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


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
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.
Gangula
P R R
PR
Department of Physiology, Center for Women's Health Research, Meharry Medical College, Nashville, TN 37208, USA. pgangula@mmc.edu
Mukhopadhyay
S
S
Pasricha
P J
PJ
Ravella
K
K
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000503:physiopathology*; D019587:Dietary Supplements; D019281:Dimerization; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D018589:Gastroparesis / Q000188:drug therapy*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D011622:Pterins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects / Q000503:physiopathology*
D001786:Blood Glucose; D007166:Immunosuppressive Agents; D011622:Pterins; C016727:sepiapterin; D052248:Nitric Oxide Synthase Type I; D008727:Methotrexate