• The Korean Journal of Physiology and Pharmacology
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• v.5 no.5
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• pp.423-431
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• 2001

Some recent investigations revealed that vasodilatory action of adenosine is mainly not mediated by surface A2 receptor and suggested the existence of an intracellular action site. In the present study, we tried to differentiate intracellular from extracellular site of adenosine action in the regulation of coronary flow. In perfused rabbit hearts, concentration-response curve of coronary flow to exogenous adenosine was constructed in the presence or absence of dipyridamole, an inhibitor of transmembrane purine transport. Inhibition of cellular adenosine uptake by dipyridamole suppressed the increase of flow rate while enhancing the decrease in heart rate induced by exogenous adenosine. In another series of experiments, perfused rabbit hearts were subjected to energy deprivation in order to increase the production of endogenous adenosine. Energy deprivation along with dipyridamole administration resulted in higher coronary flow rate. Lower perfusate adenosine concentration was observed along with higher tissue adenosine content in this group. These results implied that coronary flow rate is determined not by interstitial adenosine concentration but by intracellular activity of adenosine. To confirm the effects of dypiridamole in vivo, direct measurement of interstitial adenosine concentration by mycrodialysis along with the assay of intracellular adenosine content was performed after intranenous dipyridamole administration. After dipyridamole infusion, intracellular adenosine content was markedly increased while interstitial adenosine concentration was not altered. In another series of experiments, the right shift of concentration-response curve of adenosine-induced vasodilation by 8-phenyltheophilline, a representative adenosine receptor antagonist, was mostly abolished by prior administration of prazosin, indicating that the influence of 8-PT on the adenosine action is not attributed to the inhibition of A2 receptor but related to the suppression of ${\alpha}-adrenoceptor$ activation. From these results, we concluded that adenosine acts intracellularly to regulate the coronary blood flow.

• Korean Journal of Acupuncture
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• v.23 no.2
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• pp.113-123
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• 2006

Objectives: Pharmacopuncture which is a combination of acupuncture and herbal medicine helps to prevent and treat the diseases and symptoms including various pains. However, little was known about the therapeutic effects and its mechanisms on acute pain, although pharmacopuncture has been used frequently in acupuncture clinics. Acupuncture is known for producing analgesia for persistent ankle sprain pain in human. Furthermore, it also produces analgesia in a rat model of ankle sprain pain. Methods: To illuminate the underlying mechanisms of capsaicin pharmacopuncture-induced analgesia, weight bearing force (WBF) was observed on the acute ankle sprained rat model. Ankle sprain was induced in the rat by manually hyper-extending ligaments of the right ankle. Capsaicin pharmacopuncture was applied to SI6 (Yanglo) on the left forelimb (contralateral to the sprained ankle). Results: In behavioral test, capsaicin pharmacopuncture produced marked analgesic effects on acute ankle sprained animals as measured by WBF of the affected limb similar to manual acupuncture. Capsaicin pharmacopuncture was also suppressed by serotonin (5-HT) receptor antagonist methysergide (2 mg/kg, Lp.), but not by opioids receptor antagonist naltrexone (10 mg/kg, Lp.) and alpha adrenoceptor antagonist phentolamine (5 mg/kg, Lp.). Conclusion: The data suggest that capsaicin pharmacopuncture-induced analgesia is accomplished by activating the descending serotonergic inhibitory systems.

• YAKHAK HOEJI
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• v.41 no.6
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• pp.797-801
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• 1997

Recently we reported that water extracts of Coptidis Rhizomas showed calcium antagonistic action and alpha-adrenoceptor inhibitory action in the vascular smooth muscle. Since ca lcium antagonistic properties are important in the treatment of various diseases including asthma. In the present study, the bronchodilatory effects of crude extract of three kinds of Coptidis Rhizoma (Coptidis chinensis, Coptis japonica and root hair of Coptis japonica) was investigated using rat isolated trachea. The result showed that all extracts relaxed carbachol-contracted tracheal smooth muscle. Concentration-dependently, in which the root hair of Coptis japonica was the least potent. The inhibitory potency expressed in terms of $IC_{50}$ against carbachol contraction was 1.8${\mu}$g/ml and 2.7${\mu}$g/ml for Coptidis chinensis and Coptis japonica, respectively. These extracts also inhibited KCI-contracted tracheal smooth muscle. But the relative potency ($IC_{50}$) was 3.5 and 4.1 folds weaker than carbachol-induced contraction for Coptidics chinenesis and Coptis japonica, respectively. Pretreatment of crude extracts also inhibited carbachol- or KCI-induced contraction, non-competitively. These findings indicate that the extracts have muscarinic blocking as well as $Ca^{2+}$ channel blocking action. When provoked intracellular stored $Ca^{2+}$ release by carbachol in $Ca^{2+}$-free conditions, initial phasic contraction due to $Ca^{2+}$ release was significantly inhibited by the extracts. As taken together, we conclude that water extracts of Coptidis Rhizoma may be beneficial in bronchospasm or other broncheal tube narrowing conditions such as asthma.

