14β‐Hydroxyprogesterone binds to the digitalis receptor, inhibits the sodium pump and enhances cardiac contractility

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Abstract
1 Certain derivatives of progesterone are potent inhibitors of high affinity, specific binding of 3H-cardiac glycosides. The steroids interact at the cardiac glycoside site on Na,K-ATPase and inhibit the enzyme (the sodium pump) in cardiac and other tissues. However, the active congeners identified previously have been, unlike the cardiac glycosides, predominantly cardiodepressant. 2 Because a 14β-hydroxy substituent is an important determinant of activity of the cardiotonic cardiac glycosides, we synthesized 14β-hydroxyprogesterone. This derivative has about one-tenth the potency of the aglycone, ouabagenin, in a [3H]-ouabain binding assay. 3 Like ouabagenin, but in contrast to the cardiodepressant congeners of progesterone, 14β-hydroxyprogesterone consistently elicited positive inotropy in isolated cardiac muscle and enhanced both the magnitude and frequency of fluctuations in scattered light (an index of oscillatory intracellular release of calcium). 4 Thus, at least one hydroxylated derivative (and putative endogenous metabolite) of progesterone, mimics the cardiac effects of cardiac glycosides including enhanced contractility.