Electrophysiological properties of HBI-3000: a new antiarrhythmic agent with multiple-channel blocking properties in human ventricular myocytes.
HBI-3000 (sulcardine sulfate) has been shown to suppress various ventricular arrhythmias in animal models. The electrophysiological properties of HBI-3000 were investigated using standard microelectrode and patch-clamp techniques in single human ventricular myocytes. HBI-3000 led to concentration-dependent suppression of dofetilide-induced early afterdepolarizations in single nonfailing human ventricular myocytes and early afterdepolarizations seen in failing ventricular myocytes. The concentration-dependent prolongation of action potential duration (APD) by HBI-3000 was bell shaped with maximum response occurring around 10 μM. Interestingly, HBI-3000 at the concentration of 10 μM modestly prolonged the APD at all 3 basic cycle lengths. The slope of APD-cycle length curve of HBI-3000 was only slightly steeper than that of control (88.8 ± 7.7 ms/s vs. 78.9 ± 5.2 ms/s in control, n = 8, P > 0.05). HBI-3000 only showed a minimal use-dependent prolongation of the APD in human ventricular myocytes. HBI-3000 inhibited fast sodium current (INa-F), late sodium channel (INa-L), L-type calcium current (ICa-L), and rapidly activating delayed rectifier K current (IKr) in single human ventricular myocytes. The estimated half-maximal inhibitory concentration values of INa-F, INa-L, ICa-L, and IKr were 48.3 ± 3.8, 16.5 ± 1.4, 32.2 ± 2.9, and 22.7 ± 2.5 μM, respectively. The ion channel profile and electrophysiological properties of HBI-3000 are similar to those of ranolazine and chronic amiodarone (reduced INa-F, INa-L, ICa-L, and IKr). HBI-3000 may be a promising antiarrhythmic agent with low proarrhythmic risk.
Guo
Donglin
D
Lankenau Institute for Medical Research & Main Line Health Heart Center, Wynnewood, PA 19096, USA. guod@mlhs.org
Liu
Que
Q
Liu
Tengxian
T
Elliott
Gary
G
Gingras
Mireille
M
Kowey
Peter R
PR
Yan
Gan-Xin
GX
D000083:Acetanilides; D000200:Action Potentials / Q000187:drug effects; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D055724:Electrophysiological Phenomena; D006352:Heart Ventricles / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D032342:Muscle Cells / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D010627:Phenethylamines; D010879:Piperazines; D000069458:Ranolazine; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology; D015222:Sodium Channels / Q000494:pharmacology / Q000502:physiology; D013449:Sulfonamides; D013463:Sulfuric Acid Esters
D000083:Acetanilides; D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D010879:Piperazines; D015222:Sodium Channels; D013449:Sulfonamides; D013463:Sulfuric Acid Esters; C558473:sulcardine sulfate; D012964:Sodium; D000069458:Ranolazine; C063533:dofetilide