• Journal of Food Hygiene and Safety
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• v.29 no.4
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• pp.383-390
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• 2014

The safety of a new natural plant composition (ADP) was assessed on the genotoxicity study and 14-day repeat dose toxicity study. ADP contains a mixed water extract obtained from the mixture of Phellodendron cortex (Phellodendron amurense) and Anemarrhena rhizoma (Anemarrhena asphodeloides), and poses the contractile properties mediated by alpha-adrenoceptor of the prostate and urethra as well as antioxidant and anti-inflammatory properties. In order to evaluate genetic safety, in vivo micronucleus test was performed in ICR mice orally administered with three dose levels of 1250, 2500, 5000 mg/kg body weight, and vehicle and positive control. In the 14 days study, Sprague-Dawley rats were treated with ADP at the dose levels of 500, 1000, 2000 mg/kg once a day, and clinical signs, body weights, hematology, serum biochemistry, necropsy findings and organ weights were monitored and examined. In experimental results, ADP treatment, compared with vehicle control, did not induce the micronucleated erythrocytes from mouse bone marrow. In the 14 days study, any significant and toxicological differences in all measurements of parameters were not observed in ADP treatment groups of animals, compared with vehicle treatment. The No-Observed-Adverse-Effect-Level (NOAEL) of ADP in the 14 days study was determined to be greater than 2000 mg/kg/day in both sexes.

• The Korean Journal of Pharmacology
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• v.25 no.1
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• pp.13-21
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• 1989

The circadian rhythm of spontaneous motor activity was not significantly altered by $T_4$(4mg/kg, i.p. inj. once a day for 5 days: $T_4$) and PTU (fed ad lib in 0.01% drinking water for 5 weeks: PTU). The plasma thyroxine level was markedly increased by $T_4$ but reduced by PTU, and the plasma thyrotropin level was markedly increased by PTU but moderately increased by $T_4$. Clonidine slightly increased the plasma CS level, but the clonidine effect was significantly enhanced by $T_4-pretreatment$. The brain NE and MHPG contents were little affected by $T_4$ but the NE content was significantly decreased by PTU. The SS-induced increase of plasma CS level was moderately decreased by PTU but increased by $T_4$. However, clonidine significantly inhibited the SS-induced increase, and the inhibitory effect of clonidine was not significantly affected by PTU and $T_4$, respectively. The brain MHPG content and MHPG/NE ratio were significantly decreased by clonidine but increased by SS. The clonidine- and SS-induced changes of brain MHPG content and MHPG/NE ratio were not altered by $T_4$. PTU did not affect the SS-induced increase of brain NE turnover but significantly attenuated the clonidine-induced decrease. The SS-induced increases of brain MHPG content and MHPG/NE rtatio were markedly inhibited by clonidine, and the inhibitory effect of clonidine was not affected by $T_4$ and PTU, respectively. These results suggest that the responses to swim-stress is not signigicantly affected by the alteration of thyroid function and that the hypothalamo-adenohypophysis-adrenocortical stimulation in response to swim-stress seems to be mediated via hypothalamic noradrenergic activation, and the stress response may be inhibited by the agonistic activity of clonidine on the presynaptic ${\alpha}_2-adrenoceptor$.

• The Korean Journal of Pharmacology
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• v.14 no.1_2
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• pp.13-23
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• 1978

1) It was attempted to clarify the sites of action of central (either intraventricular or intracisternal) norepinephrine(NE) and clonidine to cause cardiac slowing and hypotension in urethane-anesthetized rabbits. 2) NE produced cardiac slowing but indistinct effect on blood pressure. Clonidine produced cardiac slowing and hypotension. 3) Intraventricular and intracisternal administration of NE, clonidine, phenylephrine and isoproterenol did not make difference in their effects, except that the onset of cardiac slowing by intracisternal NE was more rapid than intraventricular NE. 4) Upon repeated administration of NE at the intervals of about two hours, blood pressure responses changed to the pressor ones, the cardiac slowing unchanged. By this procedure the cardiac slowing as well as the hypotension by clonidine were gradually diminished. 5) Clonidine, when given during the NE effects were persisting, did not produce the lowering of blood pressure and further decrease of heart rate. NE, when given during the clonidine effects were persisting, produced marked elevation of blood pressure but did not produce further decrease of heart rate. 6) After intraventricular administration of regitine or desmethylimipramine, the cardiac slowing effect of NE and the clonidine effects were not observed, whereas NE produced marked elevation of blood pressure. 7) Reserpinized rabbits showed pressor and cardiac accelerating responses to NE; slight pressor, and little cardiac responses to clonidine. 8) It seems that the cardiac slowing by both clonidine and NE as well as the hypotetsion by clonidine are mediated by the presynaptic ${\alpha}$-adrenoceptor in the brain but the pressor responses to NE and clonidine are mediated by other site(s) than the presynaptic ones.

