Tetrahydrobiopterin (BH4), a cofactor for nNOS, restores gastric emptying and nNOS expression in female diabetic rats

Pandu R.R. Gangula, Sutapa Mukhopadhyay, Kalpana Ravella, Shijie Cai, Keith M. Channon, Robert E. Garfield, Pankaj J. Pasricha

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Gastroparesis is a debilitating disease predominantly affecting young women. Recently, dysregulation of neuronal nitric oxide synthase (nNOS) in myenteric plexus neurons has been implicated for delayed solid gastric emptying/gastroparesis in diabetic patients. In this study, we have explored the role of tetrahydrobiopterin (BH4), a major cofactor for nNOS activity and NO synthesis in diabetic gastroparesis. Diabetes was induced with single injection of streptozotocin (55 mg/kg body wt, ip) in female rats, with experiments performed on week 3 or 9 following induction, with or without 3-wk BH4 supplementation. Gastric pyloric BH4 levels were significantly decreased in diabetic female rats compared with control (18.6 ± 1.45 vs. 31.0 ± 2.31 pmol/mg protein). In vitro studies showed that 2,4-diamino-6- hydroxypyrimidine (DAHP), an inhibitor of BH4 synthesis, significantly decreased gastric NO release and nitrergic relaxation. Three-week dietary supplementation of BH4 either from day 1 or week 6 significantly attenuated diabetes-induced delayed gastric emptying for solids (3 wk: BH4, 67 ± 6.7 vs. diabetic, 36.05 ± 7.09; 9 wk: BH4, 57 ± 8.45 vs. diabetic, 33 ± 9.91) and diabetes-induced reduction in pyloric nNOS-α protein expression in female rats. Supplementation of BH4 significantly restored gastric nNOS-α dimerization in 9-wk-old diabetic female rats. In addition, BH4 treatment reversed (17.23 ± 5.81 vs. 42.0 ± 2.70 mmHg x s) the diabetes-induced changes in intragastric pressures (IGP) and gastric pyloric nitrergic relaxation (-0.62 ± 0.01 vs. -0.22 ± 0.07). BH4 deficiency plays a critical role in diabetes-induced alterations including delayed solid gastric emptying, increased IGP, reduced pyloric nitrergic relaxation, and nNOS-α expression in female rats. Supplementation of BH4 accelerates gastric emptying by restoring nitrergic system in diabetic female rats. Therefore, BH4 supplementation is a potential therapeutic option for female patients of diabetic gastroparesis.

Original languageEnglish (US)
Pages (from-to)G692-G699
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number5
StatePublished - May 2010
Externally publishedYes


  • Diabetes
  • Female rat
  • Nitrergic relaxation
  • Streptozotocin

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)


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