• Clinical and Experimental Reproductive Medicine
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• v.40 no.4
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• pp.155-162
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• 2013

Objective: Stress is known to be an inhibitor of the reproductive hypothalamic-pituitary-gonadal (HPG) axis. However, the neural and molecular connections between stress and reproduction are not yet understood. It is well established that in both humans and rodents, kisspeptin (encoded by the kiss1 gene) is a strong stimulator of the HPG axis. In the present study we hypothesized that endocannabinoids, an important neuromodulatory system in the brain, can act on the HPG axis at the level of kiss1 expression to inhibit reproductive function under stress. Methods: Adult male Wistar rats were unilaterally implanted with an intracerebroventricular cannula. Afterwards, the animals were exposed to immobilization stress, with or without the presence of the cannabinoid CB1 receptor antagonist AM251 (1 ${\mu}g/rat$). Blood samples were collected through a retro-orbital plexus puncture before and after stress. Five hours after the stress, brain tissue was collected for reverse transcriptase-quantitative polymerase chain reaction measurements of kiss1 mRNA. Results: Immobilization stress (1 hour) resulted in a decrease in the serum luteinizing hormone concentration. Additionally, kiss1 gene expression was decreased in key hypothalamic nuclei that regulate gonadotrophin secretion, the medial preoptic area (mPOA), and to some extent the arcuate nucleus (ARC). A single central administration of AM251 was effective in blocking these inhibitory responses. Conclusion: These findings suggest that endocannabinoids mediate, at least in part, immobilization stress-induced inhibition of the reproductive system. Our data suggest that the connection between immobilization stress and the HPG axis is kiss1 expression in the mPOA rather than the ARC.

• The Korean Journal of Pharmacology
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• v.22 no.2
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• pp.96-104
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• 1986

Higenamine, dl-1-( 4-hydroxybenzyl)-6, 7-dihydroxy-1 ,2, 3 ,4-tetrahydroisoquinoline has been synthesized and evaluated for hemodynamic actions using rabbits under pentobarbital anesthesia. Concentration-related fall of mean blood pressure was observed, where diastolic blood presure was significantly lowered at 10 ug/kg/min or above (p<.05), while the systolic blood pressure was slightly increased or unaffected, thereby, causing increment of pulse pressure. No significant change was occured in heart rate, however, carotid artery blood flow was significantly (p<.05) increased. These actions were inhibited with pretreatment of 0.3 mg/kg of propranolol, beta-adrenoceptor antagonist, 5 minutes before infusion of higenamine indicating that higenamine compete with propranolol for the so-called beta adrenergic receptor. As comparison, the same procedure was applied to isoproterenol as well, where typical antagonism of propranolol against isoproterenol was shown. From these findings the vasodilating and diastolic blood pressure lowing effects could be explained in terms of cardiac beta stimulating action, however, dopamine receptor activation could not be excluded because no significant changes observed in chronotropism.

• The Korean Journal of Pain
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• v.14 no.1
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• pp.46-50
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• 2001

Background: Ondansetron is both a central and peripheral serotonin (5HT) receptor antagonist and droperidol is a dopaminergic blocking drug which acts centrally at the chemoreceptor trigger zone. We assessed the efficacy and adverse effects of ondansetron, droperidol or both, in the prevention of postoperative emesis during postoperative intravenous patient-controlled analgesia (PCA) using butorphanol and ketorolac medication. Methods: We studied 60 women, aged 25-60 yrs, who underwent total abdominal hysterectomy (TAH), under general anesthesia using $N_2O-O_2$-enflurane. A bolus dose of 1 mg of butorphanol and 4 mg of ondansetron were given to patients and thereafter, PCA was started using 10 mg of butorphanol and 240 mg of ketorolac mixed into the 5% D/W solution (total volume; 100 ml, 1 ml of bolus dose, and 10 min of lockout interval). We also added ondansetron 4 mg (Group O, n = 20), ondansetron 4 mg and droperidol 2.5 mg (Group OD, n = 20), or droperidol 2.5 mg (Group D, n = 20) to the PCA drug. The severity of pain, nausea, vomiting, sedation and other side effects were assessed at 0, 1, 2, 6, 12, 24, 36 and 48 hr after awakening. Results: There was no difference in the incidence of nausea and vomiting between the three group [Group O: 4 (20%) and 3 (15%), respectively; Group OD: 1 (5%) and 1 (5%), respectively; Group D: 3 (15%) and 3 (15%), respectively]. Group O showed a lower sedation score than the other groups (P < 0.05). The pain score and other side effects did not show any difference between the groups. Conclusions: The combination of ondansetron and droperidol showed no clinical benefit compared with ondansetron or droperidol alone for prevention of postoperative nausea and vomiting during postoperative PCA using butorphanol and ketorolac.

