Effects of sarcolemmal Ca(2+) entry, ryanodine function, and kinase inhibitors on a rabbit model of heart failure.
QT prolongation may increase the risk of torsades de pointes (TdP). Early afterdepolarizations (EADs) and transmural dispersion of repolarization have been known to serve as physiological substrates and predictors for TdP. Abnormal Ca(2+) cycling is the proximate cause of EADs, and Ca(2+) cycling is abnormal in heart failure (HF). However, the mechanisms for drug-induced TdP in HF are poorly understood. The purpose of this study was to search for torsadogenic-modifying effects of verapamil, ryanodine, KB-R7943, W-7, KN-93, and H-8 on ventricular premature depolarizations (VPD) and TdP in rabbits with HF. Rabbits with HF were pretreated with propranolol followed by test articles before continuous infusion of dofetilide to induce TdP. In the control hearts, VPD and TdP were induced in all rabbits and the onsets of VPD and TdP were 3.6 +/- 1.3 minutes and 10.3 +/- 1.4 minutes, respectively. Dofetilide lengthened RR, QT and QTc. Verapamil, ryanodine and H-8 significantly delayed onset of VPD (P < 0.05) and suppressed TdP (P < 0.01). KB-R7943, W-7, and KN-93 accelerated onset of TdP. Blockades of L-type Ca(2+) channel, ryanodine channel, and protein kinase A prevent dofetilide-induced TdP, suggesting roles for intracellular Ca(2+) overload and Ca(2+) signaling pathways in drug-induced TdP.
Kijtawornrat
Anusak
A
Department of Veterinary Biosciences, The Ohio State University, USA.
Ziolo
Mark T
MT
Nishijima
Yoshinori
Y
Roche
Brian M
BM
Hamlin
Robert L
RL
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001596:Benzylamines / Q000627:therapeutic use; D004195:Disease Models, Animal; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology* / Q000628:therapy; D007546:Isoquinolines / Q000627:therapeutic use; D008297:Male; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011817:Rabbits; D012433:Ryanodine / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use; D013890:Thiourea / Q000031:analogs & derivatives / Q000627:therapeutic use; D016171:Torsades de Pointes / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D018879:Ventricular Premature Complexes / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D014700:Verapamil / Q000627:therapeutic use*; D000096926:Benzenesulfonamides
D000889:Anti-Arrhythmia Agents; D001596:Benzylamines; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D012433:Ryanodine; D013449:Sulfonamides; D013890:Thiourea; D014700:Verapamil; C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; C072105:KN 93; D000096926:Benzenesulfonamides; C017967:W 7; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide