Multiple mechanisms of early hyperglycaemic injury of the rat intestinal microcirculation.
1. Hyperglycaemia in the vast majority of humans with diabetes mellitus is the end result of profound insulin resistance secondary to obesity. For patients in treatment, hyperglycaemia is usually not sustained but, rather, occurs intermittently. In in vivo studies of the rat intestinal microcirculation, endothelial impairment occurs within 30 min at D-glucose concentrations > or = 300 mg/dL. Endothelial-dependent dilation to acetylcholine and constriction to noradrenaline is impaired. Vasodilation to exogenous nitric oxide (NO) remains normal. 2. When initiated before hyperglycaemia, suppression of oxygen radicals by both scavenging and pretreatment with cyclo-oxygenase blockade to prevent oxygen radical formation minimized endothelial impairments during hyperglycaemia. Neither treatment was effective in restoring endothelial function once it was damaged by hyperglycaemia. 3. A mechanism that may initiate the arachidonic acid- oxygen radical process is activation of specific isoforms of protein kinase C (PKC). De novo formation of diacylglycerol during hyperglycaemia activates PKC. Blockade of the beta II PKC isoform with LY-333531 prior to hyperglycaemia protected NO formation within the arteriolar wall, as judged with NO-sensitive microelectrodes. Furthermore, once suppression of endothelial dilation was present in untreated animals, PKC blockade could substantially restore endothelial-dependent dilation. 4. These results indicate that acute hyperglycaemia is far from benign and, in the rat, causes rapid endothelial impairment. Both oxygen radical scavenging and cyclo-oxygenase blockade prior to bouts of hyperglycaemia minimize endothelial impairment with limited side effects. Blockade of specific PKC isozymes protects endothelial function both as a pre- or post-treatment during moderately severe hyperglycaemia.
Bohlen
H Glenn
HG
Department of Cellular and Integrative Physiology, Indiana University Medical School, Indianapolis, Indiana 46202, USA. gbohlen@iupui.edu
Nase
Geoffrey P
GP
Jin
Jong Shiaw
JS
D000818:Animals; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000503:physiopathology*; D007413:Intestinal Mucosa / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D008833:Microcirculation / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051381:Rats