The relationship between Na+, K+-ATPase inhibition and cardiac glycoside-induced arrhythmia in dogs.
In order to determine if there is a relationship between Na+, K+-ATPase inhibition and cardiac glycoside-induced arrhythmia, the time course of the onset and offset of the arrhythmia induced by the semi-synthetic glycoside, actodigin, and the enzyme activity during arrhythmia and following reversion to normal sinus rhythm was studied in the intact, anethetized dog. An infusion of actodigin(AY22,241) at the rate of 0.1 micronmol/kg/min for 30 min induced a severe and persistent arrhythmia within 13.1 +/- 192 min of 9 dogs. Upon termination of the actodigin infusion, the arrhythmia spontaneously converted to sinus rhythm within 17.5 +/- 2.3 min. Left ventricular tissue was taken from dogs sacrificed at the peak of the actodigin-induced arrhythmic periods or from the dogs that were allowed to recover from the actodigin-induced arrhythmia. These samples were homogenized and the membrane-containing fraction was passed through a Millipore filter. The membrane fraction trapped in the filter was then assayed for Na+ + K+ stimulated, Mg2+ dependent ATPase acctivity. The results showed that, in comparison to the time matched control dogs, the cardiac microsomes prepared from the arrhythmic dogs had a markedly reduced Na+, K+-ATPase activity. On the other hand, actodigin-treated dogs that were allowed to recover from the arrhythmic episode had Na+, K+-ATPase activity that was not significantly different from the control values. The amount of 3H-actodigin bound by the cardiac muscle microsomal fraction was also investigated. The microsomes from left ventricle were isolated with a slight modification of the method of Dutta et al. (1968). The microsomal binding of 3H-actodigin was maximum at 30 min (26.6 mol/mg protein) when the sample was prepared from the dogs at the peak of the arrhythmic effect. However, the binding was significantly reduced (11.5pmol/mg protein) in the microsomal fraction from hearts that had returned to sinus rhythm. These data provide direct evidence that inhibition of Na+, K+-ATPase and cardiac glycosideinduced arrhythmia may have some cause and effect relationship.
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000201:enzymology; D002298:Cardenolides / Q000378:metabolism / Q000494:pharmacology*; D004071:Digitalis Glycosides / Q000378:metabolism / Q000494:pharmacology*; D004074:Digitoxin / Q000494:pharmacology; D004285:Dogs; D005260:Female; D049671:History, 18th Century; D008861:Microsomes / Q000201:enzymology; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology* / Q000648:ultrastructure; D011188:Potassium / Q000378:metabolism; D011485:Protein Binding; D012964:Sodium / Q000378:metabolism
D002298:Cardenolides; D004071:Digitalis Glycosides; D012964:Sodium; D004074:Digitoxin; D000251:Adenosine Triphosphatases; D011188:Potassium