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

Abstract

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.

Assessment of the Ion Channel-blocking Profile of the Novel Combined Ion Channel Blocker AZD1305 and Its Proarrhythmic Potential Versus Dofetilide in the Methoxamine-sensitized Rabbit In Vivo

“…32 Likewise, inhibition of inward calcium currents during concomitant IKr blockade would result in reduced proclivity towards repolarization-related proarrhythmias as experimentally demonstrated for several combined potassium and calcium-channel blocking antiarrhythmic drugs. 17,[33][34][35] Interestingly, Huang and others proposed that the low proarrhythmic potential of CPU228, a dofetilide analogue, could be ascribed to its calcium-blocking properties. 34 Although the present proarrhythmia model critically relies on a 1 -adrenoceptor stimulation for TdP induction, it is most unlikely that a 1 -adrenoceptor blockade underlies the low proarrhythmic potential of AZD1305 as the IC 50 value for such blockade is above 100 mmol/L (AstraZeneca, data on file).…”

Raisanberine protected pulmonary arterial rings and cardiac myocytes of rats against hypoxia injury by suppressing NADPH oxidase and calcium influx

“…[Ca 2+ ] i in cultured cardiac myocytes The primary cardiac cells isolated from adult rats were employed, and the measurements of [Ca 2+ ] i were obtained by incubation with fluorescent Fluo-3/AM at 10 µmol/L; the cardiac myocytes were stimulated using electric field stimulation, according to previous reports [20,21] . The cardiac myocytes were divided into 7 groups: Nor (normal), Hyp (hypoxic injury was mimicked by incubation with H 2 O 2 10 µmol/L), Nif (nifedipine, 0.1 µmol/L), APO (apocynin, 10 µmol/L), RSL (0.1 µmol/L), RSM (1 µmol/L) and RSH (10 µmol/L).…”

CPU86017, a berberine derivative, attenuates cardiac failure through normalizing calcium leakage and downregulated phospholamban and exerting antioxidant activity

“…Measurements of cytosolic [Ca 2+ ] i were performed as described previously [23,24] , with some modifications. Briefly, cardiomyocytes loaded with Fluo-3 were transferred to a 300-µL perfusion chamber, placed on an inverted microscope (Olympus IX71, Japan), perfused with compounds of interest or vehicle, and gassed with 95% O 2 +5% CO 2 at room temperature.…”

“…Cyclic contractions of cardiomyocyte were paced by square wave pulses of 40 V, with a 5-ms duration at 0. [24] .…”