Sepiapterin reverses the changes in gastric nNOS dimerization and function in diabetic gastroparesis

P. R R Gangula, S. Mukhopadhyay, Pankaj Jay Pasricha, K. Ravella

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalNeurogastroenterology and Motility
Volume22
Issue number12
DOIs
StatePublished - Dec 2010
Externally publishedYes

Fingerprint

Gastroparesis
Nitric Oxide Synthase Type I
Dimerization
Stomach
Gastric Emptying
Methotrexate
Protein Multimerization
Glucose
sepiapterin
Streptozocin
Electric Stimulation
Nitric Oxide
Western Blotting
Body Weight

Keywords

  • Diabetes
  • Female rat
  • Gastroparesis
  • Neuronal nitric oxide synthase dimerization
  • Nitrergic relaxation
  • Sepiapterin
  • Tetrahydrobiopterin

ASJC Scopus subject areas

  • Endocrine and Autonomic Systems
  • Gastroenterology
  • Physiology

Cite this

Sepiapterin reverses the changes in gastric nNOS dimerization and function in diabetic gastroparesis. / Gangula, P. R R; Mukhopadhyay, S.; Pasricha, Pankaj Jay; Ravella, K.

In: Neurogastroenterology and Motility, Vol. 22, No. 12, 12.2010.

Research output: Contribution to journalArticle

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abstract = "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.",
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