• 대한본초학회지
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• 제25권4호
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• pp.17-21
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• 2010

Objectives : The aim of this study was to evaluate the differential mechnism of vasodilation of alcohol steamed Rhei Tangutici Radix et Rhizoma. (ART) and Rhei Tangutici Radix et Rhizoma. (RT) in rat thoracic aorta. Methods : Rat aortic ring preparations were mounted in organ baths with oxygenated (95% $O_2$-5% $CO_2$) Krebs-Ringer bicarbonate solutions at $37{\pm}0.5^{\circ}C$ and subjected to contractions or relaxations. Results : ART exerted vasorelaxation on phenylephrine(PE)-induced contraction in a dose dependent manner. Vasorelaxation effects of ART and RT were endothelium-independent. In the $Ca^{2+}$-free high KCl (60 mM) baths, the contraction of aortic rings induced by accumulative addition of $Ca^{2+}$ (0.3-10.0 mM) was significantly reduced by pre-treatment with both ART and RT for 10 min. The magnitude of vasodilatation was biggerin ART. Moreover, verapamil ($0.001{\mu}M$) and diltiazem ($10{\mu}M$), voltage operative $Ca^{2+}$channel blockers, attenuated the relaxation effect of ART but not that of RT. In the absence of extracellular $Ca^{2+}$, pre-incubation of the aortic rings with RT ($1.0mg/m{\ell}$) significantly reduced the contraction caused by PE but not that of ART. $K^+$ channel inhibitors such as glibenclamide (Gli, $10^{-5}M$), tetraethylammonium (TEA, 1 mM) and 4-aminopyridine (4-AP, 0.2 mM) significantly reduced the ART's vasorelaxation efficacy, but not that of RT. However, the relaxation effects of ART and RT were not inhibited by pre-treatment with indomethacin ($10^{-5}M$), and atropine ($10^{-6}M$). Conclusions : These results suggest that the endothelium-independent relaxation is due to inhibition of $Ca^{2+}$ influx via the suppression of $Ca^{2+}$ release from intracelluar store in RT but via both voltage operative $Ca^{2+}$channel blockage and $K^+$ channel activation in ART.

• 대한수의학회지
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• 제43권1호
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• pp.31-39
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• 2003

We have investigated the effect of extracellular $Mg^{2+}$ ($[Mg^2+]_o$) on action potential duration (APD) in guinea pig papillary muscles by using microelectrodes. Increasing $[Mg^2+]_o$ resulted in progressive negative inotropic effect, progressive ascending depolarization of membrane potential, and increase in intracellular $Mg^{2+}$ concentration. In addition, increase in $[Mg^2+]_o$ from 1.1 to 3, 6, 10, and 20 mM produced a reversible dose-dependent shortening of both APD at 30% ($APD_{30}$) and 90% repolarization ($APD_{90}$), especially showing a tendency towards more remarkable prominent shortening in $APD_{30}$ than $APD_{90}$. Cooling from 37 to 33 and $27^{\circ}C$ diminished the $[Mg^2+]_o$-induced APD shortening. Increase in extracellular $Ca^{2+}$ concentration from 1.8 to 3.6 and 5.4 mM caused a significant depressed effect on the increasing $[Mg^2+]_o$-induced APD shortening. Furthermore, increase in $[Mg^2+]_o$ from 1.1 to 10 and 20 mM produced a significant depressed effect on the APD shortening induced by extracellular $Ca^{2+}$. Pretreatment of verapamil and imipramine significantly attenuated the increasing $[Mg^2+]_o$-induced APD shortening in both $APD_{30}$ and $APD_{90}$, whereas the $[Mg^2+]_o$-induced APD shortening was not affected by strophanthidin, glibenclamide and tetrabutylammonium. These findings suggest that the effects of $[Mg^2+]_o$ on APD are probably due to a decrease in ionic transport across plasma membrane. In conclusion, the present study indicates that $[Mg^2+]_o$ exerts antiarrhythmic activities by antagonistic actions on intracellular $Ca^{2+}$.