• Journal of Pharmaceutical Investigation
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• v.30 no.1
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• pp.61-65
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• 2000

Doxazosin, a postsynaptic selective ${\alpha}1-adrenoceptor$ antagonist, is a potent antihypertensive agent which reduces peripheral resistance and blood pressure by vasodilatation of peripheral vessels. It is also used in the treatment of urinary obstruction by benign prostatic hypertrophy. The purpose of the present study was to evaluate the bioequivalence of two doxazosin tablets, $Cardura^{TM}$ (Pfizer Korea Ltd.) and $Cardil^{TM};$ (Kyungdong Pharmaceutical Co., Ltd.), according to the guidelines of Korea Food and Drug Administration (KFDA). Sixteen normal male volunteers, $24.19{\pm}2.48$ years in age and $62.41{\pm}6.66$ kg in body weight, were divided into two groups and a randomized $2{\times}2$ cross-over study was employed. After one tablet containing 2 mg of doxazosin was orally administered, blood was taken at predetermined time intervals and the concentrations of doxazosin in serum were determined with an HPLC method using spectrofluorometric detector. Pharmacokinetic parameters such as $AUC_t,\;C_{max}\;and\;T_{max}$ were calculated and ANOVA test was utilized for the statistical analysis of the parameters. The results showed that the differences in $AUC_t,\;C_{max}\;and\;T_{max}$ between two tablets were -1.54%, -1.51 % and 3.42%, respectively, when calculated against the $Cardura^{TM}$ tablet. The powers $(1-{\beta})$ for $AUC_t,\;C_{max}\;and\;T_{max}$ were all more than 99.00%. Minimum detectable differences $(\Delta)$ at ${\alpha}=0.05\;and\;1-{\beta}=0.8$ were all less than 20% (e.g., 12.73%, 12.84% and 13.01% for $AUC_t,\;C_{max}\;and\;T_{max}$, respectively). The 90% confidence intervals were all within :${\pm}20%$ (e.g., $-8.97{\sim}5.90,\;-9.01{\sim}6.00\;and\;-4.16{\sim}11.05\;for\;AUC_t,\;C_{max}\;and\;T_{max},\;respectively)$. All of the above para- meters met the criteria of KFDA for bioequivalence, indicating that $Cardil^{TM}$ tablet is bioequivalent to $Cardura^{TM}$ tablet.

• The Korean Journal of Pharmacology
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• v.22 no.1 s.38
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• pp.34-44
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• 1986

In our previous studies, we had clarified many pharmacological effects of majarine: the bacteriostatic effect in vitro; the potentiation of hypnotic action of alcohol; hypotensive effect in rats and hypothermic effect in mice. This study was undertaken to search for a new antihypertensive drug. Red crystalline was obtained from majarine (which was extracted from Berberis koreana Palibin) by chemical methods. And this crystalline was identified as $C_{19}H＿{16}NO＿4$ contained one hydroxy group instead of methoxy group of majarine in isoquinoline ring and named 'Majarol' (5,6-Dihydro-9-hydroxy, 10-methoxybenzo-[g]-1,3-benzodioxolo [5,6-a] quinolizinium). We examined the effects of majarol on blood pressure and heart rate in urethane ancsthetized rats and the rate and amplitude of contraction of isolated frog heart. Several drugs: atropine sulfate, diphenhydramine chloride, hexamethonium bromide, phentolamine, epinephrine, propranolol and isoproterenol were used to clarify the mechanism of the hypotensive action of majarol. The results of experimints were as follows; 1. In low dose (0.5-2mg/kg, i.v.), majarol showed a typical transient hypotensive effect and slight decrease in heart rate. In high dose (5-10 mg/kg, i.v.), majarol showed a typical transient and a subsequent prolonged hypotensive effect and a significant prolonged decrease in heart rate was followed. 2. The hypotensive effects of majarol was not abolished by the pretreatments with atropine sulfate, hexamethonium bromide and diphenhydramine. The pretreatment with phentolamine inhibited significantly the hypotensive effects of majarol and the pretreatment wtih majarol blocked markedly the hypertensive effect of epinephrine. The positive chronotropic effect of isoproterenol was not blocked by the pretreatment with majarol. 3. In low dose, majarol increased the amplitude and decreased rate of contraction, but in high dose, majarol inhibited the amplitude and rate of contraction of isolated frog heart.

