Inhibition of NAD(P)H oxidase alleviates impaired NOS-dependent responses of pial arterioles in type 1 diabetes mellitus.
OBJECTIVE
The goal was to identify the role of NAD(P)H oxidase in cerebrovascular dysfunction in type 1 diabetes mellitus (T1D).


METHODS
In a first series of studies, rats were assigned to nondiabetic, diabetic (streptozotocin; 50 mg/kg IP), nondiabetic-apocynin (40 mg/kg/day in drinking water)-treated and diabetic-apocynin-treated groups. Two to three months later, the authors examined in vivo responses of pial arterioles to nitric oxide synthase (NOS)-dependent (acetylcholine and adenosine diphosphate (ADP)) and -independent (nitroglycerin) agonists. Next, they used Western blot analysis to examine protein levels for subunits of NAD(P)H oxidase in cerebral microvessels and parietal cortex tissue of nondiabetic and diabetic rats. Finally, they measured superoxide production by parietal cortex tissue in nondiabetic and diabetic rats.


RESULTS
Acetylcholine- and ADP-induced dilatation of pial arterioles was impaired in diabetic compared to nondiabetic rats. In addition, while apocynin did not alter responses in nondiabetic rats, apocynin alleviated T1D-induced impairment of NOS-dependent vasodilatation. In addition, p47phox and gp91phox proteins were elevated in cerebral microvessels and parietal cortex tissue, respectively, of diabetic compared to nondiabetic rats. Further, basal production of superoxide was increased in diabetic compared to nondiabetic rats and apocynin decreased this basal production.


CONCLUSIONS
The findings suggest that T1D impairs NOS-dependent reactivity of cerebral arterioles by a mechanism related to the formation of superoxide via activation of NAD(P)H oxidase.
Mayhan
William G
WG
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, 68198-5850, USA. wgmayhan@unmc.edu
Arrick
Denise M
DM
Sharpe
Glenda M
GM
Patel
Kaushik P
KP
Sun
Hong
H
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010841:Pia Mater / Q000098:blood supply*; D021122:Protein Subunits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D000098:Acetophenones; D004791:Enzyme Inhibitors; D021122:Protein Subunits; D013481:Superoxides; C056165:acetovanillone; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases