• BMB Reports
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• v.50 no.2
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• pp.91-96
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• 2017

Nuclear factor erythroid 2-related factor 2 (Nrf2) provides a cellular defense against oxidative stress by inducing the expression of antioxidant and detoxification enzymes. The calcium antagonist, verapamil, is an FDA-approved drug prescribed for the treatment of hypertension. Here, we show that verapamil acts as a potent Nrf2 activator without causing cytotoxicity, through degradation of Kelch-like ECH-associated protein 1 (Keap1), a Nrf2 repressor. Furthermore, verapamil-induced Keap1 degradation is prominently mediated by a p62-dependent autophagic pathway. Correspondingly, verapamil protects cells from acetaminophen-induced oxidative damage through Nrf2 activation. These results demonstrated the underlying mechanisms for the protective role of verapamil against acetaminophen-induced cytotoxicity.

• Journal of Chest Surgery
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• v.23 no.6
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• pp.1074-1083
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• 1990

This study was evaluated the metabolic, physiologic and histologic effects of myocardial protection of verapamil[isoveratril]on isolated rat hearts to 90 minutes of ischemic arrest. Heart was perfused with a modified Kreb’s Henseleit bicarbonate buffer with glucose and arrested with retrograde coronary perfusion by glucose insulin[GI], potassium and verapamil. Mean aortic systolic pressure, heart rate, coronary flows were measured and morphologic changes were examined during working heart perfusion. Perfusion and arrest were controlled four groups subjected 60 isolated rat hearts. Four groups hearts reperfused during 40 minutes after 90 minutes global ischemia for physiologic recovery. 15 hearts of four groups were assayed to histological morphologic changes. GI treated hearts recovered less than 28% of function and changed more than 80% of mitochondria of control group. Verapamil hearts[0.2, 0.1 gm/kg] recovered more than 88% of function and permitted the maintenance of continuous cellular level of Serum Glutamic Oxalaxetate Transaminase[SGOT], but declined 28% of Phosphate Kinase[CP], GI treated heart showed widespread evidence of extensive damage of mitochondria. The damage was that interstitial huge edema are present and there was contraction band formation within the swollen cells. The verapamil and potassium group were not found morphologic change compared with control group. Their functions were shown that metabolic and physiologic action of verapamil-group lasted 20 minutes longer than potassium group.

• Archives of Pharmacal Research
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• v.27 no.9
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• pp.978-983
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• 2004

The effects of glycyrrhizic acid (GLZ) on protein binding of diltiazem, verapamil, and nifedipine were investigated. Protein binding studies (human serum, human serum albumin (HSA) and (X1-acid glycoprotein (AAG)) were conducted using the equilibrium dialysis method with and without addition of GLZ. The binding parameters, such as the number of moles of bound drug per mole of protein, the number of binding sites per protein molecule, and the association con-stant, were estimated using the Scatchard plot. The serum binding of nifedipine, verapamil, and diltiazem was displaced with addition of GLZ, and the decreases of Ks for serum were observed. GLZ decreased the association constants of three drugs for HSA and AAG, while the binding capacity remained similar with addition of GLZ. Although the characteristics of interaction were not clear, GLZ seemed to mainly affect HSA binding of nifedipine rather than AAG binding, while GLZ seemed to affect both AAG- and HSA-bindings of verapamil and dilt-iazem resulting in a serum binding displacement.

• YAKHAK HOEJI
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• v.39 no.1
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• pp.61-67
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• 1995

PVC membrane electrodes based on the lipophilic neutral carrier, dibenzo-18-crown-6, cyclic oligomers of teit-butylphenol-formaidehyde condensates, calix[4]arenes as the active sensors for verapamil have been prepared and tested in a variety of plasticizers. At pH 5.0, the electrode exhibits a Nernstian response in the range of 10$^{-2}$~5$\times$10$^{-5}$ M verapamil with a slope of 49.1$\pm$0.5mV per concentration decade. The electrode constructed in this work can be used continuously for at least 1 month before any damage to the membrane occurs. And the analyses of the local anesthetic amine, which are good to select a specific compound in a mixed solution, were also accomplished by using of another neutral carrier, a DB18C6, for comparing with calix[4]arene.

• Korean Journal of Clinical Pharmacy
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• v.14 no.1
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• pp.32-35
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• 2004

The purpose of this study was to investigate the pharmacokinetic changes of verapamil in rabbits with hepatic disorder induced by carbon tetrachloride. The plasma concentrations of verapamil were increased significantly (p<0.05, in slight group; P<0.01, in moderate and severe group) in all groups of hepatic disorder compared to the control group. Morover, the $C_{max}\;in\;slight\;(77.9\%$ increase), moderate ($110\%$ increase), and severe ($174\%$ increase) hepatic disorder groups were significantly (p<0.05, in slight; p<0.01, in moderate and severe) higher than that in control rabbits. These resulted in significantly (p<0.05, in slight; p<0.01, in moderate and severe) greater area under the plasma concentration-time curve (AUC) in moderate ($49.8\%$ increase), moderate ($95.0\%$ increase), and severe ($144\%$ increase) hepatic disorder groups than that in control rabbits. Hence, the relative bioavailability values were 149, 195, and $244\%$ for slight, moderate, and severe hepatic disorder groups, respectively. This could be due to decrease in metabolism of verapamil in the liver because of suppressed hepatic function in the hepatic disorder groups because verapamil is mainly metabolized in the liver.

