Polyethylene glycol and a novel developed polyethylene glycol-nitric oxide normalize arteriolar response and oxidative stress in ischemia-reperfusion.
Polyethylene glycol (PEG) has been shown to repair cell membranes and, thus, inhibit free radical production in in vitro and in vivo models. We hypothesized that PEG and newly developed organic nitrate forms of PEG (PEG-NO) could repair endothelial dysfunction in ischemia-reperfusion (I/R) injury in the hamster cheek pouch visualized by intravital fluorescent microscopy. After treatments, we evaluated diameter and RBC velocity and flow in arterioles, as well as lipid peroxides in the systemic blood, perfused capillary length, vascular permeability, leukocyte adhesion, and amount of von Willebrand factor (vWF) in the blood after I/R injury. A control group was treated with 5,000- or 10,000-Da PEG, and three groups were treated with PG1 (1 NO molecule covalently bound to PEG, 5,170 Da), PG8 (8 NO molecules covalently bound to PEG, 11,860 Da), and PG16 (16 NO molecules covalently bound to PEG, 14,060 Da). All animals received 0.5 mg/0.5 ml. Lipid peroxides increased at 5 and 15 min of reperfusion, whereas diameter, RBC velocity, and blood flow decreased in arterioles after I/R injury. Vascular permeability, leukocyte adhesion, and vWF increased significantly. PEG and PG1 attenuated lipid peroxides and vasoconstriction during reperfusion and decreased leukocyte adhesion and vascular permeability. PG8 maintained lipid peroxides at normal levels, increased arteriolar diameter, flow, and perfused capillary length, and decreased vWF level and leukocyte adhesion (P < 0.05). PG16 was less effective than PG1 and PG8. In conclusion, PEG-NO shows promise as a compound that protects microvascular perfusion by normalizing the balance between NO level and excessive production of free radicals in endothelial cells during I/R injury.
Faculty of Medicine, Univ. of Pisa, Via Trieste 41, 56100 Pisa, Italy. sibert@ifc.cnr.it
S
S
Bertuglia
F M
FM
Veronese
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G
Pasut
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002610:Cheek / Q000098:blood supply; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D045462:Endothelium-Dependent Relaxing Factors / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007957:Leukocyte Adherence Inhibition Test; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D008647:Mesocricetus; D009061:Mouth Mucosa / Q000098:blood supply; D009566:Nitrates / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011092:Polyethylene Glycols / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000503:physiopathology*; D013501:Surface-Active Agents / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology; D014841:von Willebrand Factor / Q000378:metabolism
D045462:Endothelium-Dependent Relaxing Factors; D004791:Enzyme Inhibitors; D009566:Nitrates; C514522:PG1 compound; C514524:PG16 compound; C514523:PG8 compound; D013501:Surface-Active Agents; D014841:von Willebrand Factor; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D011092:Polyethylene Glycols