THE ANTIARRHYTHMIC PROPERTIES OF ICI 46037, A QUATERNARY ANALOG OF PROPRANOLOL

¹ University of Michigan Medical School, Department of Pharmacology, Ann Arbor, Michigan

A quaternary analog of propranolol, ICI 46037 (1-(3-diethylmethylammonium-2-hydroxy-n-propoxy) naphthalene iodide), was evaluated for its antiarrhythmic effects upon several experimentally induced cardiac arrhythmias. Studies using the isolated perfused rabbit heart and the anesthetized dog demonstrated the drug to be effective in preventing or reversing arrhythmias resulting from acetylstrophanthidin or ouabain. The effective concentration in the perfused heart was 1 X 10^-4M whereas the antiarrhythmic dose in the dog averaged 3.26 mg/kg. Arrhythmias resulting from the combined administration of halothane and epinephrine were not prevented by ICI 46037 given in a dose of 5 mg/kg. The latter arrhythmia was prevented by previous pretreatment with propranolol, 0.5 mg/kg. Spontaneous ventricular arrhythmias and epinephrine-induced arrhythmias after coronary artery ligation in the dog were uninfluenced by ICI 46037. Inotropic dose-response curves to isoproterenol demonstrated an inability to produce beta receptor blockade in atrial strips at a concentration of 1 X 10^-5 M or in the dog at a dose of 5 mg/kg. ICI 46037, 10^-5 M, blocked nerve impulse transmission in the sciatic nerve trunk. The results demonstrate that a quaternary compound can possess antiarrhythmic properties and suggest that ICI 46037, being devoid of beta adrenergic blocking actions, might possess advantages over dl-pro-pranolol in reversing digitalis-induced arrhythmias. The antiarrhythmic action may be the result of a membrane-stabilizing effect which in turn is related to the local anesthetic activity of ICI 46037.