• YAKHAK HOEJI
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• v.40 no.2
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• pp.135-140
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• 1996

Ion-selective poly(vinyl chloride)(PVC) membrane electrodes for the determination of the calcium antagonist verapamil and its pharmaceutical preparations were described. Verapam il-superchrome garnet Y(SGY), lumogallion(LG), acid red 97(AR97), Dragendorff(DD) and Meyer reagent ion pairs were inverstigated as an electroactive compound for membrane electrode. Stable potentiometric response was obtained with azo dye at pH 6.5-4.0 and with DD, and Meyer reagent at pH 6.5-3.0. The best plasticizer was 49w/w% 2-nitrophenyl octyl ether for azo dye, and 65.3w/w% tri(n-butyl) citrate for DD and Meyer reagent. Potentiometric response slopes of optimized membrane electrodes based on SGY, LG, AR97, DD, and Meyer complex for verapamil were 52.49, 54.88, 50.81, 54.13 and 49.31 mV/dec., respectively. Lower limits of linear range were $1.0{\times}10^6M$ for SGY, LG, and AR97, while those for DD and Meyer reagent were $4{\times}10^{-6}M$. Detection limits for all these electrodes were $1{\times}10^{-5}M,\;4{\times}10^{-6}M,\;1.8{\times}10^{-6}M,\;8{\times}10^{-7}M,\;and\;1{\times}10^{-6}M$ with relative standard deviation of 2.56, 3.6, 3.96, 2.56, 3.20%, respectively.

• The Korean Journal of Pharmacology
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• v.17 no.2
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• pp.7-16
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• 1981

Higenamine ($Ca_{26}H_{17}No_3$. HCI, d1-1- (4-hydroxybenzyl) -6,7-dihydroxy-1,2,3,4-tetrahydroiso-quinoline hydrochloride), which has recently teen isolated from the Aconite root, was known to the cardiotonic component of the Aconite root. The positive inotropic effect of Higenamine was observed in the isolated electrically driven left atrium from rabbits with respect to the influences of extracellular calcium and of calcium antagonists, e.g. $La^{+++}$ and verapamil. A synergistic relation in the positive inotropic effect could be demonstrated between Higenamine and extra cellular calcium. The inotropic potency of $10^{-7}\;g/ml$ Higenamine was equivalant to that of 0.058 mM of calcium in the medium. In the preparation, of which contractility had been reduced by the treatment of $La^{+++}(10^{-5}-10^{-4}M)$ and verapamil$(2{\times}10^{-7}-10^{-6}M)$, Higenamine was able to restore the contractility. These results indicated that one of the possible mechanism of positive inotropism of Higenamine was to accelerate the influx of calcium from the extracellular space through the sarcolemma.

• The Journal of Korean Medicine
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• v.15 no.2 s.28
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• pp.198-211
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• 1994

After giuing some anti-high blood pressure medicine of boiled-compressed fluid and 5-Kinds factors(Hydralazine, Verapamil, Clonidine, Furosemide and Hydrochlorothiazide with Kangsimsan to animals in single or together. I got the following conclusion in comparing blood-pressure and pulse of circulating system with urinating operation. 1. By joint-use of Kangsimsan and Hydralazine. it was found out that the effect of blood-pressure lowering continues longer in together-use than in single. And I coule see that the number of pulse increased. 2. By joint-use of Kangsimsan and Verapamil. the blood-pressure lowering operation was kept better in together-use than in single. the number of pulse was not affected any. 3. By joint-use of Kangsimsan and Clonidine the blood-pressure lowering operation was not found out any concrete result. 4. By joint-use of Kangsimsan and Furosemide. the Remarkble effect of Urinization was recognized to be much better in joint-use than in single. 5. By joint-use of Kangsimsan and Hydrochlorothiazide. the suppressing effect of urinization was recognized to be much better in joint-use than in single. Therefore in consideration of the above study and observation. when the joint-use of Kangsimsan and the blood-pressure lowering medicine. Hydralazine and Verapamil. the period of blood-pressure lowering was kept and I can conclude that in case of joint-use of Furosemide, a kind of good urinization. the effect of urinization by Furosemide is increased, but that of Hydrochlorothiazide is disturbed.

• Biomolecules & Therapeutics
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• v.6 no.2
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• pp.130-138
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• 1998