• 한국임상약학회지
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• 제22권4호
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• pp.330-339
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• 2012

Background : Hypertension is treated with both lifestyle modification and pharmacotherapy. The Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7), published in 2003, provides a streamlined management approach to hypertension for the primary care physician. The JNC-7 is the gold standard also in Korea. According to the JNC-7, special therapeutic considerations are recommended for high-risk individuals with compelling indications. The presence of compelling indications in any given patient should be considered when selecting specific pharmacotherapy to treat hypertension. However, in patients with compelling indications, it is unknown that hepatotoxicity is caused by Calcium Channel Blocker (CCB), one of 1st anti-hypertensive drugs. Now, the CCB is the most used 1st anti-hypertensive drug in Korea Therefore, we evaluated the changes in blood liver function parameters (ALT, AST, Total bilirubin, serum albumin) for the study group. Methods : We randomly collected and retrospectively analyzed Electronic Medical Record data (n=28,788) of patients, and who took calcium channel blockers(non-dihydropyridines; diltiazem, verapamil, dihydropyridines; amlodipine, barnidipine, benidipine, clinidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine), with having liver function tests (LFTs) from July 1st 2009 to June 30th 2010 at the Seoul National University Hospital in Korea. Control groups are two antihypertensive agents: RAS blockade (ARB; candesartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, ACE-I; cilazapril, enalapril, fosinopril, imidapril, perindopril, ramipril) and, Diuretics (loop; furosemide, torsemide, thiazide; hydrochlorothiazide[HCTZ], indapamide). Patients not having LFT results at these three standard points of time(baseline, during, medication, and after finishing medication) were excluded. The collected data were analyzed by using the SPSS (Version12.0) and Microsoft Excel (Version2007). Results : 711 patients who were treated CCB (297), RAS blockade (232) or Diuretics (182) monotherapy were selected for the study. In selected patients, liver damage degree(changes of each LFTs value) was higher in diuretics group than other groups, followed by RAS blockade and CCB. In diuretics group's was loop-diuretics group was higher than thiazide-diuretics group. In CCB group, Nondihydropyridine-CCB's damage degree was higher than Dihydropyrine-CCB's that. Conclusions : Despite the limitations due to the retrospective study, among patients with abnormal LFTs, the use of CCBs led to a less liver damage than other 1st anti-hypertensive agents. It can be recommended CCBs as one of the initial treatments of hypertension in patients with liver disease.

• 동의생리병리학회지
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• 제19권5호
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• pp.1391-1398
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• 2005

The anti-thrombic properties of the oriental herbal medicine Daejowhan(DJW, 大造丸) which consists of 11 kinds of herbs (indicated as ratio) of Rehmanniae Radix 24%, Hominis Placenta 5%, Testudinis Carapax 9%, Eucommiae Cortex 9%, Asparagi Radix 9%, Phellodendri Cortex 9%, Achyranthis Radix 7%, Liriopis Tuber 7%, Angelicae Sinensis Radix 7%, Ginseng Radix 5% and Schizandrae Fructus 3% were investigated. The water extracts from DJW inhibited Platelet-activating factor(PAF) induced platelet aggregation. DJW was extracted with methanol and further fractionated by ethylacetate. A 70% methanol extract showed a strong inhibition against PAF-induced aggregation in vitro and in vivo assays. The ethylacetate soluble fraction was shown to have inhibitory effect on PAF-induced platelet aggregation in vitro assay. The ethylacetate soluble fraction specially protected against the lethality of PAF, while verapamil did not afford any protection. These results indicate that the water extracts and alcoholic-fractions inhibit the action of PAF in vivo by an antagonistic effect on PAF, so that it may be useful in treating disorders caused by PAF, such as acute allergy, inflammation, asthma, gastrointestinal ulceration, toxic shock and so forth. DJW was investigated regarding its assumed anti-thrombic action on human platelets which was deduced from its ability to suppress Arachidonic acid(AA)-induced aggregation, exocytosis of ATP, and inhibition of Cyclooxygenase(COX) and Thromboxane synthase(TXS) activity. The latter two effects were estimated from the generation of Prostaglandin $E_2(PGE_2)$ and Thromboxane $A_2(TXA_2)$ respectively. Exogenously applied AA ($100{\mu}mol/{\ell}$) provoked a $89\%$ aggregation of platelets, the release of 14 pmol ATP, and the formation of either 225 pg $TXA_2$ or 45 pg $PGE_2$, each parameter being related to 106 platelets. An application of DJW 5 min before AA dose-dependently diminished aggregation, ATP-release and the synthesis of $TXA_2$ and $PGE_2$ with $IC_{50}$ values of 74, 108, 65, $72{\mu}g/m{\ell}$, respectively. The similarity of the $IC_{50}$ values suggest an inhibition of COX by DJW as primary target, thus suppressing the generation of $TXA_2$ which induces aggregation of platelets and exocytosis of ATP by its binding on $TXA_2$-receptors.

