribution of intranasal IL-1RA in the brain and its effect on proinflammatory cytokines expression were evaluated. Intranasal IL-1RA improved neurological deficit and reduced infarct size until 7 days after MCAO (p<0.05). The concentrations of the human IL-1RA in the brain tissue 24 h after MCAO were significantly greater in the IN group than in the IP group (p<0.05). The human IL-1RA was confirmed to be co-localized with neuron and microglia. Furthermore, the IN group had lower expression of $interleukin-1{\beta}$ and tumor necrosis $factor-{\alpha}$ at 6 h after MCAO than the EC group (p<0.05). These results suggest that intranasal IL-1RA can reach the brain parenchyma more efficiently and provide superior neuroprotection in the transient focal cerebral ischemia.

• The Korean Journal of Pain
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• 제13권1호
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• pp.8-18
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• 2000

Background: Intraperitoneal (IP) and intrathecal (IT) administration of $\alpha$-amino-3-hydroxy-5-methyl-4-isoxazole-propionic (AMPA) and kainate (KA) receptor antagonist attenuate hyperalgesia in various models of persistent pain. The purpose of this study was to assess the effects of IP and IT LY293558, a novel AMPA/KA receptor antagonist on mechanical hyperalgesia after incision. Methods: Sprague-Dawley rats were anesthetized with halothane and underwent plantar incision. Two hours later, responses to mechanical stimuli were assessed using the response frequency to a nonpunctate mechanical stimulus and withdrawal threshold to calibrated von Frey filaments. One group of rats received vehicle, 5 or 10 mg/kg of LY293558 IP. In the other group, vehicle, 0.2, 0.5 or 2 nmol of LY293558 was administered IT. Ataxia and motor function were also evaluated. Results: Hyperalgesia was persistent in both the vehicle and 5 mg/kg group. IP administration of 10 mg/kg of LY293558 increased withdrawal threshold at 30 and 60 min after incision; deficits in rotorod performance were observed at 30, 60, 90 and 150 min. IT administration of 0.5 nmol of LY293558 increased the median withdrawal threshold at 30 and 60 min. Motor function was only impaired at 30 min. IT administration of 2 nmol produced hemiparesis. Again, inhibition of pain behaviors outlasted the effects on motor function. Conclusions: These data further suggest AMPA/KA receptors are important for the maintenance of pain behaviors caused by incisions. IT administration of LY293558 was more effective than systemic administration and reducing pain behaviors caused by a surgical incision.

• The Korean Journal of Physiology and Pharmacology
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• 제2권3호
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• pp.279-286
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• 1998

It has been well documented that transient forebrain global ischemia causes selective neuronal degeneration in hippocampal CA1 pyramidal neurons with a delay of a few days. The mechanism of this delayed hippocampal CA1 pyramidal neuronal death (DND) is still controversial. To delineate the mechanisms of the DND, the effects of treatment with MK-801, an NMDA receptor antagonist, kynurenic acid, a NMDA/non-NMDA receptor antagonist, and/or cycloheximide, a protein synthesis inhibitor, on the DND were investigated in male Wistar rats. To examine the participation of apoptotic neuronal death in the DND, TUNEL staining was performed in ischemic brain section. Global ischemia was induced by 4-vessel occlusion for 20 min. All animals in this study showed the DND 3 and 7 days after the ischemic insult. The DND that occured 3 days and 7 days after the ischemia were not affected by pretreatment with MK-801 (1 mg/kg), but markedly attenuated by the pretreatment with kynurenic acid (500 mg/kg). Treatment with cycloheximide (1 mg/kg) also markedly inhibited the DND. The magnitudes of attenuation by the two drugs were similar. The magnitude of attenuation by co-treatments with kynurenic acid and cycloheximide was not greater than that with any single treatment. TUNEL staining was negative in the sections obtained 1 or 2 days after the ischemic insults, but it was positive at hippocampal CA1 pyramidal cells in sections collected 3 days after the ischemia. These results suggested that the DND should be mediated by the activation of non-NMDA receptor, not by the activation of NMDA receptor and that the activation of AMPA receptor should induce the apoptotic process in the DND.

• 대한약리학회지
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• 제25권1호
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• pp.23-30
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• 1989

함께 투여되는 마약성진통제에 따라 효능제 또는 길항제(mixed agonist-antagonist)로 작용하는 buprenorphine을 사용하여 개구리 좌골신경에 존재하는 아편수용체의 성질을 검토하였다. 실험은 sucrose-gap apparatus를 사용하여 활동전압에 대한 영향을 관찰하였으며 약물의 상호작용을 검토하고자 meperidine 또는 naloxone을 사용하여 다음과 같은 결과를 얻었다. 1) Buprenorphine은 현저하게 개구리 좌골신경의 활동전압을 저하시켰다. 2) 두 개의 최고작용농도를 보였는데 저농도에서는 $10^{-8}\;M$, 또 고농도에서는 $10^{-4}\;M$에서 현저하게 작용을 나타내었다. 3) Buprenorphine은 meperidine의 활동전압 저하작용을 의의있게 억제하였다. 4) Naloxone에 의하여 Buprenorphine의 저하 작용이 억제되었다. 위의 실험결과로 Buprenorphine은 순수 마약성진통제의 작용을 억제하여 차단제로 작용하는 한편 또한 효능제로 활동전압을 의의있게 억제하였다. 이로써 개구리 좌골신경에 있는 아편수용체는 세포막에 또는 세포막 주위에서 $Na^+-Channel$이 활성화되는 데 중요한 역할을 하는 것으로 간주되며 이 수용체는 또한 Naloxone에 매우 민감한 반응을 나타낸다.

