Diet-induced obesity and diabetes reduce coronary responses to nitric oxide due to reduced bioavailability in isolated mouse hearts.
OBJECTIVE
The aim of the present study was to examine nitric oxide (NO)-mediated coronary vascular responses in a mouse model of obesity and diabetes induced by a high-fat, high-carbohydrate diet. We hypothesized that endogenous NO bioavailability would be reduced in obese/diabetic mouse hearts due to enhanced superoxide anion production, and that coronary smooth muscle responses to exogenous NO would be reduced.


METHODS
Age-matched, male C57BL/6J mice were fed either a control diet or a high-fat, high-carbohydrate diet. After 15 weeks, the mice were anesthetized and their hearts were removed and perfused by the Langendorff method under constant flow conditions with an oxygenated buffer solution, and changes in coronary vascular resistance were quantified.


RESULTS
Mice fed the high-fat, high-carbohydrate diet became obese, hyperglycaemic and hyperinsulinaemic. Coronary vasoconstrictor responses to NO synthase inhibition by N(omega)-nitro-L-arginine methyl ester were reduced in obese/diabetic mice; normal responses were restored by pretreatment with the superoxide dismutase mimetic 2,2,6,6-tetramethyl-1-piperidinyloxy (Tempol). Coronary endothelium-independent vasodilation to the NO donor (+/-)-S-nitroso-N-acetylpenicillamine (SNAP) was reduced; however, 8-bromo-cyclic guanosine monophosphate (cGMP)-induced vasodilation was unchanged in obese/diabetic hearts.


CONCLUSIONS
These findings suggest that in a diet-induced mouse model of obesity and diabetes, NO bioavailability is reduced by increased superoxide NO scavenging leading to impaired NO-mediated vasodilation. Furthermore, the attenuation of SNAP-induced vasodilation may be due to increased reactive oxygen species scavenging of exogenous NO because normal vascular smooth muscle NO signalling is maintained as indicated by similar 8-bromo-cGMP responses in control and obese/diabetic hearts.
Bender
S B
SB
Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, OH 45701, USA.
Herrick
E K
EK
Lott
N D
ND
Klabunde
R E
RE
D000818:Animals; D001682:Biological Availability; D003326:Coronary Circulation / Q000502:physiology*; D003920:Diabetes Mellitus / Q000378:metabolism*; D004040:Dietary Carbohydrates / Q000008:administration & dosage / Q000378:metabolism; D006321:Heart / Q000033:anatomy & histology; D051379:Mice; D008810:Mice, Inbred C57BL / Q000033:anatomy & histology; D009569:Nitric Oxide / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D013481:Superoxides
D004040:Dietary Carbohydrates; D013481:Superoxides; D009569:Nitric Oxide