Progesterone increases cardiovascular toxicity to cocaine in nonpregnant ewes

Cocaine produces a greater hypertensive response in pregnant ewes than in nonpregnant ewes. To determine whether pregnancy-related progesterone levels augmented this cocaine response, six nonpregnant ewes were surgically oophorectomized, implanted with femoral artery and vein catheters, and later administered progesterone 10 mg/kg intramuscularly for 3 days. Consistent responses in blood pressure and heart rate to intravenous norepinephrine 0.4 and 0.6 microgram/kg, before and during progesterone treatment, indicated that progesterone did not increase alpha-adrenergic receptor sensitivity to exogenous norepinephrine. In contrast, intravenous cocaine at either 1.0 or 2.0 mg/kg produced approximately twofold greater increases in blood pressure and threefold greater increases in heart rate during each day of progesterone treatment when compared with responses to the same dose of cocaine before progesterone treatment. These results indicate that progesterone enhances the cardiovascular response to cocaine and does not involve an increase in alpha-adrenergic receptor sensitivity.