Method for the production of severe ventricular dysrhythmias in small laboratory animals.
In earlier reports from this laboratory, it was shown that 3 weeks' pretreatment with desoxycorticosterone acetate (DCA) pellet implantation and saline as drinking fluid caused a nearly 20,000-fold potentiation of the acute cardiotoxicity of isoproterenol. In such animals, the beta-receptor stimulant consistently elicited severe ventricular dysrhythmias, usually leading to ventricular fibrillation (VF) and death. In the present study, a similar enhancement of isoproterenol arrhythmogenic activity after DCA-saline pretreatment was demonstrated also in the guinea pig and albino mouse. It was found, further, that isoproterenol consistently caused an alteration of the total myocardial electrolyte content in DCA-saline-treated rats, consisting of a decrease of magnesium (Mg) and potassium (K) levels and elevation of sodium (Na). In control rats, on the other hand, isoproterenol did not alter the myocardial Mg content and increased K. The emertence of cardiac irregularities and VF could be inhibited by pretreatment with antiarrhythmic drugs. On a molar basis, these agents decreased the incidence of VF in the following descending order: dl-propranolol (100), practolol (39), d-propranolol (34), sotalol (20), quinidine (8), and lidocaine (5). In the presence of any of the listed drugs, except for lidocaine, isoproterenol did not lower Mg levels and had variable effects on those of Na and K. Pretreatment with Mg gluconate was likewise effective in preventing isoproterenol-induced dysrhythmias and death. These findings demonstrate that: a) sensitization of the myocardium by DCA-saline treatment is not species-specific for the rat; b) this phenomenon can be a useful method for the screening of antiarrhythmic drugs; and c) isoproterenol-induced dysrhythmias may be associated with myocardial electrolyte alterations involving especially Mg depletion.
D000818:Animals; D000830:Animals, Laboratory; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000188:drug therapy / Q000401:mortality; D003900:Desoxycorticosterone / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D004562:Electrocardiography; D004573:Electrolytes / Q000378:metabolism; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects; D007545:Isoproterenol; D008274:Magnesium / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D011433:Propranolol / Q000627:therapeutic use; D051381:Rats; D012965:Sodium Chloride / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000517:prevention & control
D000889:Anti-Arrhythmia Agents; D004573:Electrolytes; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D011433:Propranolol; D008274:Magnesium; D007545:Isoproterenol