Diabetes only affects nitric oxide synthase-containing myenteric neurons that do not contain heme oxygenase 2

It has been demonstrated that subpopulations of myenteric neurons are differentially susceptible to the development of neuropathy in diabetes. Within the myenteric plexus are neurons that contain neuronal nitric oxide synthase (nNOS). However, these are not a homogeneous population. Some of the nNOS-containing neurons also contain heme oxygenase 2 (HO2). Therefore, the aim of this study was to compare the effects of diabetes on HO2- and nNOS-containing neurons within the myenteric plexus of the rat ileum. Diabetes was induced in male Wistar rats (350-400 g) by a single i.p. injection of buffered streptozotocin (65 mg/kg). After 12 weeks, immunostaining of wholemount preparations of ileum revealed that diabetes induced a significant shift (P < 0.001, chi-squared test for trend) towards increased neuronal cell body size in nNOS-immunoreactive neurons while HO2-immunoreactive neurons remained unaffected. Double-labeling studies revealed that approximately 50% of nNOS-containing neurons also contained HO2 and that the diabetes-induced change in size was confined to nNOS-immunoreactive neurons that did not contain HO2 (P < 0.01). No change in the size distribution occurred in neurons in which nNOS and HO2 were colocalized. Differences in the response of these two subpopulations of nNOS-containing neurons to diabetes could occur because they supply different targets within the gastrointestinal tract or indicate that the antioxidant, HO2, protects those nNOS-containing neurons in which it is colocalized, against oxidative stress that occurs in diabetes.