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NEUROREGULATION AND MOTILITY
1Division of Gastroenterology and Hepatology, Department of Internal Medicine, and 2Department of Obstetrics and Gynecology, Reproductive Sciences, The University of Texas Medical Branch, Galveston, Texas
Submitted 31 August 2006 ; accepted in final form 16 November 2006
Diabetic gastroparesis is a disorder that predominantly affects women. However, the biological basis of this sex bias remains completely unknown. In this study we tested the hypothesis that a component of this effect may be mediated by the nitrergic inhibitory system of the enteric nervous system. Age-matched male and female Sprague-Dawley rats were studied 8 or 12 wk after streptozotocin (55 mg/kg body wt ip)-induced sustained hyperglycemia and compared with controls. Solid gastric emptying (GE) studies were performed in all the groups. Changes in gastric antrum neuronal nitric oxide synthase (nNOS) mRNA and protein levels were analyzed by real-time PCR and Western immunoblotting, respectively. nNOS dimerization studies were performed using low-temperature SDS-PAGE. In vitro nitrergic relaxation (area under curve/mg tissue wt) was studied after the application of electric field stimulation in an organ bath. Changes in intragastric pressure (mmHg·s) in freely moving rats in the presence or absence of NG-nitro-L-arginine methyl ester (nitric oxide synthase inhibitor) were examined by an ambulatory telemetric method. After diabetes induction, GE is delayed in both male and female rats. However, diabetic females exhibited significant delayed GE than in diabetic males. Compared with male controls, gastric nNOS expression and nitrergic relaxation were substantially elevated in healthy female control rats, accompanied by significantly reduced intragastric pressure. The active dimeric form and dimer-to-monomer ratio of nNOS
were also higher in healthy females compared with male rats (P < 0.05). Diabetic females, but not males, showed significant (P < 0.05) impairment in both gastric nNOS dimerization and nitrergic relaxation, accompanied by an increase in intragastric pressure. Our data provide evidence that females may have a greater dependency on the nitrergic mechanisms in health. Furthermore, diabetes seems to affect the nitrergic system to a greater extent in females than in males. Together, these changes may account for the greater vulnerability of females to diabetic gastric dysfunction.
solid gastric emptying; nitrergic relaxation; intragastric pressure
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