Induced ion currents and the endothelin pathway as targets for anti-arrhythmic agents
1China Pharmaceutical University, Research Division of Pharmacology, 24 Tong Jia Xiang, Zhongyang Road, Nanjing 210009, China. dezaidai@vip.sina.com
Abstract:
The development of novel anti-arrhythmic drugs is necessary, specifically agents that do not cause torsades de pointes (Tdp). Ion channelopathy that is involved in mechanisms underlying sudden cardiac death (SCD) includes both ion channels in the membrane, and the calcium-releasing channels and the calcium uptake process in the sarcoplasmic reticulum. Advances in the understanding of abnormalities of ion channels in the myocardium caused by congenital defects or by a failing heart and cardiomyopathy offer further insights into the relationship between channelopathy and SCD. Enhanced L-type Ca2+ current (ICa.L) activity has been detected in the hearts of patients with a mutation of the Cav1.2 gene; these patients exhibit a high risk of SCD. Rats with thyroxin-induced cardiomyopathy demonstrate an increase in ICa.L activity that is responsible for exacerbated ventricular fibrillation (VF). This is suppressed by propranolol or CPU-86017, a class III anti-arrhythmic agent with potent antioxidant activity. Interestingly, an increase in rapidly (IKr) and slowly (IKs) activating delayed rectifying K+ currents is caused by gain-of-function mutations of the KCNH2 and KCNQ1 genes, respectively, in patients with short QT syndrome (SQT). Increased IKr and IKs, which are associated with exacerbated VF, are also found in models of thyroxin-induced cardiomyopathy and are suppressed by CPU-86017. ICa.L, IKr and IKs can also be induced in cardiomyocytes when incubated with isoproterenol. A reversal of upstream lesions by an endothelin receptor antagonist CPU-0213 provides suppression of ventricular tachyarrhythmias and upregulates FK506 binding protein 12.6. CPU-86017 and its chiral isomer SR-CPU-86017 relieve upstream lesions, with mild suppression of IKr and moderate suppression of IKs and ICa.L. These agents may be promising as anti-arrhythmic agents that produce less Tdp tachyarrhythmias.
Insights
Novel anti-arrhythmic drugs are needed to prevent sudden cardiac death (SCD) without causing torsades de pointes (Tdp). CPU-86017 shows promise by suppressing abnormal ion channel activity linked to arrhythmias.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Ion channelopathies are implicated in sudden cardiac death (SCD), involving both membrane and sarcoplasmic reticulum ion channels.
- Abnormalities in myocardial ion channels, due to genetic defects or heart conditions like cardiomyopathy, offer insights into SCD mechanisms.
- Enhanced L-type Ca2+ current (ICa.L) activity is linked to SCD risk in patients with Cav1.2 gene mutations and in thyrotoxic cardiomyopathy models.
Purpose of the Study:
- To investigate novel anti-arrhythmic agents that do not induce torsades de pointes (Tdp).
- To explore the role of ion channel activity in cardiomyopathy and its suppression by specific agents.
- To evaluate the efficacy of CPU-86017 and related compounds in managing ventricular arrhythmias.
Main Methods:
- Analysis of ion channel activity (ICa.L, IKr, IKs) in patient-derived models and animal models of cardiomyopathy.
- Pharmacological intervention using propranolol, CPU-86017, and CPU-0213 to assess suppression of arrhythmias.
- Investigation of the effects of isoproterenol on cardiomyocyte ion channel activity and the impact of endothelin receptor antagonists.
Main Results:
- Increased ICa.L activity in thyrotoxic cardiomyopathy models exacerbated ventricular fibrillation (VF), suppressed by propranolol and CPU-86017.
- Gain-of-function mutations in KCNH2 and KCNQ1 genes (short QT syndrome) increased IKr and IKs, associated with VF, also suppressed by CPU-86017.
- CPU-86017 and SR-CPU-86017 demonstrated efficacy in relieving upstream lesions, with selective suppression of IKr, IKs, and ICa.L, potentially reducing Tdp.
Conclusions:
- CPU-86017 and its isomer SR-CPU-86017 show potential as anti-arrhythmic agents with a reduced risk of Tdp.
- Targeting ion channel abnormalities, including ICa.L, IKr, and IKs, is a viable strategy for managing ventricular arrhythmias.
- Further research into these agents could lead to safer and more effective treatments for conditions predisposing to sudden cardiac death.
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