[Experimental approaches to determining molecular mechanisms of antiarrhythmic and cardioprotective actions of new compounds]. / Eksperimental'nye podkhody k opredeleniiu molekuliarnykh mekhanizmov antiaritmicheskogo i kardioprotektivnogo deistviia novykh preparatov]

The comparative study of ion homeostatic regulation in the cardiomyocytes in health and in experimental hypoxia showed that the elevated diastolic concentration of free ions of sodium ([Na+]in and calcium ([Ca2+]cyt) in the cardiomyocytic cytoplasm, the lower resting potential of the cell plasma membrane (delta phi n) are major arrhythmogenic agents. The decreased (delta phi n) is mainly defined by lower Na+/K(+)-ATPase activity due to insufficient energy production. The activation of Na+/H(+)-antiport underlies the elevation of [Na+]cyt. The mechanisms responsible for increased [Ca2+]cyt are increased Na/Ca exchange and inhibited Ca-ATPases in the sarcoplasmic reticulum. A test system was developed to choose and study the antiarrhythmic activity of new agents in in vitro experiments by using isolated cardiomyocytes. The screening scheme proposed involves a consecutive evaluation of the effects of chemicals on the changes occurring in the (delta phi n) of cellular Na and Ca exchange. A concept describing the molecular and cellular factors predisposing to cardiac arrhythmias and ischemic alteration is formulated; possible points of application of the cardioprotective and antiarrhythmic agents were identified.