Combined Sodium and Calcium Channel Blockade in Prevention of Lethal Arrhythmias

Anti-arrhythmic compounds with multiple actions reduce arrhythmic death risk in post–myocardial infarction (MI) patients. Sudden death prevention, however, may rely more on implantable defibrillators than anti-arrhythmic drugs due to ineffective pharmacologic intervention. Widespread use of implantable defibrillators should not obscure the need for development of new anti-arrhythmic drugs. This study tested the hypothesis that combined blockade of INa and ICa(L) prevents ischemia-dependent ventricular fibrillation (VF) in conscious dogs after MI. INa and ICa(L) blockade was accomplished with levosemotiadil in 11 dogs known to be at high risk for VF during 2 min of coronary occlusion during submaximal treadmill exercise 30 days after MI. Negative chronotropic effect of levosemotiadil was examined using the heart rate response to isoproterenol and comparing it with response to propranolol. Levosemotiadil prevented VF in 64% (7 of 11) of the high-risk animals. Heart rate responses to myocardial ischemia and to graded doses of isoproterenol were blunted by the high dose of levosemotiadil. Propranolol prevented VF in 73% (8 of 11) of the dogs. Levosemotiadil had approximately one half the β-blocking activity of propranolol. The combination of INa and ICa(L) channel blockade coupled with partial β-adrenergic blockade was equally effective in preventing VF as propranolol.