Parallel pathways mediate inhibitory effects of vasoactive intestinal polypeptide and nitric oxide in canine fundus

Abstract

1 The gastric adaptation re¯ex is activated by the release of non-adrenergic, non-cholinergic (NANC) inhibitory transmitters, including nitric oxide (NO) and vasoactive intestinal polypeptide (VIP). The role of NO in this re¯ex is not disputed, but some investigators suggest that NO synthesis is stimulated by VIP in post-junctional cells or in nerve terminals. We investigated whether the e ects of these transmitters are mediated by independent pathways in the canine gastric fundus. 2 VIP and NO produced concentration-dependent relaxation of the canine fundus. N o -nitro-Larginine (L-NNA) reduced relaxation induced by electrical ®eld stimulation (EFS; 0.5 ± 8 Hz), but had no e ect on responses to exogenous VIP and sodium nitroprusside (SNP, 10 mM). 3 Oxyhaemoglobin reduced relaxations produced by EFS and SNP. Oxyhaemoglobin also reduced relaxation responses to low concentrations of VIP (510 nM), but these e ects were non-speci®c and mimicked by methaemoglobin which had no e ect on nitrergic responses. 4 A blocker of guanylyl cyclase, 1H-[1,2,4]oxidiazolo [4,3,-a]quinoxalin-1-one, (ODQ) inhibited responses to EFS, SNP and DETA/NONOate (an NO×donor), but had no e ect on responses to VIP. cis-N-(2-phenylcyclopentil)-azacyclotridec-1en-2-amine monohydrochloride (MDL 12,330A), a blocker of adenylyl cyclase, reduced responses to EFS, VIP and forskolin, but did not a ect responses to SNP. 5 Levels of cyclic GMP were enhanced by the NO donor S-nitroso-n-acetylpenicillamine (SNAP) but were una ected by VIP (1 mM). The increase in cyclic GMP in response to SNAP was blocked by ODQ. 6 The results suggest that at least two transmitters, possibly NO and VIP, mediate relaxation responses in the canine fundus. NO and VIP mediate responses via cyclic GMP-and cyclic AMPdependent mechanisms, respectively. No evidence was found for a serial cascade in which VIP is coupled to NO-dependent responses.

Gastrointestinal Function Regulation by Nitrergic Efferent Nerves

“…Neurogenic relaxation and IJP were reportedly mediated by the neurotransmitter NO in the gastric fundus and pyloric sphincters from the rat (Boeckxstaens et al, 1991a;McLaren et al, 1993;Jenkinson et al, 1995;Curro et al, 1996;Curro and Preziosi, 1998;De Man et al, 1998;Lefebvre, 1998), guinea pig (Kojima et al, 1993), dog (Bayguinov et al, 1999), pig (Colpaert and Lefebvre, 2000), mouse (Selemidis and Cocks, 2000;Suzuki et al, 2000;Ergun and Ogulener, 2001), Japanese monkey (N. Toda, K. Ayajiki, and T. Okamura, unpublished data), and human (Tomita et al, 1999;Tonini et al, 2000). Typical responses to nitrergic nerve stimulation of the isolated monkey pyloric sphincter are shown in Fig.…”

“…From findings that nicotine-induced NANC relaxation in the gastric fundus was reduced by a specific anti-VIP serum and that nicotine increased the outflow of VIP-and histidine isoleucine-like immunoreactivity from the strips, involvement of VIP and possibly histidine isoleucine in the mechanical response was suggested (Curro and Preziosi, 1997). According to Bayguinov et al (1999), the NANC inhibitory neurotransmitters in the gastric fundus are NO and VIP mediating responses via cyclic GMP and cyclic AMP, and there is no evidence supporting a serial cascade in which VIP is coupled to NO-dependent responses. In the proximal colon, the VIP-induced inhibitory response was reportedly induced by stimulation at the high frequency of 20 Hz only when nitrergic and purinergic NANC responses were depressed (Matsuyama et al, 2003).…”

“…A cyclic GMP-dependent mechanism appears to be involved in the nitrergic relaxation of the rat and mouse gastric fundus (Williams and Parsons, 1995;Chang et al, 1998;Bayguinov et al, 1999;Selemidis and Cocks, 2000). Cyclic GMP-dependent protein kinase I apparently plays a key role in the NO/cyclic GMP signaling pathway in the mouse gastric fundus (Ny et al, 2000).…”

Cyclic AMP‐mediated inhibition of gallbladder contractility: role of K+ channel activation and Ca2+ signaling

“…Although it is unclear if gallbladder filling involves passive and/or active mechanisms, the existence of inhibitory innervation (Davison et al, 1978;McKirdy et al, 1994;Chen et al, 1998;Alcon et al, 2001c) provides evidence to support a neurally mediated relaxation in the gallbladder. Cyclic nucleotides are known to act as intracellular mediators of relaxation in gastrointestinal smooth muscle (Jin et al, 1993;Bayguinov et al, 1999). In the gallbladder, cAMP plays a critical role in neurotransmittermediated relaxation.…”

Mechanical activity of frog esophagus muscle in response to electrical stimulation of intramural nerves

“…Nitric oxide (NO) and vasoactive intestinal peptide (VIP) are known as the transmitter substances released from NANC inhibitory nerves (Daniel et al, 1989: Desai et al, 1991: Bayguinov et al, 1999. Further study is required to elucidate the transmitter substances released by NANC excitatory and inhibitory nerves in the smooth muscle of the frog esophagus.…”