• Tuberculosis and Respiratory Diseases
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• v.50 no.2
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• pp.182-195
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• 2001

Background : Idiopathic pulmonary fibrosis(IPF) is a devastating illness for which there is little effective treatment. The key cytokines currently implicated in the fibrotic process are the transforming growth factor-${\beta}_1$(TGF-${\beta}_1$), tumor necrosis factor-$\alpha$(TNF-$\alpha$), endothelin-1(ET-1) and interferon-$\gamma$(IFN-$\gamma$). The rat model for paraquat-induced pulmonary fibrosis was chosen to investigate the role of ET-1 in this disease. Both ET-1 and TGF-${\beta}_1$ expression in lung lesions were examined using immunohistochemical staining. After $Bosentan^{(R)}$ administration, an orally active ET-$l_A$ and ET-$1_B$ receptor antagonist, the degree of pulmonary fibrosis and ET-1 and TGF-${\beta}_1$ expression were analyzed. Method : Sprague-Dawley rats were divided into three groups, the control group, the fibrosis group, and the fibrosis-$Bosentan^{(R)}$-treated group. The animals were sacrificed periodically at 1, 3, 5, 7, 10, 14 days after administering saline or paraquat. The effects between groups were compared with the results of light microscopy and immunohistochemical staining for ET-1 and TGF-${\beta}_1$. The degree of fibrosis was evaluated by H&E and Masson's trichrome staining, which were graded by a computerized image analyzer. The degree of immunohistochemical staining was categorized by a semi-quantitative analysis method. Results : The lung collagen content had increased in the paraquat instillated animals by day 3, and continued to increase up to day 14. A daily treatment by gavage with $Bosentan^{(R)}$ (100mg/kg) did not prevent the increase in collagen deposition on the lung that was induced by paraquat instillation. There were increased immunohistochemical stains of ET-1 on the exudate, macrophages, vascular endothelial cells and pneumocytes in the paraquat instillated group. Furthermore, TGF-${\beta}_1$ expression was higher on the exudate, macrophages, some inflammatory cells, pneumocytes( type I, and II), vascular endothelium and the respiratory epithelial cells around the fibrotic area. After Bosentan treatment, there were no definite changes in ET-1 and TGF-${\beta}_1$ expression. Conclusion : Fibrosis of the Paraquat instillated group was more advanced when compared with the control group. In addition, there was increased ET-1 and TGF-${\beta}_1$ expression around the fibrotic area. ET-1 is associated with lung fibrosis but there was little effect of the ET-1 receptor blocker($Bosentan^{(R)}$) on antifibrosis.Background : Idiopathic pulmonary fibrosis(IPF) is a devastating illness for which there is little effective treatment. The key cytokines currently implicated in the fibrotic process are the transforming growth factor-${\beta}_1$(TGF-${\beta}_1$), tumor necrosis factor-$\alpha$(TNF-$\alpha$), endothelin-1(ET-1) and interferon-$\gamma$(IFN-$\gamma$). The rat model for paraquat-induced pulmonary fibrosis was chosen to investigate the role of ET-1 in this disease. Both ET-1 and TGF-${\beta}_1$ expression in lung lesions were examined using immunohistochemical staining. After $Bosentan^{(R)}$ administration, an orally active ET-$1_A$ and ET-$1_B$ receptor antagonist, the degree of pulmonary fibrosis and ET-1 and TGF-${\beta}_1$ expression were analyzed. Method : Sprague-Dawley rats were divided into three groups, the control group, the fibrosis group, and the fibrosis-$Bosentan^{(R)}$-treated group. The animals were sacrificed periodically at 1, 3, 5, 7, 10, 14 days after administering saline or paraquat. The effects between groups were compared with the results of light microscopy and immunohistochemical staining for ET-1 and TGF-${\beta}_1$. The degree of fibrosis was evaluated by H&E and Masson's trichrome staining, which were graded by a computerized image analyzer. The degree of immunohistochemical staining was categorized by a semi-quantitative analysis method. Results : The lung collagen content had increased in the paraquat instillated animals by day 3, and continued to increase up to day 14. A daily treatment by gavage with $Bosentan^{(R)}$ (100mg/kg) did not prevent the increase in collagen deposition on the lung that was induced by paraquat instillation. There were increased immunohistochemical stains of ET-1 on the exudate, macrophages, vascular endothelial cells and pneumocytes in the paraquat instillated group. Furthermore, TGF-${\beta}_1$ expression was higher on the exudate, macrophages, some inflammatory cells, pneumocytes( type I, and II), vascular endothelium and the respiratory epithelial cells around the fibrotic area. After Bosentan treatment, there were no definite changes in ET-1 and TGF-${\beta}_1$ expression. Conclusion : Fibrosis of the Paraquat instillated group was more advanced when compared with the control group. In addition, there was increased ET-1 and TGF-${\beta}_1$ expression around the fibrotic area. ET-1 is associated with lung fibrosis but there was little effect of the ET-1 receptor blocker($Bosentan^{(R)}$) on antifibrosis.

