The effect of vasoactive intestinal polypeptide (VIP) on uterine smooth muscle electrical and mechanical activity in non-pregnant estradiol-treated rabbits was investigated using in vivo and in vitro methods. The studies were performed on spontaneous, oxytocin-, carbachol-, and prostaglandin-42 alpha-induced activity. VIP had a dose-related inhibitory effect on both myoelectrical and mechanical activity. The concentration needed for 50% inhibition (ID50) was 2 x 10(-10) mol VIP . 1(-1) (in vivo), an 6 x 10(-8) mol VIP . 1(-1) (in vitro). This inhibition was unaffected by the presence of atropine (10(-5) mol . 1(-1)), propranolol (10(-5)), phentolamine (10(-5)), naloxone (10(-5)), apamin (10(-5)), and tetrodotoxin (10(-5)). These findings indicate that VIP may act via a specific receptor on the smooth muscle and supports the hypothesis that VIP may be a neurotransmitter involved in the local nervous control of uterine smooth muscle activity.