In this study, the effect of verapamil (VER) on cyclosporin A (CsA)-induced nephrotoxicity was investigated in uninephrectomized rats. Male Wistar rats were administered CsA (50 mg/kg/day, p.o.) or VER (0.5 mg/kg/day, i.p.) with CsA (50 mg/kg/day, p.o.) for 20 days. The urinary N-acetyl-$\beta$-D-glucosaminidase (NAG) activity along with BUN, serum creatinine, creatinine clearance (CLcr), body weight, and 24 hr-urine output were measured and histopathologic changes of kidney were evaluated by light and electron microscopy. The results obtained from this study can be summarized as follows: While NAG activity, BUN and serum creatinine was progressively increased and CLcr significantly decreased in CsA group, VER almost signifi-cantly (p<0.05) suppressed and normalized CsA-induced changes in VER+CSA group. While urine output increased until 12th days and thereafter progressively decreased in CsA group, it gradually increased in control and VER+CSA group. While body weight progressively made a gain in control and VER+CSA groups, it significantly (p<0.05) lost in CsA group. On light microscopy, the glomerular hyperemia and proximal convoluted tubular (PCT) dilatation, focal tubular cell vacuolation and necrosis were clearly evident in CsA group, but, were not seen in other groups. Ultrastructural studies revealed thickened glomerular endothelium and basal lamina of capillary, irregular shaped pedicels of podocytes, indistinct slit pores and narrowed bowman's space. The large oval vacuoles with dense debris and phagosome were distributed in apical zone and deformed microvilli and mitochondria were seen in the PCT cell of CsA group. But, glomeruli and PCT cell were relatively preserved in normal apperance in other groups. In conclusion, it is suggested that verapamil has a protective effect on cyclosporine-induced nephrotoxicity in uninephrectomized rats.

• Journal of Chest Surgery
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• v.41 no.5
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• pp.541-549
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• 2008

Background: Vasoconstrictor-induced reduction in arterial graft diameter can cause significant flow deprivation. The aim of this study was to evaluate the effect of vasodilator pretreatment on vasoconstrictor-induced blood vessel spasm in vitro. Material and Method: Rabbit brachial arteries (BA) and celiac arteries (CA) were cut into rings $(3{\sim}4mm)$ and suspended with a force displacement transducer (TSD $125C^{(R)}$, Biopac Inc. USA) in a tissue bath filled with 5 mL modified Krebs solution bubbled with 5% $CO_2$ and 95% $O_2\;at\;38^{\circ}C$. The rings were contracted with vasoconstrictors, and the developed tension changes were considered control values. The rings were then pre- treated with $30{\mu}M$ nitroglycerin, nicardipine, verapamil, and papaverine, respectively, for 40 minutes and rinsed with the physiologic buffered salt solution three times every 15 min. The vasoconstrictor-induced tension changes after the previous procedure were considered experimental values. Data are expressed as the percentage tension induced by vasoconstrictors before and after pretreatment with vasodilators. Result: Nicardipine depressed vasoconstriction induced by norepinephrine, angiotensin II (All), and U46619 in both the BA and the CA more significantly than did nitroglycerin (p<0.01) and verapamil (p<0.05). Verapamil depressed vasoconstriction induced by 5-hydroxytryptamine (5HT), All, and U46619 in the BA and by 5HT in the CA more significantly than did nitroglycerin (p<0.01). Conclusion: These findings suggest that both nicardipine and verapamil effectively depressed vasoconstrictor action. Nicardipine is thought to be more effective than verapamil for the prevention of vasoconstrictor action.

• The Korean Journal of Nuclear Medicine
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• v.37 no.3
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• pp.178-189
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• 2003

Purpose: Cellular uptakes of $^{99m}Tc-sestamibi(MIBI)\;and\;\;^{99m}Tc-tetrofosmin$ into cancer cell lines expressing multidrug resistance(MDR) were investigated and compared. The effects of verapamil and cyclosporin A, well-known multidrug resistant reversing agents, on cellular uptakes of both tracers were also compared. Materials and Methods: Doxorubicin-resistant HCT15/CL02 human colorectal cell and doxorubicin-resistant K562(Adr) and vincristine-resistant K562(Vcr) human leukemic cells were studied. RT-PCR analysis was used for the detection of mdr1 mRNA expression. MDR-reversal effects with verapamil and cyclosporine A were evaluated at different drug concentrations after incubation with MIBI and tetrofosmin for 1, 15, 30, 45 and 60 min, using single-cell suspensions at $1{\times}10^6cells/ml$ incubated at $37^{\circ}C$. Radioactivity in supernatants and pellets were measured with gamma well counter. Results: The cellular uptakes of MIBI and tetrofosmin in K562(Adr) and K562(Vcr) were lower than those of parental K562 cell. In HCT15/CL02 cells and K562(Adr) cells, there were no significant difference in cellular uptakes of both tracers, but cellular uptake of MIBI was higher than that of tetrofosmin in K562(Vcr) cells. Coincubation with verapamil resulted in a increase In cellular uptakes of MIBI and tetrofosmin. Verapamil increased cellular uptakes of MIBI and tetrofosmin by HCT15/CL02 cell by 11.9- and 6.8-fold, by K562(Adr) cell by 14.3- and 8-fold and by K562(Vcr) cell by 7- and 5.7-fold in maximum, respectively. Cyciosporin A increased cellular uptakes of MIBI and tetrofosmin by HCT15/CL02 cell by 10- and 2.4-fold, by K562(Adr) cell by 44- and 13-fold and by K562(Vcr) cell by 18.8- and 11.8-fold in maximum, respectively Conclusion: Taking together, MIBI and tetrofosmin are considered as suitable radiopharmaceuticals for defecting multidrug resistance. However, MIBI seems to be a better tracer than tetrofosmin for evaluating MDR reversal effect of the modulators. Since cellular uptakes of both tracers might differ in different cell types, further experiments regarding differences in cellular uptakes between cell types should be explored.

