Platelet-activating factor and nitric oxide mediate microvascular permeability in ischemia-reperfusion injury.
Increased microvascular permeability is a hallmark of ischemia-reperfusion (I/R) injury. We hypothesized that platelet-activating factor (PAF) and nitric oxide (NO) are involved in the extrvasation of macromolecules in I/R injury. To block endogenous PAF, we used a PAF-receptor antagonist (WEB 2086; 2 mg/kg, i.v). To inhibit endogenous nitric oxide, we employed L-NG-monomethyl arginine (10(-5) M L-NMMA), a NO synthase inhibitor. We assessed microvascular permeability to FITC-dextran 150 by measuring changes in integrated optical intensity (delta IOI) using computer-assisted image analysis in the hamster cheek pouch. We examined one area of ischemia and one control area in each pouch. Ischemia was induced for 2 hr and was followed by 1 hr of reperfusion. Six groups were investigated. Group 1 (n = 5) had no pharmacologic intervention; Group 2 (n = 5) received WEB 2086 15 min before reperfusion; Group 3 (n = 5) received WEB 2086 at reperfusion; Group 4 (n = 5), WEB 2086 was infused 15 min after the onset of reperfusion. Group 5 (n = 3) received topical L-NMMA (30 min prior to reperfusion and continuously for the remainder of the experiment). Group 6 (n = 3) received both L-NMMA (as in Group 5) and WEB 2086 (administered 15 min after reperfusion). In Group 1, I/R increased the mean (+/- SEM) delta IOI value from 61.5 +/- 11.1 to 127.2 +/- 26.1. WEB 2086 inhibited the increase in delta IOI at each time point. Similarly, the groups given L-NMMA alone and L-NMMA + WEB 2086 showed no difference between ischemic and control groups. Our data demonstrate that (1) PAF and nitric oxide are involved in the permeability changes associated with the microvascular dysfunction of ischemia-reperfusion injury; (2) inhibitors of PAF and nitric oxide synthase are effective in attenuating macromolecular extravasation when given during ischemia or after initiation of reperfusion.
Noel
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AA
Department of Surgery, UMDNJ-New Jersey Medical School, Newark 07103-2714, USA.
Hobson
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Durán
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D000818:Animals; D002199:Capillary Permeability; D002610:Cheek / Q000098:blood supply / Q000473:pathology; D006224:Cricetinae; D008297:Male; D008647:Mesocricetus; D008833:Microcirculation / Q000503:physiopathology*; D009569:Nitric Oxide / Q000502:physiology*; D010972:Platelet Activating Factor / Q000502:physiology*; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*
D010972:Platelet Activating Factor; D009569:Nitric Oxide