Roles of PACAP and PHI as inhibitory neurotransmitters in the circular muscle of mouse antrum

Abstract

Mediators of neurogenic responses of the gastric antrum were studied in wild-type and pituitary adenylate cyclase-activating polypeptide (PACAP) -knockout (KO) mice. Electrical field stimulation (EFS) to the circular muscle strips of the wild-type mouse antrum induced a triphasic response; rapid transient relaxation and contraction, and sustained relaxation that was prolonged for an extended period after the end of EFS. The transient relaxation and contraction were completely inhibited by L-nitroarginine and atropine, respectively. The sustained relaxation was significantly inhibited by a PACAP receptor antagonist, PACAP(6-38). The antral strips prepared from PACAP-KO mice unexpectedly exhibited a tri-phasic response. However, the sustained relaxation was decreased to about one-half of that observed in wild-type mice. PACAP(6-38) inhibited EFS-induced sustained relaxation (33.5% of control) in PACAP-KO mice. Anti-peptide histidine isoleucine (PHI) serum partially (the 30% inhibition) or significantly (the 60% inhibition) inhibited the sustained relaxations in the wild-type and PACAP-KO mice, respectively. The immunoreactivities to the anti-PACAP and anti-PHI serums were found in myenteric ganglia of the mouse antrum. These results suggest that nitric oxide and acetylcholine mediate the transient relaxation and contraction, respectively, and that PACAP and PHI separately mediate the sustained relaxation in the antrum of the mouse stomach.

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

“…Besides its effects on the secretory activity of exocrine and endocrine cells, PACAP induces a concentrationdependent relaxation of gastric smooth muscles (Katsoulis et al, 1996;Robberecht et al, 1998;Mukai et al, 2006;Toyoshima et al, 2006), causing a decrease of gastric motility and a delay in stomach emptying (Ozawa et al, 1999). PACAP also exerts a relaxant effect on intestinal smooth muscles from rat (Mungan et al, 1992a;Schwörer et al, 1992;Katsoulis et al, 1993b;Grider et al, 1994;Ekblad and Sundler, 1997;Olsson and Holmgren, 2000), guinea pig (Mungan et al, 1992a;Schwörer et al, 1992;Katsoulis et al, 1993b;Grider et al, 1994;Ekblad and Sundler, 1997;Olsson and Holmgren, 2000) and Atlantic cod, Gadus morhua (Mungan et al, 1992a;Schwörer et al, 1992;Katsoulis et al, 1993b;Grider et al, 1994;Ekblad and Sundler, 1997;Olsson and Holmgren, 2000), thus reducing the motility of the bowel (Lä uff et al, 1999).…”

VIP and PACAP: recent insights into their functions/roles in physiology and disease from molecular and genetic studies

“…PAC KO studies also demonstrated that PACAP is an important neurotransmitter in mediating GI motility [46–48]. Studying PACAP KO mice, PACAP, as well as PHI, were found to function as inhibitory neurotransmitters in the circular muscle of the mouse antrum [46–48].…”

“…Studying PACAP KO mice, PACAP, as well as PHI, were found to function as inhibitory neurotransmitters in the circular muscle of the mouse antrum [46–48]. PHI and PACAP mediated sustained relaxation in the gastric antrum [46,46], and PACAP’s action required the activation of a big conductance calcium-activated K+ (BK) channel [48]. …”

Presence and Effects of Pituitary Adenylate Cyclase Activating Polypeptide Under Physiological and Pathological Conditions in the Stomach

“…The role of endogenous PACAP in the regulation of motility is supported by the inhibition of the sustained relaxation by a PACAP receptor antagonist, PACAP6–38 ( 85 ). Furthermore, muscle strips prepared from PACAP knockout mice showed decreased level of sustained relaxation, which was about one-half of that observed in wild-type mice ( 85 ). PACAP6–38 inhibited electrical field stimulation-induced sustained relaxation (33.5% of control) in PACAP knockout mice.…”