• The Korean Journal of Pharmacology
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• v.21 no.2
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• pp.119-127
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• 1985

The renal function is under regulatory influence of the central nervous system, mainly through activation of sympathetic nerve to the kidney, and it was recently reported that clonidine, an agonist to ${\alpha}_2$-adrenoceptors, induces diuresis and natriuresis when injected directly into a lateral ventricle of the rabbit brain (i.c.v.). This study was undertaken, therefore, to obtain further information as to the role of the central ${\alpha}_2$-adrenoceptors in regulating renal function, by observing the effects of i.c.v. yohimbine, a specific antagonist of adrenoceptors of ${\alpha}_2$-type, on the rabbit renal function, and to elucidate the mechanism involved in it. With 10 ${\mu}g/kg$ i.c.v. of yohimbine sodium excretion transiently increased along with increasing tendency of urine flow, renal plasma flow and glomerular filtration rate. These responses decreased with increasing doses. With 100 and 300 ${\mu}g/kg$ i.c.v. marked antidiuresis and antinatriuresis as well as profound decreases of renal perfusion and glomerular filtration were noted. Systemic blood pressure transiently increased. In reserpinized rabbits, 100 ${\mu}g/kg$ yohimbine i.c.v. did not produce any significant changes in urine flow, sodium excretion as well as in renal hemodynamics. The pressor response was also abolished. In preparations in which one kidney was denervated and the other left intact as control, i.c.v. yohimbine elicited typical antidiuretic antinatriuretic response in the innervated control kidney, whereas the denervated experimental kidney responded with marked diuresis and increases in excretory rates of sodium and potassium and in osmolar clearance in spite of absence of increased filtration and perfusion . Systemic blood pressure responded as in the normal rabbits. These observations indicate that i.c.v. yohimbine affects renal function in dual ways in opposite directions, the first being the antidiuretic antinatriuretic effects which results from decreased renal perfusion and glomerular filtration due to sympathetic activation and which is predominantly expressed in the normal rabbits, and the second less apparent effect being the diuretic and natriuretic action which is not mediated by nerve pathway but brought about by some humoral mechanism and which is effected by decreased sodium reabsorption in the tubules, possibly of the proximal portion.

• Journal of Dental Anesthesia and Pain Medicine
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• v.16 no.4
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• pp.295-302
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• 2016

Background: Reactive oxygen species play critical roles in homeostasis and cell signaling. Dexmedetomidine, a specific agonist of the ${\alpha}2$-adrenoceptor, has been commonly used for sedation, and it has been reported to have a protective effect against oxidative stress. In this study, we investigated whether dexmedetomidine has a protective effect against $H_2O_2$-induced oxidative stress and the mechanism of $H_2O_2$-induced cell death in normal human fetal osteoblast (hFOB) cells. Methods: Cells were divided into three groups: control group-cells were incubated in normoxia without dexmedetomidine, hydrogen peroxide ($H_2O_2$) group-cells were exposed to $H_2O_2$ ($200{\mu}M$) for 2 h, and Dex/$H_2O_2$ group-cells were pretreated with dexmedetomidine ($5{\mu}M$) for 2 h then exposed to $H_2O_2$ ($200{\mu}M$) for 2 h. Cell viability and apoptosis were evaluated. Osteoblast maturation was determined by assaying bone nodular mineralization. Expression levels of bone-related proteins were determined by western blot. Results: Cell viability was significantly decreased in the $H_2O_2$ group compared with the control group, and this effect was improved by dexmedetomidine. The Hoechst 33342 and Annexin-V FITC/PI staining revealed that dexmedetomidine effectively decreased $H_2O_2$-induced hFOB cell apoptosis. Dexmedetomidine enhanced the mineralization of hFOB cells when compared to the $H_2O_2$ group. In western blot analysis, bone-related protein was increased in the Dex/$H_2O_2$ group. Conclusions: We demonstrated the potential therapeutic value of dexmedetomidine in $H_2O_2$-induced oxidative stress by inhibiting apoptosis and enhancing osteoblast activity. Additionally, the current investigation could be evidence to support the antioxidant potential of dexmedetomidine in vitro.