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-17 alpha-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, less than 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 3 beta-hydroxy derivative and converted to the more water-soluble 3 beta-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.(ABSTRACT TRUNCATED AT 250 WORDS)