Enhanced Late Na and Ca Currents as Effective Antiarrhythmic Drug Targets.

Front Pharmacol

Cardiovascular Research Laboratory, Departments of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, USA; Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, USA; Department of Physiology, David Geffen School of Medicine, University of California, Los AngelesLos Angeles, CA, USA.

Published: February 2017

AI Article Synopsis

  • Recent research has improved understanding of how antiarrhythmic drugs (AADs) work, but their effects on arrhythmias (irregular heartbeats) are still not fully clear.
  • AADs are currently classified into five classes based on how they block specific ionic currents in heart cells, with a new focus on a potential "Class VI" aimed at targeting late inward currents.
  • New prototype drugs like GS-967 and roscovitine have shown promise in inhibiting harmful electrical activities tied to increased calcium sensing in heart conditions, offering a safer treatment option for severe arrhythmias like ventricular tachycardia and fibrillation.

Article Abstract

While recent advances clarified the molecular and cellular modes of action of antiarrhythmic drugs (AADs), their link to suppression of dynamical arrhythmia mechanisms remains only partially understood. The current classifications of AADs (Classes I, III, and IV) rely on blocking peak Na, K and L-type calcium currents (I), with Class II with dominant beta receptor blocking activity and Class V including drugs with diverse classes of actions. The discovery that the calcium and redox sensor, cardiac Ca/calmodulin-dependent protein kinase II (CaMKII) enhances both the late Na (I) and the late I in patients at high risk of VT/VF provided a new and a rational AAD target. Pathological rise of either or both of I and late I are demonstrated to promote cellular early afterdepolarizations (EADs) and EAD-mediated triggered activity that can initiate VT/VF in remodeled hearts. Selective inhibition of the I without affecting their peak transients with the highly specific prototype drug, GS-967 suppresses these EAD-mediated VT/VFs. As in the case of I, selective inhibition of the late I without affecting its peak with the prototype drug, roscovitine suppressed oxidative EAD-mediated VT/VF. These findings indicate that specific blockers of the late inward currents without affecting their peaks (gating modifiers), offer a new and effective AAD class action i.e., "Class VI." The development of safe drugs with selective Class VI actions provides a rational and effective approach to treat VT/VF particularly in cardiac conditions associated with enhanced CaMKII activity such as heart failure.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292429PMC
http://dx.doi.org/10.3389/fphar.2017.00036DOI Listing

Publication Analysis

Top Keywords

late currents
8
selective inhibition
8
prototype drug
8
late
5
enhanced late
4
currents effective
4
effective antiarrhythmic
4
antiarrhythmic drug
4
drug targets
4
targets advances
4

Similar Publications

Diagnostic accuracy of folate receptor-positive circulating tumor cells in differentiating between benign and malignant pulmonary nodules.

Transl Cancer Res

December 2024

Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, Guangzhou, China.

Background: Currently, traditional blood biomarkers such as neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCCA) etc. are mostly elevated in the late stage of tumour, and patients have already lost the chance of tumour eradication when the relevant indexes are found to be elevated. Therefore, there is a need for blood biomarkers with higher sensitivity, better specificity, and better accessibility.

View Article and Find Full Text PDF

Background: The lack of predictive biomarkers contributes notably to the poor outcomes of patients with pancreatic ductal adenocarcinoma (PDAC). Cancer-associated fibroblasts (CAFs) are the key components of the prominent PDAC stroma. Data on clinical relevance of CAFs entering the bloodstream, known as circulating CAFs (cCAFs) are scarce.

View Article and Find Full Text PDF

China witnessed an Omicron COVID-19 outbreak at the end of 2022. During this period, medical crowding and enormous pressure on the healthcare systems occurred, which might result in the occurrence of occupational burnout among healthcare workers (HCWs). This study aims to investigate the prevalence of occupational burnout and associated mental conditions, such as depressive symptoms, anxiety, PTSD symptoms, perceived social support, resilience, and mindfulness among HCWs of the Chinese mainland during the Omicron COVID-19 outbreak, and to explore the potential risk and protective factors influencing occupational burnout of HCWs.

View Article and Find Full Text PDF

Hepatocellular carcinoma (HCC) is a predominant cause of cancer-related mortality globally, noted for its propensity towards late-stage diagnosis and scarcity of effective treatment modalities. The process of metabolic reprogramming, with a specific emphasis on lipid metabolism, is instrumental in the progression of HCC. Nevertheless, the precise mechanisms through which lipid metabolism impacts HCC and its viability as a therapeutic target have yet to be fully elucidated.

View Article and Find Full Text PDF

Elemental cryo-imaging reveals SOS1-dependent vacuolar sodium accumulation.

Nature

January 2025

Laboratory for Biological Geochemistry, School of Architecture, Civil and Environmental Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

Increasing soil salinity causes significant crop losses globally; therefore, understanding plant responses to salt (sodium) stress is of high importance. Plants avoid sodium toxicity through subcellular compartmentation by intricate processes involving a high level of elemental interdependence. Current technologies to visualize sodium, in particular, together with other elements, are either indirect or lack in resolution.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!