• The Korean Journal of Physiology and Pharmacology
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• v.1 no.3
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• pp.325-335
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• 1997

Evidence for the existance of at least two subclasses of renal adenosine receptors has been presented. N-6-cyclohexyladenosine (CHA) is a relatively selective $A_1$ adenosine agonists, whereas 5'-N-ethylcarboxamidoadenosine (NECA) acts as a preferential agonist of $A_2$ adenoisne receptor. N6-(L-2-phenylisoproryl)-adenosine (PIA) almost unselectively activates both $A_1\;and\;A_2$ adenosine receptors at micromolar concentrations. During the characterization of adenosine receptor in the kidney, we have discovered a novel phenomenon, that is, an intramuscular administration of CHA for 3 days caused a diuresis and a suppression of urinary concentrating ability. To further characterize this novel phenomenon, an intramuscular administration of adenosine and other adenosine angonists, PIA and NECA, and prior treatment of adenosine antagonists, caffeine, theophylline and 1,3-diethyl-8-phenyl-xanthine (DPX) were performed. Systemic administration of CHA, PIA, and NECA for 3 days caused a suppression in heart rate, blood pressure and general motor activity without change in rectal temperature. Systemic administration of CHA, 0.5, 1 and 2 mg/kg/day, for 3 days caused a dose-dependent increase in urine volume and decrease in urinary osmolarity and free water reabsorption. This phenomenon was reversible and repeatable. Administration of adenosine (40 mg/kg/day) produced no apparent effect on the renal function, whereas PIA (2 mg/kg/day) produced an similar effect to CHA on the renal function. Systemic adminstration of NECA, 0.025, 0.05 and 0.25 mg/kg/day, for 3 days caused a dose-dependent increase in urine volume and dose-dependent increases in excreted amount of creatinine, urinary osmolarity and free water reabsorption. These renal effects of adenosine agonist were maximum at second day during the drug administration. In terms of increase in urine volume and the suppression of urinary concentrating ability, NECA was potent than CHA. Prior treatment of caffeine (50 mg/kg/day) or theophylline (50 mg/kg/day) abolished the diuretic effect of CHA, whereas DPX (50 mg/kg/day) did not affect the CHA effect. CHA, 0.5 mg/kg/day, produced no change in plasma renin activity and plasma levels of aldosterone, epinephrine, and norepinephrine. These results suggest that this novel phenomenon produced by an activation of renal adenosine receptors plays an important role in urinary concentrating mechanism.

• Journal of Korean Society of Health-System Pharmacists
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• v.35 no.4
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• pp.430-440
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• 2018

