Sepiapterin reverses the changes in gastric nNOS dimerization and function in diabetic gastroparesis
Article first published online: 22 AUG 2010
© 2010 Blackwell Publishing Ltd
Neurogastroenterology & Motility
Volume 22, Issue 12, pages 1325–e352, December 2010
How to Cite
Gangula, P. R. R., Mukhopadhyay, S., Pasricha, P. J. and Ravella, K. (2010), Sepiapterin reverses the changes in gastric nNOS dimerization and function in diabetic gastroparesis. Neurogastroenterology & Motility, 22: 1325–e352. doi: 10.1111/j.1365-2982.2010.01588.x
- Issue published online: 4 NOV 2010
- Article first published online: 22 AUG 2010
- Received: 9 June 2010 Accepted for publication: 14 July 2010
- female rat;
- nitrergic relaxation;
- neuronal nitric oxide synthase dimerization;
Background We have demonstrated previously that in vivo supplementation of tetrahydrobiopterin (BH4); a co-factor for neuronal nitric oxide synthase (nNOS) significantly restored delayed gastric emptying and attenuated nitrergic relaxation in diabetic rat. In this study, we have investigated whether supplementation of sepiapterin (SEP), a precursor for BH4 biosynthesis via salvage pathway restores gastric emptying and nitrergic system in female diabetic rats.
Methods Diabetic rats (streptozotocin-induced) were supplemented with BH4 or SEP (20 mg kg−1 body weight). Gastric nitrergic relaxation in the presence or absence of high glucose and SEP were measured by electric field stimulation. Gastric muscular strips from healthy or diabetic female rats were incubated in the presence or absence of high glucose, SEP and/or methotrexate (MTX). Nitric oxide release was measured colorimetrically by NO assay kit. The expression of nNOSα and dimerization was detected by Western blot.
Key Results In vitro studies on gastric muscular tissues showed that MTX, an inhibitor of BH4 synthesis via salvage pathway, significantly decreased NO release. In vivo treatment with MTX reduced both gastric nitrergic relaxation and nNOSα dimerization. Supplementation of SEP significantly attenuated delayed gastric emptying in diabetic rats. In addition, SEP supplementation restored impaired nitrergic relaxation, gastric nNOSα protein expression, and dimerization in diabetic rats.
Conclusions & Inferences The above data suggests that supplementation of SEP accelerated gastric emptying and attenuated reduced gastric nNOSα expression, and dimerization. Therefore, SEP supplementation is a potential therapeutic option for female patients of diabetic gastroparesis.