• Bulletin of the Korean Chemical Society
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• v.35 no.8
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• pp.2317-2325
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• 2014

P-glycoprotein (P-gp) is a member of the ATP-Binding Cassette transporter superfamily and mediates transmembrane efflux of many drugs. Since it is involved in multi-drug resistance activity in various cancer cells, the development of P-gp inhibitor is one of the major concerns in anticancer therapy. Human P-gp protein has at least two "functional" drug binding sites that are called "H" site and "R" site, hence it has multi-binding-specificities. Though the amino acid residues that constitute in drug binding pockets have been proposed by previous experimental evidences, the shapes and the binding poses are not revealed clearly yet. In this study, human P-gp structure was built by homology modeling with available crystal structure of mouse P-gp as a template and docking simulations were performed with inhibitors such as verapamil, hoechst33342, and rhodamine123 to construct the interaction between human P-gp and its inhibitors. The docking simulations were performed 500 times for each inhibitor, and then the interaction frequency of the amino acids at the binding poses was analyzed. With the analysis results, we proposed highly contributing residues that constitute binding pockets of the human P-gp for the inhibitors. Using the highly contributing residues, we proposed the locations and the shapes of verapamil binding site and "R" site, and suggested the possible position of "H" site.

• Journal of Pharmaceutical Investigation
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• v.36 no.5
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• pp.315-320
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• 2006

Silymarin showed P-glycoprptein(P-gp) inhibitory activity as much as verapamil, a well-known P-gp inhibitor, by decreasing $IC_{50}$ value of daunomycin(DNM)($16.0{\pm}0.7{\mu}M$), increasing the DNM accumulation($224.9{\pm}3.2%$), and decreasing DNM efflux($58.5{\pm}6.7%$), concurrently. In this study, we clarified the mechanism of action of silymarin for P-gp inhibitory function. First, silymarin may bind to the ATP-binding site and thus, prevent ATP hydrolysis. Second, the P-gp inhibitory activity of silymarin is not related to changing the cellular P-gp level. Third, the cytotoxicity of silymarin was increased in the presence of verapamil, reflecting that silymarin is a competent P-gp substrate against verapamil in the P-gp-overexpressed adriamycin-resistant MCF-7 breast cancer(MCF-7/ADR) cells. Conclusively, silymarin had the P-gp inhibitory activity through the action of competent binding to the P-gp substrate-binding site. Therefore, silymarin can be a good candidate for safe and effective MDR reversing agent in clinical chemotherapy by administering concomitantly with anticancer drugs.

• Archives of Pharmacal Research
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• v.19 no.5
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• pp.342-347
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• 1996

Doxorubicin, one of the clinically most useful anticancer agents, is used alone or in combination with other drugs against a wide variety of tumors, recently. But cancer cells developed resistance to this agent in many ways. This resistance is an important limiting factor of doxorubicin for anticancer drug. We newly established doxorubicin-resistant HCT15/CL02 subline from parental HCT15 human adenocarcinoma colon cancer cells. HCT15/CL02 revealed resistance to doxorubicin about 85-fold of its parental cells, and it also revealed cross-resistance to actinomycin D, etoposide and vinblastine but not to displatin and tamoxifen. And verapamil, a reversal agent of multidrug-resistance (MDR) by P-glycoprotein, elevated the cytotoxicity of doxorubicin against both HCT15 and GCT15/CL02 cells. But the relative resistant rate was not reduced. Verapamil had no effects on the tosicity of cisplatin to the both cell lines. These results indicate that HCT15/CL02 cells have some functionally complex mechanisms for MDR.

• The Korean Journal of Physiology
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• v.16 no.1
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• pp.25-30
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• 1982

The in vitro experiments for isometric contraction were done to investigate the different action mechanism of calcium ion on phasic and tonic components of K-contracture in guinea pig's taenia coli. The results were as follows: 1) The degrees of K-contracture were increased gradually from 4 mM to 15, 20, 40 & 100 mM of$[K^+]_0$. The maximal developed tension in tonic component was observed in 100 mM of $[K^+]_0$. 2) The phasic components were not so affected by 2, 4, 8 & 16 mM of $[Ca^{++}]_0$ in 100 mM K-contracture, but the tonic components were gradually increased in a dose-responsive manner. 3) The K-contracture was not influenced by norepinephrine, 1 mg/l, but was completely abolished by verapamil, 2 mg/l. 4) The phasic component was little affected by verapamil, 0.01 mg/l, 0.1 mg/l, and 1 mg/l, but the tonic component was completely disappeared at the concentration of verapamil 1 mg/l. The above results suggest that $[Ca^{++}]_0.$ primarily affected the tonic component than the phasic component of K-contracture in guinea pig's taenia coli.