The shift to the fetal alpha 3 isoform of Na+, K+ ATPase in cardiac hypertrophy alters ouabain binding and toxicity, potentially explaining variable clinical responses to digitalis.
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May explain variable digitalis responses in hypertrophy; leaves open clinical translation of isoform shifts.
Cardiac adaptation to permanent overload induces several phenotypic changes which finally result in a system which works more economically, together with a slower Vmax. The molecular target of digitalis is the NA+, K+ ATPase, which is a polymorphic molecule. We have recently demonstrated that during cardiac hypertrophy this target is modified and that a shift occurs in the alpha 1 subunit, from the normally present alpha 2 isosubunit to alpha 3, which is a fetal isoform with a lower affinity for sodium and a higher affinity for ouabain. Such a shift explains why, in rat cardiac hypertrophy ouabain is less toxic than normal and is released from its target more slowly. It may also explain at least in part the discrepancies observed in clinical trials on the efficacy of digitalis.
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Charlemagne et al. (1995) studied this question.
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