| Tetrahydrobiopterin (BH4), a cofactor for nNOS, restores gastric emptying and nNOS expression in female diabetic rats. | |
| | |
MedLine Citation:
|
PMID: 20185690 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
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-alpha protein expression in female rats. Supplementation of BH4 significantly restored gastric nNOS-alpha 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-alpha 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. |
| | |
Authors:
|
Pandu R R Gangula; Sutapa Mukhopadhyay; Kalpana Ravella; Shijie Cai; Keith M Channon; Robert E Garfield; Pankaj J Pasricha |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural Date: 2010-02-25 |
Journal Detail:
|
Title: American journal of physiology. Gastrointestinal and liver physiology Volume: 298 ISSN: 1522-1547 ISO Abbreviation: Am. J. Physiol. Gastrointest. Liver Physiol. Publication Date: 2010 May |
Date Detail:
|
Created Date: 2010-04-20 Completed Date: 2010-05-06 Revised Date: 2011-08-01 |
Medline Journal Info:
|
Nlm Unique ID: 100901227 Medline TA: Am J Physiol Gastrointest Liver Physiol Country: United States |
Other Details:
|
Languages: eng Pagination: G692-9 Citation Subset: IM |
Affiliation:
|
Department of Obstetrics and Gynecology, Center for Women's Health Research, Meharry Medical College, Nashville, Tennessee 37208, USA. pgangula@mmc.edu |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Biopterin / analogs & derivatives*, metabolism, pharmacology Blood Glucose / metabolism Diabetes Mellitus, Experimental / physiopathology* Female GTP Cyclohydrolase / antagonists & inhibitors Gastric Emptying / drug effects* Gastroparesis / physiopathology Hypoxanthines / pharmacology Male Muscle Relaxation / drug effects Nitric Oxide Synthase Type I / biosynthesis*, metabolism Nitric Oxide Synthase Type III / metabolism Pylorus / metabolism Rats Rats, Sprague-Dawley |
| Grant Support | |
ID/Acronym/Agency:
|
G12 RR003032/RR/NCRR NIH HHS; R21 DK076704-01A2/DK/NIDDK NIH HHS; R21 DK076704-02/DK/NIDDK NIH HHS; R21 DK076704-03/DK/NIDDK NIH HHS; R21 DK076704-03S1/DK/NIDDK NIH HHS; R21DKO76704//PHS HHS |
| Chemical | |
Reg. No./Substance:
|
0/Blood Glucose; 0/Hypoxanthines; 17528-72-2/5,6,7,8-tetrahydrobiopterin; 22150-76-1/Biopterin; 56-06-4/2,4-diaminohypoxanthine; EC 1.14.13.39/Nitric Oxide Synthase Type I; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 1.14.13.39/Nos3 protein, rat; EC 3.5.4.16/GTP Cyclohydrolase |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: PRESYNAPTIC INHIBITION OF NEURAL VASODILATOR PATHWAYS TO SUBMUCOSAL ARTERIOLES BY RELEASE OF PURINES...
Next Document: Differential Processing of Pro Glucose-Dependent Insulinotropic Polypeptide (ProGIP) in Gut.