The present study was designed to determine the mechanism(s) underlying the excitatory effects of several sulfidopeptide leukotrienes (LTs) on the muscularis mucosae in three regions of the rabbit colon. Proximal colonic muscularis mucosae was refractory to LTs C4, D4, and E4. In addition, it exhibited no responses to prostaglandin (PG) E2 and only a minimal contractile response to PGF2 alpha. Mid and distal colonic muscularis mucosae each responded to LTs C4, D4, and E4 and PGs E2 and F2 alpha with concentration-dependent contractions. In both regions, responses to LTD4 and LTE4 were abolished by indomethacin (10(-6) M) pretreatment. LTC4-induced responses were reduced approximately 50% by this procedure. The residual contraction to LTC4 was resistant to both tetrodotoxin (10(-6) M) and atropine (10(-6) M). In separate experiments, responses to LTC4 were also reduced by approximately 50% if LTC4 conversion to LTD4 and LTE4 was first prevented by L-serine borate (45 mM) in combination with L-cysteine (10 mM). It is concluded that proximal colonic muscularis mucosae lacks the appropriate functional excitatory LT and PG receptors. On mid and distal colonic muscularis mucosae, the actions of LTD4 and LTE4 and, in part, LTC4 are the result of PG production, whereas LTC4 has an additional direct action, possibly mediated through a selective LTC4 receptor.