title: Calcium antagonist property of CPU228, a dofetilide derivative, contributes to its low incidence of torsades de pointes in rabbits.
abstract: 1. Torsades de pointes (TDP) is a severe adverse effect during the clinical use of dofetilide, a selective blocker of the rapid component of the delayed rectifier potassium channel (I(Kr)). The present study was designed to test whether CPU228, a derivative of dofetilide with calcium (Ca(2+)) antagonist properties, could reduce TDP without reducing the blockade of I(Kr). 2. The incidence of TDP in a rabbit model and the effective refractory period (ERP) were measured and compared for dofetilide and CPU228. Suppression of I(Kr) and the L-type Ca(2+) current (I(Ca,L)) and the Ca(2+) transients of isolated cardiomyocytes were investigated by whole-cell patch-clamp and Fluo-3 dye spectrophotometry. 3. The incidence of TDP was greatly reduced by CPU228 relative to dofetilide, occurring in only one of six rabbits compared with five of six rabbits following dofetilide (P < 0.05). In isolated atria, prolongation of ERP by CPU228 was less than that of dofetilide and no reverse frequency dependence was observed. Negative inotropism by CPU228 was significant against positive inotropism by dofetilide. CPU228 inhibited both I(Kr) and I(Ca,L) currents and the IC(50) for I(Ca,L) inhibition was 0.909 micromol/L. At 3 micromol/L, CPU228 significantly suppressed the Ca(2+) transients. 4. CPU228 is able to block I(Ca,L), contributing to decreased TDP, while also blocking I(Kr) activity. By combined blockade of I(Kr) and I(Ca,L), CPU228 shares the property of complex Class III anti-arrhythmic agents.
authors.affiliation: Research Division of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zhi-Jiang
authors.initials: ZJ
authors.lastname: Huang
authors.forename: De-Zai
authors.initials: DZ
authors.lastname: Dai
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Na
authors.forename: Min
authors.initials: M
authors.lastname: Ji
authors.forename: Yin
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000465:Algorithms; D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008729:Methoxamine / Q000008:administration & dosage / Q000633:toxicity; D015394:Molecular Structure; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology*; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors / Q000502:physiology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: C521406:1-(methanesulfonamido-1-naphthyloxy)-2-(N-(4-methane sulfonamidophenethyl)-N-acetamido)ethane; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D009281:Naphthalenes; D010627:Phenethylamines; D024661:Potassium Channels, Inwardly Rectifying; D013449:Sulfonamides; D008729:Methoxamine; C063533:dofetilide