Multiple Mechanisms Of Early Hyperglycaemic Injury Of The Rat Intestinal Microcirculation

Authors: Bohlen, H Glenn; Nase, Geoffrey P; Jin, Jong Shiaw

Source: Clinical and Experimental Pharmacology and Physiology, Volume 29, Numbers 1-2, January/February 2002 , pp. 138-142(5)

Publisher: Wiley-Blackwell

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Abstract:

SUMMARY

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 atD-glucose concentrations ≥ 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 βII 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.

Keywords: diabetes; hyperglycaemia; nitric oxide

Document Type: Research article

DOI: http://dx.doi.org/10.1046/j.1440-1681.2002.03617.x

Affiliations: 1: Department of Cellular and Integrative Physiology, Indiana University Medical School, Indianapolis, Indiana, USA

Publication date: 2002-01-01

Multiple Mechanisms Of Early Hyperglycaemic Injury Of The Rat Intestinal Microcirculation

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