• 동의생리병리학회지
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• 제29권6호
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• pp.492-497
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• 2015

In the present study, vasorelaxant effect of the extract of seeds of Oenothera odorata (SOO) and its possible mechanism responsible for this effect were examined in vascular tissues isolated from rats. Changes in vascular tension, 3',5'-cyclic monophosphate (cGMP) levels were measured in thoracic aorta rings from rats. Methanol extract of seeds of Oenothera odorata relaxed endothelium-intact thoracic aorta in a dose-dependent manner. A dose-dependent vascular relaxation was also revealed by treatment of ethylacetate, n-butanol, and H₂O (aqua extract of seeds of Oenothera odorata , ASOO) extracts partitioned from methanol, but not by hexane extract. However, the vascular relaxation induced by ASOO were abolished by removal of endothelium of aortic tissues. Pretreatment of the endothelium-intact vascular tissues with N^G-nitro-L-arginine methyl ester (L-NAME) or ¹H-[1,2,4]-oxadiazole-[4,3-α]-quinoxalin-1- one (ODQ) significantly inhibited vascular relaxation induced by ASOO. Moreover, incubation of endothelium-intact aortic rings with ASOO increased the production of cGMP. However, ASOO-induced increases in cGMP production were blocked by pretreatment with L-NAME or ODQ. The vasorelaxant effect of ASOO was attenuated by tetraethylammonium (TEA), 4-aminopyridine, and glibenclamide attenuated. On the other hand, the ASOO-induced vasorelaxation was not blocked by verapamil, and diltiazem. Taken together, the present study demonstrates that ASOO dilate vascular smooth muscle via endothelium-dependent NO-cGMP signaling pathway, which may be closely related with the function of K⁺ channels.

• 동의생리병리학회지
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• 제21권2호
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• pp.408-413
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• 2007

Vascular tone plays an important role in the regulation of blood pressure. In the present study, the methanol extract of Rosae multiflora Radix (MRM) induced dose-dependent relaxation of phenylephrine-precontracted aorta, which was abolished by removal of functional endothelium. Pretreatment of the endothelium-intact aortic tissues with $N^G$-nitro-L-arginine methly ester (L-NAME) or 1H-[1,2,4]-oxadiazole-[4,3-${\alpha}$]-quinoxalin-1-one (ODQ) inhibited the relaxation induced by MRM, respectively. But, the relaxation effect of MRM was not blocked by indomethacine, glibenclamide, tetraethylammonium (TEA), verapamil, diltiazem, atropine, and propranolol, respectively. Moreover, incubation of endothelium-intact aortic rings with MRM increased the production of cGMP. Taken together, the present results suggest that MRM relaxes vascular smooth muscle via endothelium-dependent nitric oxide/cGMP signaling. These results would be useful for further study to MRM on animal models with cardiovascular diseases.

