Pirenzepine is an antisecretory anticholinergic type drug that has recently been shown to be relatively free of usual anticholinergic side effects on esophageal smooth muscle. It has also been suggested that this drug might release some of the inhibitory control of the esophagus and allow increased muscle contractions. To test this hypothesis, we compared the response of the lower esophageal sphincter (LES) and esophageal peristaltic contractions to bethanechol in 12 healthy controls after background oral doses of placebo, pirenzepine (50 mg), and propantheline (30 mg). After baseline placebo, bethanechol (40 micrograms/kg subcutaneously) produced the expected significant increases in LES pressure and amplitude of peristaltic contractions. Maximal increases were 51.9 +/- 14.9 and 29.5 +/- 7.0%, respectively. Also as expected, propantheline inhibited the cholinergic stimulation from bethanechol, allowing only a 10.1 +/- 13.6% increase in LES pressure and a decrease in peristaltic contraction amplitudes (-44.1 +/- 5.0%) after bethanechol. After background pirenzepine, the responses to bethanechol were intermediate between the other two drugs. A significant increase (44.2 +/- 16.4%) in LES pressure occurred after bethanechol while no significant changes (6.9 +/- 5.8%) were noted in peristaltic amplitudes with this drug. Typical side effects of dry mouth were noted in six of the 12 subjects with propantheline and in only three subjects after pirenzepine. These studies once again confirm the absence of usual anticholinergic side effects with oral pirenzepine compared to oral propantheline in the doses studied. We could find no evidence for a release of cholinergic inhibition after pirenzepine administration.