• The Korean Journal of Pharmacology
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• v.23 no.2
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• pp.133-141
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• 1987

The effects of verapamil and tetracaine on acetylcholine-and oxytocin-induced contraction of uterus from estrogen-treated rat were examined. Isometric tensions were recorded on the Physiograph and stored in TriGem 20XT computer as digitized data for off-line analysis of the components, which described the contraction patterns: trought tension (T), peak tension (P), contraction frequency (F), and duration (D). In the acetylcholine-induced contraction, verapamil $(0.25\;{\mu}M)$ significantly decreased P and D. In contrast, tetracaine $(42{\mu}M)$ decreased F, but increased D. In the low oxytocin-induced contraction, verapamil $(0.25\;{\mu}M)$ decreased P and D, and tetracaine $(42{\mu}M)$ decreased F but increased D. In the high oxytocin-induced contraction, verapamil decreased P and D, but tetracaine decreased P without affecting on other components. These results suggest that the analysis of effects of a certain inhibitor on the components of contraction allow to postulate its specific inhibitory mechanism of the smooth muscle contraction.

• Journal of The Korean Society of Clinical Toxicology
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• v.16 no.1
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• pp.9-14
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• 2018

Purpose: Intravenous lipid emulsion (ILE) has been shown to have significant therapeutic effects on calcium channel blocker overdose in animal studies and clinical cases. In this preliminary experiment, we investigated the hemodynamic changes and survival in a rat model of verapamil intoxication. Methods: Fourteen male Sprague-Dawley rats were sedated and treated with ILE or normal saline (control), followed by continuous intravenous infusion of verapamil (20 mg/kg/h). Mean arterial pressure and heart rate of rats were monitored during the infusion. In addition, the total dose of infused verapamil and the duration of survival were measured. Results: Survival was prolonged in the ILE group ($32.43{\pm}5.8min$) relative to the control group ($24.14{\pm}4.3min$) (p=0.01). The cumulative mean lethal dose of verapamil was higher in the ILE group ($4.3{\pm}0.7mg/kg$) than in the control group ($3.2{\pm}0.5mg/kg$; p=0.017). Conclusion: ILE pretreatment prolonged survival and increased the lethal dose in a rat model of verapamil poisoning.

• The Korean Journal of Physiology
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• v.18 no.2
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• pp.125-137
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• 1984

The effects of external $Ca^{2+}$ ana the inhibition of Na-pump on vanadate-induced contraction in isolated human and rat uterine smooth muscle were studied and the following results were observed. 1) Vanadate induced contraction in rat uterine muscle and showed maximal contraction at concentration of $5{\times}10^{-4}$M, and the contractile response to vanadate was more sensitive in human than rat uterine muscle. 2) Vanadate-induced contraction was not completely inhibited by $Ca^{2+}$ removal from PSS and the response to $Ca^{2+}$ removal was more sensitive in human than rat uterine muscle. 3) Vanadate-induced contraction decreased with increasing concentration of verapamil, but even in the presence of $3{\times}10^{-5}M$ verapamil which inhibited 100 K-induced contraction completely. about 40% of maximal contraction remained, and its amplitude was similar to that of contraction in $Ca^{2+}$-free solution. 4) Vanadate-induced contraction was increased by the inhibition of Na-pump and this increase also could be observed in the presence of $3{\times}10^{-5}M$ verapamil. 5) After pretreatment with $Ca^{2+}$-free PSS containing ouabain Vanadate-induced contraction was not increased, but the contractile response of these tissues to the addition of external $Ca^{2+}$ was remarkably increased in the presence of vanadate. 6) $3{\times}10^{-5}$M verapamil inhibited vanadate-induced $Ca^{45}$ influx completely, but after pretreatment with ouabain vanadate could induce remarkable $Ca^{45}$ influx even in the presence of verapmil. 7) With increasing the time of pretreatment with ouabain or $K^+$-free solution, the degree of increase in contraction by vanadate was more remarkable. 8) $10^{-4}M$ papaverine stowed a considerable inhibition of the increase in the vanadate-induced contraction by pretreatment with ouabain. 9) Acetylcholine-induced contraction increased with lengthening the duration of Na-pump inhibition even in the presence of verapamil. Considering above results it seems that the uterine muscle of human is more sensitive to vanadate than that of rat, and both internal and external $Ca^{2+}$ is utilized in vanadate·induced contraction. In the case of Na-pump inhibition several smooth muscle contracting agents seems to induce $Ca^{2+}$ influx which is not inhibited by verapamil. This $Ca^{2+}$ influx seems to be inhibited by papaverine and to be associated with membrane potential, although its precise characteristics is not certain.

• Proceedings of the PSK Conference
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• 2003.04a
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• pp.306.2-307
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• 2003

The purpose of this study was to investigate the effect of verapamil (5, 10, 20 mg/kg) on the pharmacokinetic parameters and the bioavailability of paclitaxel (50 mg/kg) orally coadministered in rats. The plasma concentration of paclitaxel with verapamil increased dose-dependently, and increased significantly in both coadministration (p<0.05) and pretreatment group (p<0.01) compared to that of control. (omitted)

• 한국임상약학회:학술대회논문집
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• 2007.12a
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• pp.165-165
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• 2007