Mechanism of cardiac glycoside-induced toxicity: physiology, biochemistry, and electron microscopy.
The addition of an arrhythmogenic concentration of ouabain (1.37 X 10(-6) M) results in a number of physiological, biochemical, and ultrastructural changes in isolated perfused guinea pig (Langendorff) heart preparations. Chronologically the following alterations occurred: first, a transient rise in ventricular cyclic AMP followed by a reduction in ventricular ATP, relatively minor electrocardiograph abnormalities (e.g., occasional missed beats, transient episodes of tachycardia, and occasional premature ventricular contractions), and a significant decline in coronary flow. A short time later, preparations became tachycardic and within 10 min asystole supervened. Simultaneously with the occurrence of tachyarrhythmias, there was a significant increase in the release of creatine kinase and lactate dehydrogenase into the coronary effluent. Ultrastructural analysis of the ventricular endocardium revealed marked alterations in the mitochondria, disappearance of cytosolic glycogen granules, and chromatin clumping in the nuclei. Pretreatment with d,l-propranolol (3.38 X 10(-6) M) 15 min before ouabain abolished alterations caused by ouabain alone. Studies where ouabain-treated hearts were paced or coronary flow maintained suggest that changes in neither heart rate nor coronary flow are responsible for the protective action of propranolol. Results obtained indicate that ouabain-induced toxicity may in part result from an increase in coronary resistance producing myocardial hypoxia, cell damage, and arrhythmias. Preliminary studies suggest that the membrane-stabilizing action of propranolol appears to be the basis of its protective effect.
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D002301:Cardiac Glycosides / Q000633:toxicity*; D003326:Coronary Circulation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D004562:Electrocardiography; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D008854:Microscopy, Electron; D009206:Myocardium / Q000378:metabolism; D010042:Ouabain / Q000633:toxicity; D011433:Propranolol / Q000494:pharmacology
D002301:Cardiac Glycosides; D010042:Ouabain; D011433:Propranolol; D000242:Cyclic AMP