VK-II-86

VK-II-86 is an inhibitor of store-overload-induced calcium release (SOICR) and a derivative of carvedilol .¹ It inhibits SOICR in HEK293 cells expressing the ryanodine receptor 2 (RyR2) R4496C (RyR2^R4496C) mutation (IC₅₀ = 16.8 µM), a mutation that results in spontaneous calcium release from the endoplasmic reticulum. VK-II-86 (1 µM) inhibits the inward-rectifier potassium channel 2.1 (K_ir2.1), cardiac late sodium current (late I_Na), and L-type calcium current (I_Ca) in isolated canine cardiomyocytes and delayed-rectifier potassium current (I_Kr) in HEK293 cells expressing human-ether-a-go-go (hERG), also known as K_v11.1, in pokalaemic, but not normokalaemic, conditions.² It is also an antagonist of toll-like receptor 4 (TLR4; IC₅₀ = 32.55 µM in HEK293 cells expressing the human receptor) and inhibits perpolarization-activated cyclic nucleotide gated potassium channel 4 (HCN4) in COS-7 cells expressing HCN4 when used at a concentration of 10 µM.³ VK-II-86 prevents pokalaemia-induced ventricular arrthmia in isolated Langendorff-perfused mouse hearts.² Unlike the β-adrenergic receptor antagonist carvedilol, it does not reverse isoproterenol-induced increases in heart rate or decrease resting heart rate in RyR2^R4496C-expressing mice.⁴