Progesterone antagonist mifepristone (RU 486) decreases cardiotoxicity of cocaine

RU 486, a potent progesterone antagonist, was used to determine whether RU 486 blocks the enhanced cardiotoxicity of cocaine mediated by progesterone upon rat papillary muscles. Groups of nonpregnant rats were pretreated with: progesterone for 3 days (n = 12); progesterone + RU 486 for 3 days (n = 12); progesterone for 3 days + single low dose RU 486, progesterone for 3 days + single high dose RU 486, and RU 486 for 3 days (n = 6); or were untreated (n = 12). Papillary muscles from these groups were electrically paced during exposure to cocaine concentrations ranging from 10(-14) M to 10(-3) M. One group (n = 6) was pretreated with RU 486, but not exposed to cocaine. The results showed that all muscles from rats pretreated with RU 486 for 3 days were functional when exposed to cocaine concentrations one to four orders of magnitude higher than tolerated by muscles from untreated or progesterone-treated rats. As indicated by alterations in contraction response patterns, RU 486 treatment for 3 days reversed progesterone-enhanced cardiotoxicity of cocaine. Single low dose and high dose RU 486 administrations also reversed progesterone's effects upon cocaine-induced cardiotoxicity.