Vasoactive intestinal peptide receptor subtypes and signalling pathways involved in relaxation of human stomach

Abstract

Vasoactive intestinal peptide (VIP) relaxes smooth muscle by interacting with receptors coupled to cAMP- or cGMP-signalling pathways. Their relative contribution to human gastric relaxation is unknown. This study aimed at investigating, in terms of biological activity, receptor expression and related signalling pathways, the action of VIP separately on the human fundus and the antrum. VIP caused greater relaxation of smooth muscle cells (SMC) and strips of the antrum presenting on the former a higher efficacy and potency (ED(50): 0.53 +/- 0.17 nmol L(-1)) than on the fundus (ED(50): 3.4 +/- 1.4 nmol L(-1)). On both fundus and antrum strips, its effect was tetrodotoxin insentitive. Reverse transcriptase-polymerase chain reaction analysis showed the sole expression of VPAC2 and natriuretic peptide clearance receptors, with VPAC2 being more abundant in the antrum. Functional regional differences in receptor-related signalling pathways were found. Activation of the cAMP-pathway by forskolin or its inhibition by adenylate cyclase (2'5'-dideoxyadenosine) or kinase (Rp-cAMPs) inhibitors had more pronounced effects on antrum SMC. Activation of the cGMP-pathway by sodium nitroprusside or its inhibition by guanylate cyclase (LY83583) or kinase (KT5823) inhibitors had more effects on fundus SMC, on which a higher expression of endothelial nitric oxide synthase was found. In conclusion, regional differences in VIP action on human stomach are related to distinct myogenic properties of SMC of the antrum and the fundus.

Relaxation Patterns of Human Gastric Corporal Smooth Muscle by Cyclic Nucleotides Producing Agents

“…Most mechanical and electrical properties in human GI tract have been investigated using electrogastrograph (EGG) and ultrasonography (Hocke et al, 2009;Matsumoto et al, 2009), although several in vitro GI motility studies have been reported (Tonini et al, 2000;Farrelly et al, 2003;Severi et al, 2006;Wang et al, 2007). In this in vitro study, we first characterized mechanical properties.…”

“…Phasic component was blocked by 1 μM nifedipine (data not shown), however, ACh-induced sustained tonic contraction was partially inhibited: 55% and 58% of the control by 1 and 2 μM nifedipine, respectively. Many studies have suggested ISO and vasoactive intestinal peptide (VIP) as mediators of relaxation in several types of smooth muscle (Schultz et al, 1977;Jin et al, 1993;Smith et al, 1993;Severi et al, 2006). β-Adrenergic nerve and VIP containing neurons in myenteric plexus, which project to the smooth muscle layers, have been reported to exist in the gut, and their stimulation inhibits slow wave and contraction via increasing cAMP and/or cGMP (Andersson and Nilsson, 1972;Jin et al, 1993;Smith et al, 1993).…”

“…In general, GI motility is regulated by various intrinsic and/or extrinsic factors of neurohormones. Among these factors, muscarinic cholinergic contraction and β-adrenergic relaxation as well as production of nitric oxide (NO) are well known (Schultz et al, 1977;Ozaki et al, 1992;Jin et al, 1993;Smith et al, 1993;Severi et al, 2006). Isoproterenol (ISO) and nitric oxide (NO) produce membrane hyperpolarization, decrease slow wave, and then inhibit contraction via activation of adenylate and guanylate cyclase in GI tract (Ozaki et al, 1992;Jin et al, 1993;Smith et al, 1993;Severi et al, 2006).…”

“…Especially, NO is recognized as a neurotransmitter of nonadrenergic non-cholinergic (NANC) nerves in the myenteric plexus throughout the GI tract and is responsible for gastric receptive relaxation (Ozaki et al, 1992;Jin et al, 1993;Smith et al, 1993;Tonini et al, 2000). In addition, sodium nitroprusside (SNP), known NO-releasing compound, is reported to stimulate guanylate cyclase and then increase intracellular guanosine 3',5'-cyclic monophosphate (cGMP) levels, while forskolin (FSK) to stimulate adenylate cyclase and then adenosine 3',5'-cyclic monophosphate (cAMP) levels in many smooth muscles, including GI tract (Katsuki et al, 1977;Huizinga et al, 1991;Ozaki et al, 1992;Jin et al, 1993;Smith et al, 1993;Severi et al, 2006). Therefore, the resultant activation of cAMP-dependent protein kinase A (PKA) and cGMP-dependent protein kinase G (PKG) seems to be linked to the inhibitory effects of FSK, ISO and SNP (Schultz et al, 1977;Jin et al, 1993;Smith et al, 1993).…”

“…Among these factors, muscarinic cholinergic contraction and β-adrenergic relaxation as well as production of nitric oxide (NO) are well known (Schultz et al, 1977;Ozaki et al, 1992;Jin et al, 1993;Smith et al, 1993;Severi et al, 2006). Isoproterenol (ISO) and nitric oxide (NO) produce membrane hyperpolarization, decrease slow wave, and then inhibit contraction via activation of adenylate and guanylate cyclase in GI tract (Ozaki et al, 1992;Jin et al, 1993;Smith et al, 1993;Severi et al, 2006). Especially, NO is recognized as a neurotransmitter of nonadrenergic non-cholinergic (NANC) nerves in the myenteric plexus throughout the GI tract and is responsible for gastric receptive relaxation (Ozaki et al, 1992;Jin et al, 1993;Smith et al, 1993;Tonini et al, 2000).…”