CPUY11018, an azimilide derivative, ameliorates isoproterenol-induced cardiac insufficiency through relieving dysfunctional mitochondria and endoplasmic reticulum

Q3 · MEDICINE

Article

Author: Tang, Yi-Qun ; Du, Rong-Hui ; Shi, Fang-Hong ; Hussein, Humed Khan ; Dai, Yin ; Dai, De-Zai ; Li, Meng

AbstractObjectivesDeterioration of cardiac performance under stress may be partly mediated by dysfunctional mitochondria and endoplasmic reticulum (ER) that is likely related to an activation of NADPH oxidase (NOX) and an increase in pro-inflammatory factors. We investigated if a new compound CPUY11018 (CPUY) derived from Azimilide could ameliorate the stress impaired cardiac performance.MethodsForty-eight male Sprague Dawley rats were randomly divided into six groups and were injected with isoproterenol (ISO, 1 ml/kg, s.c.) for 10 days. Cardiac myocytes and fibroblasts from neonate rats were incubated with ISO. CPUY was employed and compared with apocynin (APO) – an inhibitor of NOX.Key findingsIn ISO-treated group, the compromised haemodynamics and cardiac remodelling were significant with dysfunctional mitochondria indicated by decreased MnSOD and mitochondrial membrane potential, and an enhanced reactive oxygen species genesis. Downregulation of FKBP12.6, CASQ2 and SERCA2a was also remarkable in vivo and in vitro implying an abnormal ER. Upregulated Nox4, p22phox and p47phox were significant, associated with upregulation of Src, IκBβ and NFκB, and downregulation of pAMPK/AMPK and Cx40 in vivo and in vitro. These abnormalities were relieved by CPUY and APO.ConclusionsCPUY is potential in managing cardiac insufficiency through normalizing mitochondria and ER in the affected heart.

01 May 2013·Drug Development Research

Antiarrhythmic Efficacy of CPUY11018 Under Pathological Conditions

Author: Shan, Jiao‐jiao ; Yu, Peng ; Yang, Qian ; Tang, Yi‐qun ; You, Qi‐dong ; Meng, Jia‐ning ; Xu, Jing

Abstract

Preclinical Research

In the present study, we investigated the antiarrhythmic potential of the multichannel blocker CPUY11018 (CY18) in rat cardiac hypertrophy, induced using 7‐day treatment with isoproterenol (ISO) (2.5 mg/kg day, s.c.). Arrhythmias were produced using a coronary ligation‐reperfusion procedure. CY18 (3 and 10 mg/kg per day, i.p.) and valsartan (10 mg/kg per day, p.o.) were administrated on days 4–7 of ISO treatment. Heart weight index, hemodynamic parameters, electrocardiogram (ECG II) parameters, and arrhythmic scores were monitored and recorded. We examined the ability of CY18 to block the IKr channel under conditions of acidosis and excess reactive oxygen species production in CHO cells expressing the hERG. CY18 had strong antiarrhythmic effects, potentially due to multichannel inhibition. The protective role of CY18 against ISO‐induced myocardial hypertrophy was further confirmed using ECG. Incidences of ventricular tachycardia and ventricular fibrillation, heart weight/body weight ratios, and arrhythmic scores were higher in the model group and were suppressed with CY18 treatment. Under simulated pathological conditions, the inhibitory effect of CY18 was impaired in cells treated with 30 μM H2O2, which was more effective than acidosis in attenuating CY18‐induced inhibition of hERG channel activity.

01 Jun 2012·Drug Development Research

The Multiple Ion Channel Blocker CPUY11018 Prevents Aconitine‐Induced Arrhythmias

Author: Yu, Peng ; Wang, Min‐Hui ; Guo, Xiang ; Zhong, Hao ; Le, Xiao‐Yong ; Yang, Qian ; Zhao, Na ; Tang, Yi‐Qun ; You, Qi‐Dong ; Yin, Yue‐Miao

Abstract

Strategy, Management and Health PolicyEnabling Technology, Genomics, ProteomicsPreclinical ResearchPreclinical Development Toxicology, Formulation Drug Delivery, PharmacokineticsClinical Development Phases I‐III Regulatory, Quality, ManufacturingPostmarketing Phase IV

In the present study, the potential antiarrhythmic activities of a new multiple ion channel blocker, CPUY11018 (Y18) were investigated. The effects of Y18 on ICa,L and INa were studied using whole‐cell patch clamp techniques in ventricular muscle cells from normal rats and guinea pigs. The antiarrhythmic effects were tested using a rat model of aconitine‐induced arrhythmias. The effects of Y18 on induction of QT prolongation and torsades de pointes (TdP) were investigated in anesthetized rabbits during stimulation with methoxamine. Y18 produced a concentration‐dependent inhibition of ICa,L and INa in rat ventricular myocytes with IC50 values of 88 μmol/l and 6.5 μmol/l, respectively. In the Y18 treatment group, the development of arrhythmias was significantly delayed. Doses of aconitine that induced ventricular fibrillation were decreased following treatment with 6 mg/kg Y18 (3.8 ± 0.4 μg/100 g vs 6.2 ± 1.3 μg/kg). A significant decrease in the occurrence of atrial fibrillation (100% to 33%;

< 0.05) occurred following Y18 administration. Y18 induction of TdP was significantly less than that seen with dofetilide and azimilide (Az). Thus, Y18 significantly inhibited the production of aconitine‐induced arrhythmias with a low potency for TdP induction. These results suggest that Y18 is a multiple channel blocker with promising antiarrhythmic potential.

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Indication	Highest Phase	Country/Location	Organization	Date
Arrhythmias, Cardiac	Preclinical	China	China Pharmaceutical University	01 Mar 2009

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