Suppression of positive inotropic and toxic effects of cardiac glycosides by amiloride.
Effects of amiloride on the inotropic and toxic actions of cardiac glycosides were examined using left atrial muscle isolated from guinea pig heart. Preincubation of atrial muscle with amiloride significantly decreased the maximum positive inotropic effect of dihydrodigoxin but failed to reduce that of isoproterenol. Amiloride prevented the contracture and significantly reduced the incidence of arrhythmias induced by 2 microM digoxin. Similar experiments examining 5 microM digoxin-induced arrhythmias showed that amiloride increased both the time required to produce arrhythmias and the fractional occupancy of sarcolemmal Na,K-ATPase by digoxin at the onset of arrhythmias. The antagonism of cardiac glycoside actions was best observed during the decline in developed tension elicited by amiloride subsequent to its initial positive inotropic effect. Amiloride had no effect on binding site concentration for ATP-dependent [3H]ouabain binding but decreased affinity of the binding sites for ouabain in membrane preparations obtained from guinea pig heart. Furthermore, amiloride inhibited Na,K-ATPase activity and increased the IC50 value for ouabain inhibition of the enzyme. These results indicate that amiloride antagonizes the positive inotropic and toxic effects of cardiac glycosides. Possible mechanisms for the antagonism include inhibition of sarcolemmal Na+/Ca2+ or Na+/H+ exchange.
D000584:Amiloride / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001667:Binding, Competitive / Q000187:drug effects; D002301:Cardiac Glycosides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004077:Digoxin / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010042:Ouabain / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013997:Time Factors
D002301:Cardiac Glycosides; D011955:Receptors, Drug; C028996:cardiac glycoside receptors; D010042:Ouabain; D004077:Digoxin; D000584:Amiloride; D000254:Sodium-Potassium-Exchanging ATPase