Blockade on sodium, potassium, and calcium channels by a new antiarrhythmic agent CPU 86017

Dai, De‐Zai; Feng, Yu; Li, Haitao; Tang, Yiqun; An, Lu-Fan; Huang, Wenlong; Peng, Sixun; Hao, Xiaolei; Zhou, Bei-Ai; Hu, Chai-Hong

doi:10.1002/(sici)1098-2299(199610)39:2<138::aid-ddr5>3.0.co;2-q

Cited by 22 publications

(7 citation statements)

References 25 publications

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“…Thus, the benefit of CPU0213 is stemming mainly from ET A R blockade. We did not conduct the DADs (delayed after depolarizations) resultant from increased diastolic calcium in the cardiomyopathy, and in previous study prolongation of APD was found [35], that can be explained due to an augmented I Ca.L [13,32] which retards repolarization, thus, DADs are likely occur. Thus, elevated calcium levels in the cardiomyopathy may be in part due to an increased calcium influx.…”

Section: Limitationsmentioning

confidence: 86%

Downregulated FKBP12.6 expression and upregulated endothelin signaling contribute to elevated diastolic calcium and arrhythmogenesis in rat cardiomyopathy produced by l-thyroxin

Zhang¹,

Huang²,

Dai³

et al. 2008

International Journal of Cardiology

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Section: Limitationsmentioning

confidence: 86%

Downregulated FKBP12.6 expression and upregulated endothelin signaling contribute to elevated diastolic calcium and arrhythmogenesis in rat cardiomyopathy produced by l-thyroxin

Zhang¹,

Huang²,

Dai³

et al. 2008

International Journal of Cardiology

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“…Blockade of both I Kr and I Ca,L contributes to the major characteristics of complex Class III agents, such as amiodarone, CPU86017, 34–36 dronedarone 37 and azimilide 1,2,7 . All these agents cause a lower incidence of TDP and are more potent at suppressing ventricular arrhythmias.…”

Section: Discussionmentioning

confidence: 99%

Calcium Antagonist Property of Cpu228, a Dofetilide Derivative, Contributes to Its Low Incidence of Torsades De Pointes in Rabbits

Huang

Dai

et al. 2007

Clin Exp Pharma Physio

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1. Torsades de pointes (TDP) is a severe adverse effect during the clinical use of dofetilide, a selective blocker of the rapid component of the delayed rectifier potassium channel (I(Kr)). The present study was designed to test whether CPU228, a derivative of dofetilide with calcium (Ca(2+)) antagonist properties, could reduce TDP without reducing the blockade of I(Kr). 2. The incidence of TDP in a rabbit model and the effective refractory period (ERP) were measured and compared for dofetilide and CPU228. Suppression of I(Kr) and the L-type Ca(2+) current (I(Ca,L)) and the Ca(2+) transients of isolated cardiomyocytes were investigated by whole-cell patch-clamp and Fluo-3 dye spectrophotometry. 3. The incidence of TDP was greatly reduced by CPU228 relative to dofetilide, occurring in only one of six rabbits compared with five of six rabbits following dofetilide (P < 0.05). In isolated atria, prolongation of ERP by CPU228 was less than that of dofetilide and no reverse frequency dependence was observed. Negative inotropism by CPU228 was significant against positive inotropism by dofetilide. CPU228 inhibited both I(Kr) and I(Ca,L) currents and the IC(50) for I(Ca,L) inhibition was 0.909 micromol/L. At 3 micromol/L, CPU228 significantly suppressed the Ca(2+) transients. 4. CPU228 is able to block I(Ca,L), contributing to decreased TDP, while also blocking I(Kr) activity. By combined blockade of I(Kr) and I(Ca,L), CPU228 shares the property of complex Class III anti-arrhythmic agents.

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“…It is a synthetic derivative of tetrahydroberberine, which is an effective component extracted from Chinese herbal medicines, such as Coptis chinensis Franch. Pharmacology studies indicate that chlorobenzylidine has a strong antiarrhythmic and antiventricular action 12–18. Patents for this drug have been filed in several countries 19–22.…”

Section: Introductionmentioning

confidence: 99%

Spectroscopic studies of interaction of chlorobenzylidine with DNA

Zhong

Huang

et al. 2001

Biopolymers

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Electronic absorbance and fluorescence titrations are used to probe the interaction of chlorobenzylidine with DNA. The binding of chlorobenzylidine to DNA results in hypochromism, a small shift to a longer wavelength in the absorption spectra, and emission quenching in the fluorescence spectra. These spectral characteristics suggest that chlorobenzylidine binds to DNA by an intercalative mode. This conclusion is reinforced by fluorescence polarization measurements. Scatchard plots constructed from fluorescence titration data give a binding constant of 1.3 x 10(5) M(-1) and a binding site size of 10 base pairs. This indicates that chlorobenzylidine has a high affinity with DNA. The intercalative interaction is exothermic with a Van't Hoff enthalpy of -143 kJ/mol. This result is obtained from the temperature dependence of the binding constant. The interaction of chlorobenzylidine with DNA is affected by the pH value of the solution. The binding constant has its maximum at pH 3.0. Upon binding to DNA, the fluorescence from chlorobenzylidine is quenched efficiently by the DNA bases and the fluorescence intensity tends to be constant at high concentrations of DNA when the binding is saturated. The Stern-Volmer quenching constant obtained from the linear quenching plot is 1.6 x 10(4) M(-1) at 25 degrees C. The measurements of the fluorescence lifetime and the dependence of the quenching constant on the temperature indicate that the fluorescence quenching process is static. The fluorescence lifetime of chlorobenzylidine is 1.9 +/- 0.4 ns.

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Blockade on sodium, potassium, and calcium channels by a new antiarrhythmic agent CPU 86017

Cited by 22 publications

References 25 publications

Downregulated FKBP12.6 expression and upregulated endothelin signaling contribute to elevated diastolic calcium and arrhythmogenesis in rat cardiomyopathy produced by l-thyroxin

Downregulated FKBP12.6 expression and upregulated endothelin signaling contribute to elevated diastolic calcium and arrhythmogenesis in rat cardiomyopathy produced by l-thyroxin

Calcium Antagonist Property of Cpu228, a Dofetilide Derivative, Contributes to Its Low Incidence of Torsades De Pointes in Rabbits

Spectroscopic studies of interaction of chlorobenzylidine with DNA

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