Intrinsic Neural Control

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The importance of nitric oxide (NO) as an intestinal neurotransmitter regulating gastropyloric function is increasingly recognized. Mice with a targeted genomic deletion of neuronal nitric oxide synthase (nNOS) develop pyloric hypertrophy and gastric dilatation. Similarly, loss of pyloric nNOS is associated with infantile hypertrophic pyloric stenosis. This is supported by the observation that exogenous NO reduces the number and amplitude of isolated pyloric pressure waves in normal humans.

Abnormalities of nNOS have been observed in animal models of diabetes. Stomachs of spontaneously diabetic rats and rats with streptozotocin-induced diabetes exhibit decreased NO-mediated relaxation of gastric muscle strips and decreased expression of nNOS. Watkins et al. (33) have subsequently demonstrated that nNOS protein and mRNA are depleted in the pyloric myenteric neurons of diabetic mice. Insulin treatment restores pyloric nNOS protein and reverses the delay in gastric emptying observed in such mice. Sildenafil, a cGMP phosphodiesterase inhibitor augments NO signaling and also reverses delayed gastric

FIGURE 3 Measurement of changes in gastric volume using single photo emission computed tomography after labeling of the stomach wall with intravenous 99mTc pertechnetate. Source: From ref. 35.

emptying in diabetic mice. These data suggest that reversible down regulation of NOS may play an important role in the pathogenesis of diabetic gastropathy.

Neuronal nitric oxide synthase (nNOS)-derived NO acts as a smooth muscle cell relaxant by binding to and activating smooth muscle cell guanylate cyclase (37). The expression of nNOS is particularly high in the pyloric sphincter (38) and nNOS mice exhibit pyloric hypertrophy, gastric dilatation and delayed gastric emptying (39). In humans, inhibition of NOS decreases gastric emptying time and fundic volume (40). Similarly, in murine models of diabetes, NOS expression and activity is decreased but is restored by insulin administration (41).

Peptidergic and serotonergic (42,43) innervation is abnormal in animal models of diabetes.

The interstitial cells of Cajal (ICC) play an important role in the regulation of GI motility. ICC are distributed throughout the GI tract, interspersed in the circular and longitudinal muscle layers and, in the murine and human small intestine and form a dense plexus at the level of the neuronal myenteric plexus ICCs generate the electrical slow wave, required for normal GI motility.

Defects of ICC have been associated with several human gut motility diseases including slow transit constipation, hypertrophic pyloric stenosis, Hirschsprung's disease and pseudoobstruction. Ordog et al. (44) demonstrated that "spontaneously diabetic mice" develop delayed gastric emptying, impaired electrical slow waves, and reduced motor neurotransmission. They also observed greatly reduced ICCs in the distal stomach. Moreover, the association of the ICC and enteric nerve cells was disrupted.

Loss of ICC has been reported in a patient with type 1 diabetes (45) who underwent full-thickness jejunal biopsy. However, it remains to be ascertained whether defects of ICC are consistently present in patients with GI dysmotility due to diabetes. Altered ICC networks have also been implicated in chronic intestinal pseudoobstruction (46) and idiopathic slow transit constipation (47), underscoring the importance of ICC in health and disease. Diabetes may alter GI function by causing structural, numerical or functional changes in ICC.

Carbon Monoxide (CO) is an important regulator of neurotransmission, smooth muscle tone and response to cellular injury. Two heme oxygenase enzymes (HO1 and HO2) catalyze the formation of CO from heme. Neurons express high concentrations of HO2 (48), and HO1 expression is induced by injury or inflammation (49). Induction of HO1 ameliorates tissue injury in animal models of tissue injury/ileus and therefore modulation of this pathway may be a therapeutic target in the treatment of diabetic enteropathy. A polymorphism in HMOX-1 (the gene that codes for HO1) is associated with predisposition to diseases in which oxidative damage is central to pathogenesis (50,51). CO is a hyperpolarizing factor in the GI muscle layers. CO production and heme oxygenase activity mirror the smooth muscle membrane potential present across the muscle layers. Since the degree of polarization of smooth muscle determines recruitment of muscle in response to a stimulus, CO is likely to be important in controlling intestinal contractility. Of relevance to this discussion is the fact that nonadrenergic, noncholinergic neurotransmission is nearly abolished in HO-2 knockout mice and this can be restored by addition of exogenous CO.

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