Biphasic Effect of Diabetes on Neuronal Nitric Oxide Release in Rat Mesenteric Arteries.
BACKGROUND
We analysed possible time-dependent changes in nitrergic perivascular innervation function from diabetic rats and mechanisms implicated.


METHODS
In endothelium-denuded mesenteric arteries from control and four- (4W) and eight-week (8W) streptozotocin-induced diabetic rats the vasoconstriction to EFS (electrical field stimulation) was analysed before and after preincubation with L-NAME. Neuronal NO release was analysed in the absence and presence of L-arginine, tetrahydrobiopterine (BH4) and L-arginine plus BH4. Superoxide anion (O2-), peroxynitrite (ONOO-) and superoxide dismutase (SOD) activity were measured. Expressions of Cu-Zn SOD, nNOS, p-nNOS Ser1417, p-nNOS Ser847, and Arginase (Arg) I and II were analysed.


RESULTS
EFS response was enhanced at 4W, and to a lesser extent at 8W. L-NAME increased EFS response in control rats and at 8W, but not at 4W. NO release was decreased at 4W and restored at 8W. L-arginine or BH4 increased NO release at 4W, but not 8W. SOD activity and O2- generation were increased at both 4W and 8W. ONOO- decreased at 4W while increased at 8W. Cu-Zn SOD, nNOS and p-NOS Ser1417 expressions remained unmodified at 4W and 8W, whereas p-nNOS Ser847 was increased at 4W. ArgI was overexpressed at 4W, remaining unmodified at 8W. ArgII expression was similar in all groups.


CONCLUSIONS
Our results show a time-dependent effect of diabetes on neuronal NO release. At 4W, diabetes induced increased O2- generation, nNOS uncoupling and overexpression of ArgI and p-nNOS Ser847, resulting in decreased NO release. At 8W, NO release was restored, involving normalisation of ArgI and p-nNOS Ser847 expressions.
Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.|Instituto de Investigación La Paz (IdIPAZ), Madrid, Spain.
Esther
E
Sastre
Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.|Instituto de Investigación La Paz (IdIPAZ), Madrid, Spain.
Laura
L
Caracuel
Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.|Instituto de Investigación La Paz (IdIPAZ), Madrid, Spain.
Javier
J
Blanco-Rivero
Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
María
M
Callejo
Departamento de Fisiologia e Farmacologia, Universidade Federal de Pernambuco, Recife, Brazil.
Fabiano E
FE
Xavier
Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.|Instituto de Investigación La Paz (IdIPAZ), Madrid, Spain.
Gloria
G
Balfagón
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004558:Electric Stimulation; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism; D051381:Rats; D013311:Streptozocin; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*
D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D013311:Streptozocin; D013482:Superoxide Dismutase; D019331:NG-Nitroarginine Methyl Ester