• 대한수의학회지
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• 제38권1호
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• pp.29-42
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• 1998

$Mg^{2+}$ is one of the most abundant divalent cations in mammalian body(0.2~1.0mM) and the important physiological roles are : first, the cofactor of many enzyme activities, second, the regulator of glycolysis and DNA synthesis, third, the important role of bioenergetics by regulating of phosphorylation, fourth, the influence of cardiac metabolism and function. In this work we have investigated the regulation of the $Mg^{2+}$ induced by ${\alpha}_1-adrenoceptor$ stimulation in perfused guinea pig hearts and isolated myocytes. The $Mg^{2+}$ content of the perfusate or the supernatant was measured by atomic absorbance spectrophotometry. The elimination of $Mg^{2+}$ in the medium increased the force of contraction of right ventricular papillary muscles, and the left ventricular pressure. Phenylephrine also enhanced the force of contraction in the presence of $Mg^{2+}-free$ medium. ${\alpha}_1-Agonists$ such as phenylephrine and methoxamine were found to induce $Mg^{2+}$ efflux in both perfused hearts and myocytes. These effects were blocked by prazosin, an ${\alpha}_1-adrenoceptor$ antagonist. The $Mg^{2+}$ influx could also be induced by phenylephrine and R59022, a diacylglycerol kinase inhibitor. In the presence of protein kinase C(PKC) inhibitors, phenylephrine produced an increase in $Mg^{2+}$ efflux from perfused hearts. Furthermore, $Mg^{2+}$ efflux by phenylephrine was amplified by phorbol 12-myristate 13-acetate(PMA). This enhancement of $Mg^{2+}$ efflux by PMA was blocked by prazosin in perfused hearts. By contrast, the $Mg^{2+}$ influx could be induced by verapamil, nifedipine, ryanodine in perfused hearts, but not in myocytes. $W^7$, a $Ca^{2+}$/calmodulin antagonist, completely blocked the phenylephrine-induced $Mg^{2+}$ efflux in perfused hearts. In conclusion, $Mg^{2+}$ is responsible for the cardiac activity associated with ${\alpha}_1-adrenoceptor$ stimulation. The mobilization of $Mg^{2+}$ is decreased or increased by ${\alpha}_1-adrenoceptor$ stimulation in guinea pig hearts. These responses may be related specifically to the respective pathways of signal transduction. A decrease in $Mg^{2+}$ efflux by ${\alpha}_1-adrenoceptor$ stimulation in hearts can be through PKC dependent and intracellular $Ca^{2+}$ levels.

• Journal of Ginseng Research
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• 제44권2호
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• pp.247-257
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• 2020

Background: Multidrug resistance (MDR) to chemotherapy drugs remains a major challenge in clinical cancer treatment. Here we investigated whether and how ginsenoside Rg5 overcomes the MDR mediated by ABCB1 transporter in vitro and in vivo. Methods: Cytotoxicity and colon formation as well as the intracellular accumulation of ABCB1 substrates were carried out in MDR cancer cells A2780/T and A549/T for evaluating the reversal effects of Rg5. The expressions of ABCB1 and Nrf2/AKT pathway were determined by Western blotting. An A549/T cell xenograft model was established to investigate the MDR reversal activity of Rg5 in vivo. Results: Rg5 significantly reversed ABCB1-mediated MDR by increasing the intracellular accumulation of ABCB1 substrates without altering protein expression of ABCB1. Moreover, Rg5 activated ABCB1 ATPase and reduced verapamil-stimulated ATPase activity, suggesting a high affinity of Rg5 to ABCB1 binding site which was further demonstrated by molecular docking analysis. In addition, co-treatment of Rg5 and docetaxel (TXT) suppressed the expression of Nrf2 and phosphorylation of AKT, indicating that sensitizing effect of Rg5 associated with AKT/Nrf2 pathway. In nude mice bearing A549/T tumor, Rg5 and TXT treatment significantly suppressed the growth of drug-resistant tumors without increase in toxicity when compared to TXT given alone at same dose. Conclusion: Therefore, combination therapy of Rg5 and chemotherapy drugs is a strategy for the adjuvant chemotherapy, which encourages further pharmacokinetic and clinical studies.

