Endothelial dysfunction accompanies a pro-oxidant, pro-diabetic challenge in the insulin resistant, obese Zucker rat in vivo.
We have recently made the novel observation that a pro-oxidant challenge with hydroquinone in combination with buthionine sulfoximine (each at 50 mg/kg i.p. daily for 7 days) provokes the onset of type II diabetes mellitus in a model of insulin resistance, the obese Zucker rat. Since endothelial dysfunction in oxidant stress may aggravate in vivo insulin resistance, we have now investigated endothelium-dependent and nitric oxide (NO)-mediated vascular responses in the obese Zucker rat in vivo following this pro-oxidant insult. Pro-oxidant-treated animals exhibited defective vasodepression to the endothelium-dependent agent acetylcholine and to a lesser extent, the NO donor glyceryl trinitrate, together with a reduction in circulating levels of cGMP. Our data therefore suggest that the progression to type II diabetes mellitus in the obese Zucker rat mediated by a pro-oxidant insult is associated with impairments in agonist-stimulated, endothelium-dependent vasodilation and vascular NO signalling.
Laight
D W
DW
The William Harvey Research Institute, St Bartholomew's and the Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. d.w.laight@mds.qmw.ac.uk
Desai
K M
KM
Anggård
E E
EE
Carrier
M J
MJ
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D019540:Area Under Curve; D001835:Body Weight / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D006152:Cyclic GMP / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006873:Hydroquinones / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D009765:Obesity / Q000378:metabolism*; D016877:Oxidants / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker
D000975:Antioxidants; D004791:Enzyme Inhibitors; D006873:Hydroquinones; D016877:Oxidants; D019328:Buthionine Sulfoximine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D006152:Cyclic GMP; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester; C031927:hydroquinone