Systemic administration of calmodulin antagonist W-7 or protein kinase A inhibitor H-8 prevents torsade de pointes in rabbits.
BACKGROUND
The ventricular arrhythmia torsade de pointes (TdP) occurs after QT interval prolongation and is associated with sudden cardiac death. The afterdepolarizations that initiate TdP are facilitated by protein kinase A and the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase).


RESULTS
In this study, we evaluated the feasibility of suppression of TdP through systemic therapy with kinase inhibitory agents in an established animal model. Under control conditions, TdP was inducible in 6 of 8 rabbits. CaM kinase blockade with the calmodulin antagonist W-7 reduced TdP in a dose-dependent fashion (4 of 7 inducible at 25 micromol/kg and 1 of 7 inducible at 50 micromol/kg). Increased intracellular Ca(2+) has been implicated in the genesis of afterdepolarizations, but pretreatment with high-dose W-7 did not prevent TdP in response to the L-type Ca(2+) channel agonist BAY K 8644 (300 nmol/kg), suggesting that CaM kinase-independent activation of L-type Ca(2+) current was not affected by W-7. Compared with control animals, W-7 reduced TdP inducibility without shortening the QT interval, increasing heart rate, or reducing the blood pressure. The protein kinase A antagonist H-8 also caused a dose-dependent reduction in TdP inducibility (5 of 6 at 1 micromol/kg, 4 of 6 at 5 micromol/kg, and 0 of 6 at 10 micromol/kg), but unlike W-7, H-8 did so by shortening the QT interval.


CONCLUSIONS
These findings show that the acute systemic application of W-7 and H-8 is hemodynamically tolerated and indicate that kinase inhibition may be a viable antiarrhythmic strategy.
Mazur
A
A
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA.
Roden
D M
DM
Anderson
M E
ME
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000316:Adrenergic alpha-Agonists; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001794:Blood Pressure; D002120:Calcium Channel Agonists; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate; D007546:Isoquinolines / Q000494:pharmacology*; D008133:Long QT Syndrome / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D008729:Methoxamine; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D016171:Torsades de Pointes / Q000188:drug therapy* / Q000201:enzymology / Q000517:prevention & control*
D000316:Adrenergic alpha-Agonists; D000889:Anti-Arrhythmia Agents; D002120:Calcium Channel Agonists; D002147:Calmodulin; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D000644:Quaternary Ammonium Compounds; D013449:Sulfonamides; C017967:W 7; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; C022799:clofilium; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D008729:Methoxamine