Contraction dynamics of isolated papillary heart muscles from nonpregnant, pregnant, and progesterone-treated nonpregnant Long Evans rats were studied during exposure to cocaine. With increasing cocaine concentrations from 10(-16) to 10(-4) M, papillary muscles from nonpregnant rats demonstrated a biphasic pattern of positive, then negative, inotropy. Only negative inotropy with increasing cocaine concentrations was observed in papillary muscles from pregnant and progesterone-treated nonpregnant rats. Papillary muscles from pregnant and progesterone-treated nonpregnant rats became nonfunctional at cocaine concentrations 1-4 orders of magnitude lower than those for nonpregnant rats. These findings demonstrate that pregnancy and progesterone treatment alter cocaine effects upon cardiac papillary muscle function and response patterns and shift the cocaine dose-function curve to the left when compared to the nonpregnant group. We conclude that pregnancy increases the direct cardiotoxicity to cocaine, and progesterone may be responsible for this enhanced cocaine toxicity.