Ouabain-induced tachyarrhythmias and cell damage in isolated perfused guinea-pig hearts: I. Protection by propranolol

Abstract

An arrhythmogenic concentration of ouabain (1.37 × 10 −6 m) was added to the media perfusing guinea-pig Langendorff hearts after a 60 min period for establishment of a steady-state. Within 15 min following the addition of ouabain, a significant though transient increase in ventricular cyclic-AMP occurred. The first appearance of electrocardiographic abnormalities occurred at a mean time of +22.6 (±5.1) min following ouabain, a fall in ATP, coronary flow and myocardial oxygen consumption (MVO 2) at +28 min, tachycardia at +33.9 (±6.7) min, and asystole (due to fibrillation) at 42.2 (±2.6) min. When ATP levels, coronary flow and MVO 2 declined, they remained depressed for the duration of the experiments. While these changes were occurring following ouabain, creatine kinase (CK) activity in the coronary effluent began a progressive increase at +45 min, as did lactate dehydrogenase (LDH) at +60 min, indicative of cellular damage. Electron microscopic analysis of tissues exposed to ouabain for 1 h revealed changes in the mitochondria (e.g. swelling, fragmentation or loss of cristae and loss of calcium granules) similar to those seen in anoxia and ischemia. The prior administration of propranolol (3.38 × 10 −6 m) attenuated the rise in creatine kinase activity, and abolished all other effects elicited by ouabain. Neither increasing coronary flow, alpha-adrenergic blockade with phentolamine (1 × 10 −6 m) nor “washing” preparations with drug-free media for 1 h affected the results observed with ouabain. On the basis of these results, we conclude that arrhythmogenic doses of ouabain activate the formation of cyclic-AMP, lending support to the hypothesis that increased levels of the nucleotide may act as a triggering event for the subsequent development of arrhythmias. The sequence of events obtained suggests that arrhythmogenic doses of ouabain produce an oxygen deficit similar to that observed in ischemia, as evidenced by the fall in coronary flow, MVO 2 and ATP, the rise in released LDH and CK, and changes in mitochondrial ultrastructure. This deficit, at least in part, appears to be responsible for the development and maintenance of arrhythmias induced by the concentration of ouabain used in this model.