14 beta-Hydroxyprogesterone binds to the digitalis receptor, inhibits the sodium pump and enhances cardiac contractility.
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 14 beta-hydroxy substituent is an important determinant of activity of the cardiotonic cardiac glycosides, we synthesized 14 beta-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, 14 beta-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.
Bose
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Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Canada.
Elliott
D
D
Kobayashi
T
T
Templeton
J F
JF
Kumar
V P
VP
LaBella
F S
FS
D000328:Adult; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D004285:Dogs; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D006908:Hydroxyprogesterones / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008027:Light; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D010042:Ouabain / Q000378:metabolism; D011169:Portal Vein / Q000187:drug effects; D011188:Potassium / Q000494:pharmacology; D011955:Receptors, Drug / Q000378:metabolism*; D012414:Rubidium Radioisotopes; D012542:Scattering, Radiation; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase
D006908:Hydroxyprogesterones; D011955:Receptors, Drug; D012414:Rubidium Radioisotopes; C027082:digitalis receptor; C053404:14-hydroxyprogesterone; D010042:Ouabain; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D011188:Potassium