INHIBITORY TRANSMISSION IN GUINEA-PIG STOMACH MEDIATED BY DISTINCT RECEPTORS FOR PITUITARY ADENYLATE CYCLASE-ACTIVATING PEPTIDE

Previous studies have shown that inhibitory transmission in guinea pig stomach involves an interplay between vasoactive intestinal peptide ( VIP) and nitric oxide (NO). The present study examined the contributio n of pituitary adenylate cyclase-activating peptide (PACAP), a homolog ous peptide present in gastric and intestinal myenteric neurons. VIP, PACAP-27 and PACAP-38 induced concentration-dependent relaxation that was partly inhibited by the antagonists VIP10-28 and PACAP6-38 and the NO synthase inhibitor N-G-nitro-L-arginine (L-NNA). Only relaxation i nduced by PACAP-27 and PACAP-38 was partly inhibited by apamin. Electr ical field stimulation (0.25-16 Hz) induced frequency-dependent relaxa tion and PACAP release (maximum of 35.7 fmol/100 mg-min or 7-fold abov e basal levels). Electrical field stimulation-induced relaxation was p artly inhibited by a combination of selective monoclonal antibodies to PACAP-27 and PACAP-38 (42 +/- 7% at 16 Hz) and by the antagonists VIP 10-28 (29 +/- 9%) and PACAP6-38 (29 +/- 3%). The relaxation was also p artly inhibited by L-NNA (51 +/- 12% at 16 Hz) and apamin (36 +/- 4%). The effects of a combination of apamin and L-NNA were additive, amoun ting to 75 +/- 3% inhibition. The effect of L-NNA reflected inhibition of NO release from nerve terminals, as well as NO generation in muscl e cells by the action of VIP and PACAP; the effect of apamin reflected blockade of the action of PACAP. Thus, inhibitory transmission in gui nea pig gastric fundus represents the combined actions of VIP, PACAP a nd NO released from nerve terminals and NO generated in muscle cells. The postjunctional actions of PACAP are mediated by a VIP/PACAP-II rec eptor and by a PACAP-specific, apamin-sensitive receptor.