New antiarrhythmic targets to control intracellular calcium handling

Abstract

Sudden cardiac death due to ventricular arrhythmias is a major problem. Drug therapies to prevent SCD do not provide satisfying results, leading to the demand for new antiarrhythmic strategies. New targets include Ca2+/Calmodulin-dependent protein kinase II (CaMKII), the Na/Ca exchanger (NCX), the Ryanodine receptor (RyR, and its associated protein FKBP12.6 (Calstabin)) and the late component of the sodium current (INa-Late), all related to intracellular calcium (Ca2+) handling. In this review, drugs interfering with these targets (SEA-0400, K201, KN-93, W7, ranolazine, sophocarpine, and GS-967) are evaluated and their future as clinical compounds is considered. These new targets prove to be interesting; however more insight into long-term drug effects is necessary before clinical applicability becomes reality.

Effects of JTV‐519 on stretch‐induced manifestations of mechanoelectric feedback

“…JTV‐519, also known as K201, is a 1,4‐benzothiazepine derivative with cardioprotective effects against cardiac cell damage related to high intracellular calcium levels . It inhibits Ca 2+ release from the sarcoplasmic reticulum, and has multichannel effects, including inhibition of the Na + current (INa), Ca 2+ current (ICa), rapidly‐activating delayed rectifier current (IKr), muscarinic acetylcholine receptor‐operated K current (IKAch), and inwardly rectifying K + current (IK 1 ).…”

K201 (JTV519) is a Ca2+-Dependent Blocker of SERCA and a Partial Agonist of Ryanodine Receptors in Striated Muscle

“…In principle, these differences with our results may relate to the lack of ATP/Mg 21 and the very low luminal Ca 21 in the SR in [ 3 H] ryanodine binding studies, which made RyRs less sensitive to agonists (Sitsapesan and Williams, 1990;Ogawa, 1994;Fill and Copello, 2002 A SERCA Role for the Cell-Protective Action of K201? There is consensus that the "normalization" of EC-coupling induced by K201 correlates with improved cardiovascular cell function in pathologies, including arrhythmia and heart failure (Yano et al, 2003;Wehrens et al, 2005;Loughrey et al, 2007;Toischer et al, 2010;Driessen et al, 2014;Sedej et al, 2014;Kim et al, 2015). K201 also benefits ischemic SkM (Wehrens et al, 2005).…”

“…K201 also benefits ischemic SkM (Wehrens et al, 2005). Still, K201 mechanism of action is unclear, as it is apparent that there are many targets, including Ca 21 and K 1 channels, that may contribute to the cellular actions of the drug (Driessen et al, 2014).…”

The Role of Peptidyl Prolyl Isomerases in Aging and Vascular Diseases

“…Therefore the treatment with FK506 and rapamycin may contribute to vascular dysfunction and hypertension by induced intracellular leakage of calcium ions in endothelial cells 56,62 . A novel antiarrhythmic compound, K201 (JTV-519), which binds to FKBP12.6, thus stabilising RyRs channels and decreasing spontaneous calcium release, is currently in clinical trials 63 .…”