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)
D000818:Animals; D002715:Chlormadinone Acetate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D010042:Ouabain / Q000031:analogs & derivatives / Q000494:pharmacology; D011374:Progesterone / Q000031:analogs & derivatives*; D011868:Radioisotopes; D011955:Receptors, Drug / Q000378:metabolism*; D012413:Rubidium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase
D011868:Radioisotopes; D011955:Receptors, Drug; C027082:digitalis receptor; D002715:Chlormadinone Acetate; D011374:Progesterone; D010042:Ouabain; C043235:chlormadinone-17-acetate 3 beta-hemisuccinate; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D012413:Rubidium; C008721:ouabagenin