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 I(Na) and I(Ca(L)) prevents ischemia-dependent ventricular fibrillation (VF) in conscious dogs after MI. I(Na) and I(Ca(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 beta-blocking activity of propranolol. The combination of I(Na) and I(Ca(L)) channel blockade coupled with partial beta-adrenergic blockade was equally effective in preventing VF as propranolol.
Adamson
Philip B
PB
Department of Physiology, Cardiovascular Diseases Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. philip-adamson@ouhsc.edu
Vanoli
Emilio
E
Shibano
Toshiro
T
Foreman
Robert D
RD
Schwartz
Peter J
PJ
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control*; D003864:Depression, Chemical; D004285:Dogs; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006339:Heart Rate / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D009203:Myocardial Infarction / Q000150:complications; D010805:Physical Conditioning, Animal; D011433:Propranolol / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000209:etiology / Q000401:mortality / Q000517:prevention & control*
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D026941:Sodium Channel Blockers; D013844:Thiazoles; D011433:Propranolol; C064356:sesamodil; D007545:Isoproterenol