To elucidate whether, in principle, motilin could serve a role in LESP regulation, the effects of 13-norleucine-motilin (13-nle-m)-synthetic analogue of motilin and biologically just as active as the natural polypeptide-on LESP were investigated in normal subjects. LESP was monitored with the continual withdrawal method. Sets of tests: (1) i.v. pulse doses of 13-nle-m (0.05, 0.1, 0.2, and 0.4 mug/kg) were given to 6 subjects in random order on different days, (2) i.v. bolus injections of 0.6 mug/kg pentagastrin were given to elicit maximal LES contractions, (3) i.v. infusions of 13-nle-m (0.1, 0.2, and 0.4 mug/kg-h; doses doubling every 30 min) were used in 7 individuals, and (4) the effect of atropine infusion of 13-nle-m-stimulated LESP was studied in 6 subjects. RESULTS (1) Graded i.v. pulse doses of 13-nle-m caused LESP to increase dose-dependently with maximum pressures exceeding basal levels by about 160% (p less than 0.01). After each bolus injection, peak values were achieved within 1-2 min followed by a steady decrease in LESP. (2) Maximum response to 0.4 mug/kg 13-nle-m was about 65% of that to 0.6 mug/kg pentagastrin. (3) i.v. infusions of varying doses of 13-nle-m caused a significant and dose-dependent increase in average LESP. (4) The stimulating effect of an i.v. pulse dose of 0.1 mug/kg 13-nle-m on LESP could be suppressed by concomitant atropine. CONCLUSIONS the human LES is responsive, indeed, to exogenous motilin.