• 대한약학회:학술대회논문집
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• 대한약학회 2000년도 춘계총회 및 학술대회
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• pp.139.1-139.1
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• 2000

• 대한수의학회지
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• 제32권2호
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• pp.165-173
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• 1992

The present study was carried out to investigate the effects of dopaminergic drugs and the role of specific dopamine(DA) receptors on the release of TSH, $T_4$ and $T_3$. Serum TSH levels (cold-induced, $4{^{\circ}C}$) were determined using RIA(radioimmunoassay) at 30 min after administration of dopamine agonists and antagonists. Serum $T_4$ and $T_3$ levels were detected after these dopaminergic drugs were administered subcutaneously twice a day for a week. The results of the study are summarized as follows : Apomorphine, a nonspecific DA receptor agonist, produced a dose-depedent decrease in serum TSH, $T_4$ and $T_3$ levels. However, only low doses (0.3, 1.0mg/kg) of SKF38393, a specific $D_1$-receptor agonist, produced a decrease in serum lelvels of TSH. I,Y171555, a specific $D_2$-receptor agonist, produced a dose dependent decrease in serum TSH, $T_4$ and $T_3$ levels. However, SCH23390, a specific $D_1$-receptor antagonist, produced a decrease except in serum T levels which were increased dose dependently. High doses (1.0, 3.0mg/kg) of sulpiride, a specific $D_2$-receptor antagonist, made a increase in the serum levels of TSH and $T_3$. The effects of dopaminergic drugs in serum TSH and $T_4$ levels was potentiated by the pretreatment of apomorphine. The overall results of this study suggest that the regulation of TSH, $T_4$ and $T_3$ secretion were mediated via specific $D_1$ and $D_2$ receptor.

• Biomolecules & Therapeutics
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• 제20권4호
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• pp.413-417
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• 2012

Chrysanthemum indicum Linne is an ancient herbal medicine used to treat bone and muscle deterioration, ocular inflammation, headache, and anxiety in Korea, China, and Japan. Furthermore, tea derived from Chrysanthemum indicum Linne has been used to treat anxiety by facilitating relaxation and curing insomnia. However, no reports exist on the anxiolytic-like effects of Chrysanthemum indicum Linne water extract (CWE) in mice. In the present study, we investigated the anxiolytic-like effects of CWE using the elevated plus-maze (EPM) test in mice. CWE, at a dose of 500 mg/kg (p.o.), significantly increased the time spent in the open arms of the EPM compared to a vehicle-injected control group. Moreover, the effect of CWE (500 mg/kg) was blocked by bicuculline (a selective $GABA_A$ receptor antagonist) and WAY 100635 (a selective 5-$HT_{1A}$ receptor antagonist). Taken together, these findings suggest that the anxiolytic-like effects of CWE might be mediated by the $GABA_A$ receptor and the 5-$HT_{1A}$ receptor.

• Biomolecules & Therapeutics
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• 제8권4호
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• pp.325-331
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• 2000

The present study was designed to assess the role of spinal adenosine $A_2$ receptor in the regulation of cardiovascular functions such as mean arterial pressure (MAP) and heart rate (HR) in male Sprague-Dawley rats. Rats (250~300 g) were anesthetized with urethane and paralyzed with d-tubocurarine and artificially ventilated. blood pressure and HR were continuously monitored via a femoral catheter connected to a pressure transducer and a polygraph. Drugs were administered intrathecally using injection cannula through guide cannula which was inserted inthrathecally at lower thoracic level through a puncture of an atlantooccipital mombrane. Intrathecal injection of an adenosine $A_2$ receptor agonist, 5'-(N-cyclopropyl)-carboxamaidoadenosine (CPCA; 1, 2 and 3 nmol, respectively), produced a dose-dependent decrease in MAP and HR. Pretreatment with $N^{G}$-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor or 10 nmol of MDL-12,330, an adenylate cyclase inhibitor blocked significantly the depressor and bradycardic effect of 2 nmol of CPCA. But, Pretreatment with 3 nmol of bicuculline, gamma-aminobutyric acid A (GAB $A_{A}$) receptor antagonist, or 50 nmol of 5-aminovaleric acid, GAB $A_{B}$ receptor antagonist did not inhibit the depressor and bradycardic effect of 2 nmol of CPCA. These results indicate that adenosine $A_2$ receptor in the spinal cord plays an inhibitory role in the regulation of cardiovascular function and that the depressor and bradycardic action of adonosine $A_2$ receptor are mediated via the synthesis of nitric oxide and the activation of adenylate cyclase in the spinal cord of rats.s.s.s.

• The Korean Journal of Physiology and Pharmacology
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• 제14권5호
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• pp.299-304
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• 2010

Losartan is a selective angiotensin II (Ang II) type 1 ($AT_1$) receptor antagonist which inhibits vascular smooth muscle cells (VSMCs) contraction and proliferation. We hypothesized that losartan may prevent cell proliferation by activating AMP-activated protein kinase (AMPK) in VSMCs. VSMCs were treated with various concentrations of losartan. AMPK activation was measured by Western blot analysis and cell proliferation was measured by MTT assay and flowcytometry. Losartan dose- and time-dependently increased the phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase (ACC) in VSMCs. Losartan also significantly decreased the Ang II- or 15% FBS-induced VSMC proliferation by inhibiting the expression of cell cycle associated proteins, such as p-Rb, cyclin D, and cyclin E. Compound C, a specific inhibitor of AMPK, or AMPK siRNA blocked the losartan-induced inhibition of cell proliferation and the $G_0/G_1$ cell cycle arrest. These data suggest that losartan-induced AMPK activation might attenuate Ang II-induced VSMC proliferation through the inhibition of cell cycle progression.