• The Korean Journal of Physiology
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• 제24권2호
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• pp.293-303
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• 1990

The contractile action of barium $(Ba^{2+})$ was investigated in the arterial strip of rabbit renal artery. The helical strip of isolated renal artery was immersed in the Tris-buffered Tyrode's solution equilibrated with 100% $O_2$ at $37^{\circ}C$ and its isometric tension was measured. $Ba^{2+}-induced$ contraction of arterial strip was dose-dependent and its maximal tension corresponded to $92.1{\pm}4.5%$ of tension by $K^+(100\;mM)$. $Ba^{2+}-induced$ contraction did not show the tachyphylactic phenomenon in the normal Tyrode's solution. $Ba^{2+}$ induced the tonic contraction in the $Ca^{2+}-free$ tyrode's solution and that was increased by the extracellula addition of $Ca^{2+}$. During the repeated exposure of the same dose of $Ba^{2+}\;(10\;mM)$ in the $Ca^{2+}-free$ Tyrode's solution, $Ba^{2+}-induced$ contraction was progressively decreased. Even though the intracellular NE-and caffeine-sensitive $Ca^{2+}$ was depleted, $Ba^{2+}$ induced the tonic contraction. After the pretreatment of lanthnum or verapamil, $Ba^{2+}$ did not induce contraction. $Ba^{2+}-induced$contraction was suppressed by extracellular $K^+$ in the normal Tyrode's solution and that was dependent on $K^+$ concentration. Suppressive effect of $K^+\;(14\;mM)$ on the $Ba^{2+}-induced$ contraction was also dependent on the intracellular $Ca^{2+}$ concentration. From the above resuts, it is suggested that $Ba^{2+}$ activate indirectly the contractile process by promoting the mobilization of intracellular $Ca^{2+}$ and the influx of extracellular $Ca^{2+}$. It is also suggested that action of $Ba^{2+}$ on the $Ca^{2+}-activated$ $K^+$ channel can result in the depolarization of cell membrane in the rabbit renal artery.

• 대한수의학회지
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• 제36권4호
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• pp.873-886
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• 1996

For better understanding the interrelationship of hemorrhage and aggregation mechanism, cyclopiazonic acid(CPA) known as promoting the aggregation of platelet, aflatoxin $B_1(AFB_1)$ inhibiting platelet aggregation were used as toxic mycotoxins in these studies. In order to investigate the potential role of prostaglandin metabolism on the platelet aggregation, a variety of prostaglandin metabolites such as $PGF_{2{\alpha}}$, $PGE_2$ and $TXB_2$ were measured in homogenized rabbit platelets by TLC and LSC. And the role of $Ca^{{+}{+}}$ on the platelet aggregation was investigated by flow cytometer. Finally, the morphological effects of mycotoxins on platelet were determined by transmission electron microscope. The results and conclusions obtained from these studies are: 1) CPA induced no changes but $AFB_1$ increased $PGE_2$ and $TXB_2$. 2) CPA promoted ADP, collagen, thrombin, A.A., and PAF-induced $Ca^{{+}{+}}$ release. $AFB_1$, however, decreased $Ca^{{+}{+}}$ level except collagen-induced $Ca^{{+}{+}}$ release. When the calcium blocker, verapamil, was used, CPA decreased thrombin-induced $Ca^{{+}{+}}$ release and increased collagen, ADP, PAF and A.A.-induced $Ca^{{+}{+}}$ release. $AFB_1$ in contrast decreased the all factors induced $Ca^{{+}{+}}$ release. 3) $AFB_1$ did not induce any ultrastructural changes except large vacuole formation in a few platelets. And CPA also did not induce any changes except moderate shape change, indicator of platelet activation. In conclusion, CPA promoted platelet aggregation by the increases of $Ca^{{+}{+}}$ release but had no changes in A.A. metabolites. Antiaggregating effects of $AFB_1$ may be due to decreases of $Ca^{{+}{+}}$ release and increases of $PGE_2$ and $PGF_{2{\alpha}}$ formation. These data provide the basis for the future study of mobilization and function of $Ca^{{+}{+}}$ in platelet aggregation.