Mechanisms of Age-Related Differences in the Cardiotoxic Action of Digitalis

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Abstract
Age-associated ouabain sensitivity was investigated in isolated perfused guinea pig heart and the findings were correlated with its receptor function. Ouabain (0.1 .mu.mol/l) produced average positive inotropic responses of 22% in 15-day-old, 25% in 4-6 mo.-old, and 34% in 18-24 mo.-old guinea pig hearts. The time required to produce the greatest positive inotropic response was 28 min in 15-day to 6-mo.-old guinea pig hearts and 20 min in 18-24-mo.-old guinea pig hearts. To cause arrhythmias and cardiac arrest, 2.1 .mu.mol/l ouabain was required in age groups of 15 days to 6 mo., and 1.2 .mu.mol/l in age groups of 12-24 mo. The time of onset of arrhythmias and cardiac arrest was also significantly less in older than in younger animals. Cardiac membranes for 12-24 mo.-old guinea pig hearts had significantly lower Na+, K-ATPase activity per mg of sarcolemmal protein and numbers of [3H]ouabain binding sites than those from 28-day- to 6-mo.-old hearts. The enzyme inhibition by 0.1 .mu.mol/l ouabain was less in younger than in older groups. The difference in the inhibition of enzyme was reflected in lower ouabain binding affinity (Kd) in younger animals. The data confirm the existence of an age-related difference in ouabain sensitivity and suggest that these differences may be due to changes in receptor function.