Background : Hyponatremia is the most common electrolyte disturbance in hospitalized patients and has been associated with increased morbidity and mortality. Tolvaptan, a vasopressin receptor antagonist, is increasingly used for the treatment of euvolemic and hypervolemic hyponatremia. The aim of this study was to evaluate the effectiveness and safety of tolvaptan for the management of hyponatremia. Methods : This study was a retrospective evaluation of 106 patients who received at least one dose of tolvaptan for hyponatremia at a single tertiary academic hospital between January 2014 and June 2015. The primary endpoint was the change in serum sodium concentration after tolvaptan administration within 24 hours, with secondary endpoints of overcorrection and adverse effects. Results : The mean initial dose of tolvaptan was $20.2{\pm}7.2mg$ and the median duration of treatment was 15 days (range, 1-261 days). The maximal changes in sodium levels at 24 and 48 hours were $8.2{\pm}4.7mmol/L$ and $10.5{\pm}15.3mmol/L$, respectively. Of 99 patients in whom sodium concentrations were followed up, sodium overcorrection was observed in 26 (26.3%) patients, which was associated with concomitant use of an enzyme inhibitor (odds ratio [OR] = 4.80, 95% Cl: 1.27-18.15). However, sex, body mass index (BMI), serum albumin, a daily dose of tolvaptan, and concomitant use of hypertonic saline did not show any significant difference in overcorrection. The most commonly reported adverse effects were mild and related to aquaresis, such as polyuria, thirst, and constipation. However, severe adverse effects such as hyperkalemia, hypotension, and one death related to osmotic demyelination were also reported. Conclusions : Tolvaptan is effective for treating hyponatremia. Nevertheless, the drug should be used cautiously due to serious adverse effects related to sodium overcorrection.

• Journal of the Korea Academia-Industrial cooperation Society
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• v.16 no.2
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• pp.1200-1206
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• 2015

The major target for drug discovery, G-protein coupled receptor (GPCR) is involved in many physiological activities and related to various diseases and disorders. Among experimental techniques relating to the GPCR drug discovery process, various cell-based screening methods are influenced by cell conditions used in the overall process. Recently, the utilization of frozen cells is suggested in terms of reducing data variation and cost-effectiveness. The aim of this study is to evaluate various conditions in cell freezing such as temperature conditions and storage terms. The stable cell lines for calcium sensing receptor and urotensin receptor were established followed by storing cultured cells at $-80^{\circ}C$ up to 4 weeks. To compare with cell stored at liquid nitrogen, agonist and antagonist responses were recorded based on the luminescence detection by the calcium induced photoprotein activation. Cell signals were reduced as the storage period was increased without the changes in $EC_{50}$ and $IC_{50}$ values $EC_{50}:3.46{\pm}1.36mM$, $IC_{50}:0.49{\pm}0.15{\mu}M$). In case of cells stored in liquid nitrogen, cell responses were decreased comparing to those in live cells, however changes by storage periods and significant variations of $EC_{50}/IC_{50}$ values were not detected. The decrease of cell signals in various frozen cells may be due to the increase of cell damages. From these results, the best way for a long-term cryopreservation is the use of liquid nitrogen condition, and for the purpose of short-term storage within a month, $-80^{\circ}C$ storage condition can be possible to adopt. As a conclusion, the active implementation of frozen cells may contribute to decrease variations of experimental data during the initial cell-based screening process.

• The Korean Journal of Pain
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• v.18 no.1
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• pp.1-9
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• 2005

Background: Spinal metabotropic glutamate receptors (mGluRs) and opioid receptors are involved in the modulation of nociception. Although opioid receptors agonists are active for pain, the effects of the compounds for the mGluRs have not been definitely investigated at the spinal level. We examined the effects of the intrathecal mGluR compounds and morphine in the nociceptive test, and then we further clarified the role of the spinal mGluRs. In addition, the nature of the pharmacological interaction after the coadministration of mGluRs compounds with morphine was determined. Methods: Catheters were inserted into the intrathecal space of male SD rats. For the induction of pain, $50{\mu}l$ of 5% formalin solution or a thermal stimulus was applied to the hindpaw. An isobolographic analysis was used for the evaluation of the drug interaction. Results: Neither group I mGluR compounds nor group III mGluR compounds produced any antinociceptive effect in the formalin test. The group II mGluR agonist (APDC) had little effect on the formalin-induced nociception. The group II mGluR antagonist (LY 341495) caused a dose-dependent suppression of the phase 2 flinching response on the formalin test, but it did not reduce the phase 1 response of the formalin test nor did it increase the withdrawal latency of the thermal stimulus. Isobolographic analysis revealed a synergistic interaction after the intrathecal delivery of a LY 341495-morphine mixture. Conclusions: These results suggest that group II mGluRs are involved in the facilitated processing at the spinal level, and the combination of LY 341495 with morphine may be useful to manage the facilitated pain state.

