The study of antiarrhythmic activity of some derivatives of 7-alkyl-8-piperazine-3-methylxanthine

Abstract

Some of appropriate 7-alkyl-8-piperazine derivatives of 3-methylxanthine were tested for their effect oncirculatory system, protection against adrenaline-, strophanthin-, and calcium chloride-induced arrhythmias, as wellascatecholamine metabolism in the heart of experimental animals. The most prominent antiarrhythmicactivity in this row was demonstrated by7-isopropyl-8-piperazine-3methylxanthine (compound 3) that in a conditional therapeutic dose of 13.7mg/kg prevented or decreased the incidence of adrenaline, strophanthine and calcium chloride evoked arrhythmias. In adrenaline and calcium-evoked model of arrhythmia compound 3decreased or delayed the incidence of arrhythmias by 37% and 55.7% respectively, as well as episodes and severity of extrasystoles by 37%, efficiently prevented bigeminy (70%, p < 0.01) and diminished (42.8%, p<0.05) mortality of animals. Some of investigated compounds (2-5) decreased heart rate by 10-18%, prolonged P-Q section, QRS complex and Q-T interval. 34 Iryna B. Samura et al. The most potent and significant negative chronotropic effect and markedly prolonged duration of P-Q section was demonstrated by compound 3. Theinfluence of investigated compounds on ECG components suggests that activity of compound 3 is similar to class 1A antiarrhythmic agents according to VoughanWilliams classification of antiarrhythmic drugs, because of prolongation of P-Q and Q-T intervals and extension of QRS complex. Compounds 3in a dose of 13.7 mg/kg within 0.5 h after intraperitoneal administration showed to protect against CaCl2-induced abnormalities in the metabolism of catecholamines–decarboxylation of 3,4-dihydroxyphenylalanine (DOPA) and methylation of norepinephrine. The mechanism of antiarrhythmic action of compound 3is most likely to include blockade of sodium channels of the conducting system of the heart, consequent indirect suppression of potassium ion exit from the cell as well as normalization of heart tissue catecholamines and their precursors content, along with the interference in the activity of the enzyme systems participating in the biotransformation of catecholamines.