Cocaine use in pregnancy is associated with a premature labor rate as high as 50%, but little is known about its effect on uterine contractility. To determine whether cocaine directly augments pregnant uterus contractility, uterine strips from 27-day pregnant New Zealand White rabbits (term, 31 days) were exposed to cocaine alone (30 mumol/L) or cocaine plus epinephrine (10(-9) to 10(-5) mol/L) or oxytocin (10(-10) to 10(-6) mol/L). Cocaine alone produced no contractions, but increased the epinephrine sensitivity by 51% and the maximal response by 33%. When beta-adrenoceptors were blocked with DL-propranolol (2 mumol/L), the contractile response to epinephrine was increased, and cocaine's effect was blocked. In the presence of the stereoisomer D-propranolol (2 mumol/L) with no beta-adrenergic antagonist activity, the contractile response to epinephrine was unchanged, but the effect of cocaine was still blocked. We conclude that cocaine directly augments the alpha-adrenergic contractile response of the pregnant rabbit uterus by a mechanism that is blocked by the non-beta-adrenergic effects of propranolol.