Effect of protein kinase C and phospholipase A2 inhibitors on the impaired ability of human diabetic platelets to cause vasodilation

Helgi J Oskarsson; Timothy G Hofmeyer; Lawrence Coppey; Mark A Yorek

doi:10.1038/sj.bjp.0702617

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Effect of protein kinase C and phospholipase A2 inhibitors on the impaired ability of human diabetic platelets to cause vasodilation

Journal article

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Effect of protein kinase C and phospholipase A2 inhibitors on the impaired ability of human diabetic platelets to cause vasodilation

Helgi J Oskarsson, Timothy G Hofmeyer, Lawrence Coppey and Mark A Yorek

British journal of pharmacology, Vol.127(4), pp.903-908

06/1999

DOI: 10.1038/sj.bjp.0702617

PMCID: PMC1566093

PMID: 10433497

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Abstract

The aim of this study was to examine the mechanism of impaired platelet-mediated endothelium-dependent vasodilation in diabetes. Exposure of human platelets to high glucose in vivo or in vitro impairs their ability to cause endothelium-dependent vasodilation. While previous data suggest that the mechanism for this involves increased activity of the cyclo-oxygenase pathway, the signal transduction pathway mediating this effect is unknown. Platelets from diabetic patients as well as normal platelets and normal platelets exposed to high glucose concentrations were used to determine the role of the polyol pathway, diacylglycerol (DAG) production, protein kinase C (PKC) activity and phospholipase A 2 (PLA 2 ) activity on vasodilation in rabbit carotid arteries. We found that two aldose-reductase inhibitors, tolrestat and sorbinil, caused only a modest improvement in the impairment of vasodilation by glucose exposed platelets. However, sorbitol and fructose could not be detected in the platelets, at either normal or hyperglycaemic conditions. We found that incubation in 17 m M glucose caused a significant increase in DAG levels in platelets. Furthermore, the DAG analog 1-oleoyl-2-acetyl-sn-glycerol (OAG) caused significant impairment of platelet-mediated vasodilation. The PKC inhibitors calphostin C and H7 as well as inhibitors of PLA 2 activity normalized the ability of platelets from diabetic patients to cause vasodilation and prevented glucose-induced impairment of platelet-mediated vasodilation in vitro . These results suggest that the impairment of platelet-mediated vasodilation caused by high glucose concentrations is mediated by increased DAG levels and stimulation of PKC and PLA 2 activity.

Papers

signal-transduction

platelet

Glucose

vasodilation

diabetes

Details

Title: Subtitle: Effect of protein kinase C and phospholipase A2 inhibitors on the impaired ability of human diabetic platelets to cause vasodilation
Creators: Helgi J Oskarsson - Department of Internal Medicine, University of Iowa and Veterans Administration Medical Center, Iowa City, IA, U.S.A
Timothy G Hofmeyer - Department of Internal Medicine, University of Iowa and Veterans Administration Medical Center, Iowa City, IA, U.S.A
Lawrence Coppey - Department of Internal Medicine, University of Iowa and Veterans Administration Medical Center, Iowa City, IA, U.S.A
Mark A Yorek - Department of Internal Medicine, University of Iowa and Veterans Administration Medical Center, Iowa City, IA, U.S.A
Resource Type: Journal article
Publication Details: British journal of pharmacology, Vol.127(4), pp.903-908
DOI: 10.1038/sj.bjp.0702617
PMID: 10433497
PMCID: PMC1566093
ISSN: 0007-1188
eISSN: 1476-5381
Language: English
Date published: 06/1999
Academic Unit: Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984094735602771

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