• YAKHAK HOEJI
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• v.34 no.3
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• pp.180-191
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• 1990

A comparison was made of the effects of selective ${\alpha_1}-adrenoceptor$ agonist phenylephrine and selective ${\alpha_2}-adrenoceptor$ agonist clonidine on endothelium-containing and endothelium-denuded rings of the rat aorta. In the case of phenylephrine, removal of endothelium increased sensitivity 2.5 fold at $EC_{50}$ level and maximum contractive response 1.4 fold. In the case of clonidine, which gave only 15% of maximum contractive response given to phenylephrine on endothelium-containing rings, removal of the endothelium increased sensitivity 5.6 fold at $EC_{50}$ level and maximum contractive response 5 fold, which was about 55% of that given by phenylephrine. In endothelium-denuded ring, phenylephrine-induced contraction tended to be more increased in tonic contraction than in phasic contraction as compared to that in endothelium-containing ring, while clonidine-induced contraction was monophasic and was increased only in tonic contraction. In the calcium-free solution or in the presence, of verapamil, contraction stimulated by clonidine was almost abolished while that stimulated by phenylephrine produced only phasic contraction. The depression of sensitivity to these agonists in rings with endothelium appeared to be due to the vasodepressor action of endothelium derived relaxing factor (EDRF), because hemoglobin, a specific blocking agent of EDRF, abolished this depression. It is unlikely that the endothelium-dependent relaxation was due to stimulation of release of EDRF, because clonidine did not produce endothelium-dependent relaxation in 5-hydroxytryptamine-precontracted ring even when its contractile action was blocked by the ${\alpha_1}-adrenoceptor$ antagonist, prazosin. When the efficacy of phenylephrine was reduced to about the initial efficacy of clonidine by pretreatment with dibenamine, the contraction-response curves for phenylephrine became very similar to the corresponding curves obtained for clonidine before receptor inactivation. In the dibenamine-treated rings, contraction of phenylephrine was abolished in calcium-free solution or in the presence of verapamil like that obtained for clonidine before receptor inactivation. These results suggest that EDRF spontaneously released from endothelium depress contraction more profoundly in a case of an agonist with low efficacy and the phenylephrine-induced contraction was totally dependent on extracellular calcium as was that obtained for clonidine when the efficacy of phenylephrine was reduced to that of clonidine by irreversible inactivation of ${\alpha_1}-adrenoceptor$ with dibenamine.

• IMMUNE NETWORK
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• v.3 no.3
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• pp.242-247
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• 2003

Background: Psoriasis is an inflammatory skin disorder that is characterized by a marked proliferation of keratinocytes, vascular dilation and leukocyte infiltration. Cytokines play important roles in the pathogenesis of inflammatory disorders. An overexpression of proinflammatory cytokines was characterized in psoriasis plaque. Among these cytokines, IL-$1{\beta}$ is major pro-inflammatory cytokine synthesized during the infection and inflammatory process. The IL-1 receptor antagonist (IL-1Ra) competes for the same IL-1 receptor for $IL-1{\alpha}$ and $-1{\beta}$, which prevents activation of the target cells. Three single nucleotide polymorphisms (SNPs) in the IL-$1{\beta}$ gene have been reported at position -31, -511 and +3954. Within the IL-1Ra gene (IL-1RN), there is a variable number of tandem repeats (VNTR) of an 86 bp length in intron 2. These polymorphisms related to cytokine production and associated with various diseases. Methods: We investigated the polymorphisms of IL-1B (promoter -511 and +3954) and IL-1RN on 114 psoriasis patients and 311 healthy normal controls in Korean. We performed PCR-RFLP on single nucleotide polymorphisms (SNPs) of IL-1B (promoter -511 and +3954) and fragment analysis on IL-1RN 86 bp VNTR polymorphism. Results: The frequency of IL-1B $-511^*1$ allele (patients vs. controls; 50.0% vs. 42.3%, RR=1.4) was significantly increased and IL-1B $-511^*2$ allele (patients vs. controls; 50.0% vs. 57.7%, RR=0.7) decreased in psoriasis patients compared to normal controls. We also analyzed the IL-1B -511 polymorphism according to patients' characters (age of onset, sex and family history). The IL-1B -511 alleles were significantly associated in patients with male and family history than health normal controls. There were no significant associations of IL-1B +3954 and IL-1RN polymorphisms with psoriasis patients. Conclusion: These results suggest that the polymorphism of IL-1B -511 could be genetic susceptibility to psoriasis in Koreans.