The inhibitory effects of nifedipine, verapamil, cinnarizine (calcium entry blockers), chlorpromazine (a putative calmodulin antagonist) and fenoterol (a beta 2-adrenoceptor agonist) on contractility in human isolated pregnant myometrium were studied. Spontaneous contractions (present in 93% of the preparations) were inhibited in a concentration-related manner by these compounds in the following order of potency: nifedipine greater than verapamil much greater than cinnarizine greater than chlorpromazine. Cinnarizine was effective only at a concentration greater than 100 microM. Fenoterol, at 10 microM, did not produce an inhibitory effect but decreased the frequency of spontaneous contractions. All drugs, except fenoterol, produced a concentration-dependent relaxation of K+-induced contractions in the following order of sensitivity: nifedipine greater than verapamil much greater than chlorpromazine. Cinnarizine produced only about 40% of relaxation. Under these conditions nifedipine and verapamil were about 80 and 5 fold more potent respectively than when tested against spontaneous contractions. The potencies of chlorpromazine and cinnarizine did not differ in the two experimental conditions. Both the spontaneous and K+-induced contractions were inhibited in a time-dependent manner in Ca2+-free media and the responses were almost completely abolished in 70-100 min. Calcium addition to the medium rapidly restored both spontaneous or K+-induced contractions. To investigate further the role of intracellular calcium, K+-depolarized preparations contracted by calcium 3 mM (40-60% of maximal contractions) were relaxed by these compounds. Nifedipine and verapamil showed a relaxation time course similar to that induced by calcium removal. Cinnarizine and fenoterol had no relaxant effect while chlorpromazine induced a slight and slow relaxation. 6 These findings suggest that calcium influx and calmodulin are involved in spontaneous contractions of pregnant human myometrium in vitro. Since nifedipine and verapamil were more potent against K+-induced than spontaneous contractions, calcium channels activated by these conditions could be different. Finally, fenoterol, a beta 2-adrenoceptor agonist, widely used as a tocolytic agent, blocked neither spontaneous nor K+-induced contractions.