Progesterone derivatives that bind to the digitalis receptor: effects on 86Rb uptake and contractility in the isolated guinea pig heart

Chlormadinone acetate, 6-chloro-4,6-pregnadien-17α-ol-3,20-dione 17-acetate (CMA), a progestin that binds to the cardiac glycoside (CG) receptor, inhibits 86Rb uptake in slices of the guinea pig heart (Langendorff preparation), previously perfused with the steroid in Krebs – Henseleit – bicarbonate with or without 0.125% serum albumin. CMA consistently inhibits 86Rb uptake at low concentrations, < 10−8 M, is more potent than ouabain in this regard, and at these concentrations usually does not affect contractility, although occasional instances of transient positive inotropy occur. At higher concentrations, (10−7 and 10−6 M) uptake of 86Rb by CMA is depressed further and is usually accompanied by diminished contractile force. CMA was reduced to the 3β-hydroxy derivative and converted to the more water-soluble 3β-hemisuccinate (CMA-S). Occasional positive, although transient, increases in contractile force were elicited by CMA-S, but cardiac depression predominated, and higher concentrations induced cardiotoxicity. The addition of 10−7 to 10−6 M CMA-S to perfusion medium containing a cardiostimulant concentration (10−6 M) of ouabagenin resulted in depression of contractility. We propose several alternative hypotheses to explain our results: (a) CMA and CG compete for the same receptor site (Na+–K+ ATPase) and both drugs inhibit the enzyme; only the CG-induced conformation of the receptor is coupled to the mechanism responsible for positive inotropy; (b) CMA and CG compete for sites coupled to both pump inhibition and positive inotropy, but CMA, additionally, has effects on the cardiac cell that antagonize positive inotropy; the often described depressant action of progesterone on cardiac tissue may reside, as well, in CMA and might counteract to a variable extent any inherent positive inotropic action; (c) both CMA and CG inhibit the pump; only CG interacts with an additional site linked to positive inotropy and this action is antagonized by CMA; and (d) occasional transient increases but more frequent depression in contractile force elicited by the progesterone derivatives, the depression of contractility by low concentrations of CG, and the apparent pump stimulation by low concentrations of both classes of compounds reflect the differing affinities of CMA, CMA-S, and individual CGs for receptor sites mediating pump inhibition, positive inotropy, and negative inotropy.