High glucose concentrations lead to the formation of advanced glycosylation end-products (AGE). Increased glucose concentrations are found during the systemic inflammatory response syndrome and during coronary artery bypass surgery. This study examines the pharmacological effect of AGE on venous endothelial-dependent and -independent relaxation and seeks to determine if aminoguanidine, a known AGE inhibitor, can prevent changes induced by the presence of high glucose concentrations. Standard isometric tension studies on rings from endothelialized and deendothelialized rabbit external jugular veins were performed after incubation for 6 hr in 5.5 mM glucose (control) or 44 mM glucose. The effects of preincubation with either indomethacin (10 μM) to inhibit cyclo-oxygenase activity or aminoguanidine (10 μM) to inhibit protein glycosylation were also studied. In the presence of 44 mM glucose, there was a significant reduction in acetylcholine (endothelial cell based)- and forskolin-induced (smooth muscle cell based) relaxation without associated alterations in serotonin-, calcium ionophore-, and sodium nitroprusside-mediated relaxations. The alterations in acetylcholine-mediated relaxation were inhibited by the addition of indomethacin; co-incubation with aminoguanidine prevented the decrease in acetylcholine-mediated and forskolin-mediated responses. This study shows that in vitro elevated glucose concentrations lead to a reduction in both endothelial cell and smooth muscle cell relaxation, which may he due to AGE- mediated generation of endothelial cell cyclo-oxygenase products and AGE- induced changes in cAMP-mediated relaxation. Therefore, AGE production in the vessel wall cells produces alterations in receptor-dependent and receptor- independent cyclo-oxygenase production and these changes result in altered endothelial- and nonendothelial-mediated relaxation. Alterations in the endothelial and smooth muscle cell responses can be inhibited by aminoguanidine, suggesting that means to reduce or prevent glycosylation are beneficial in ameliorating the acute changes induced by short-term exposure to elevated glucose concentrations.
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