What is the role of nitric oxide on the pyloric tone and gastric emptying?
M. Anvari (Hamilton)
Non adrenergic-non cholinergic (NANC) nerves are present throughout the gastrointestinal tract but the transmitters responsible for their action have not been identified with certainty. In sphincteric regions, this NANC innervation is mostly inhibitory and is considered to be of physiological importance for the relaxation of sphincters and of pathophysiological importance by its absence in diseases like achalasia [1, 2].
Recent studies have shown that the enzyme, nitric oxide synthase (NOS) which synthesizes NO, is present in the enteric nervous system where it has been proposed as a putative NANC mediator [3-10].
Evidence that the pylorus plays an important role in control of gastric emptying has accumulated recently [11-13]. Understanding the neurochemical control of this sphincter can be used to clinical advantage in patients who suffer from abnormal gastric emptying and is related symptoms.
There have been a number of in vivo models with anesthetized animals which have examined pyloric motor activity in response to intra-arterial and intravenous stimuli, as well as stimulation of extrinsic and intrinsic nerves [14-17]. Using these models investigators have demonstrated that the canine pyloric muscle possesses a potent NANC inhibitory innervation in vivo [14] and in vitro [1, 15]. This inhibitory innervation could be activated by electrical stimulation of either the distal antrum or the cervical vagus. Vasoactive intestinal peptide (VIP) mimicked this inhibitory response in the canine pylorus in vivo. However, VIP was only minimally effective in vitro although a clear NANC inhibitory response was present, suggesting that the NANC response in the canine pylorus involved another mechanism besides VIP. Inhibition of NOS inhibited this NANC inhibition [17]. In this study, pyloric activity induced by duodenal field stimulation was inhibited by antral field stimulation and electrical vagal stimulation. Intra-arterial L-NG-arginine-methyl-ester (L-NAME), a substance known to inhibit the generation of NO from L-arginine, reduced the inhibition from antral or vagal stimulation. Intravenous infusion of L-NAME also blocked the inhibitory effect of vagal and antral stimulation, but left the tetrodotoxin-insensitive action of intra-arterial VIP and sodium nitroprusside unchanged. L-arginine reversed the effect of L-NAME whereas D-arginine did not. L-NAME enhanced pyloric contractions to intra-arterial acetylcholine. In vitro the NANC inhibition of the substance P-stimulated pyloric response was blocked by L-NAME and reversed by addition of L-arginine [15]. Sodium nitroprusside was an effective relaxant in vitro but VIP was not. Thus, NO is the putative NANC inhibitory neurotransmitter at the pylorus, but the only study which has examined the effect of NO related compounds in gastric function in conscious animals or in humans did not evaluate pyloric function directly [18].
In order to assess the physiological relevance of NO pathways in control of gastric emptying, its sites of action in control of transpyloric flow were recently investigated in 6 conscious dogs. Antropyloroduodenal motility was measured with a seven-lumen sleeve/sidehole catheter during concurrent measurements of transpyloric flow and gastric emptying for 30 min after instillation of 500 ml of saline into the stomach. Intravenous L-NNA (5 mg/kg) was used to block NO synthesis (Figure 1).
Infusion of L-NNA was associated with retardation of gastric emptying (65 ± 6%) in the 30 min period, in comparison to the saline controls (90 ± 3%) or L-arginine (90 ± 2%). This effect was prevented by infusion of L-arginine prior to L-NNA, after which 89 ± 3% of the liquid emptied in 30 min. Under each condition, most of the liquid meal emptied in the first 10 minutes. During this period, there was a significant difference (p < 0.05) in the number and volume of flow pulses (Figure 2), and the pyloric tone (p < 0.05) (Table I) after L-NNA infusion in comparison to the other three test conditions. There were no differences, however, in the number of antropyloric pressure waves, or isolated pyloric pressure waves under the four conditions (Table I). These findings suggest that NO mechanisms influence gastric emptying and transpyloric flow of non-nutrient liquids by altering the pyloric tone, thus increasing resistance to flow.
Figure 1. Gastric emptying of 500 ml saline under four test conditions.
Figure 2. Frequency and mean volume of transpyloric flow pulses in the first 10 minutes after instillation of 500 ml saline into the stomach.
Further more, NO mechanisms can alter gastric emptying through alteration in fundic tone. In another set of experiments using a similar conscious dog model, administration of L-NNA (10 mg/kg) resulted in increased fundic tone measured by an electronic barostat [19]. The L-NNA effects on fundic tone were blocked by both vagal blockade and atropine, but not by hexamethonium. This suggests that NO plays a role in control of fundic tone primarily through inhibition of cholinergic activity.
In summary, the recent data suggest that NO pathways can influence gastric emptying through a number of mechanisms involving the fundic or the pyloric tone. Inhibition of NO-S activity by intravenous L-NNA increases fundic tone and is expected to increase the rate of liquid gastric emptying. This is, however, prevented by the L-NNA stimulated increase in pyloric tone produced by NO-S inhibition.
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