Obligatory role of nitric oxide in platelet-activating factor-induced microvascular leakage.
We examined the independent and interdependent effects of platelet-activating factor (PAF) and nitric oxide (NO) on microvascular leakage of fluorescein isothiocyanate (FITC)-dextran in the cheek pouch microcirculation of anesthetized hamsters. Superfusing the cheek pouch microcirculation with 100-nM PAF elicited rapid leakage of FITC-dextran that was markedly inhibited by prior treatment with a nitric oxide synthase (NOS) inhibitor, N(omega)-nitro-L-arginine (L-NA; 1 microM). This inhibition by L-NA was completely reversed by application of a NO donor (S-nitroso-N-acetylpenicillamine, SNAP; 10 microM) at the same time PAF was applied. SNAP alone, however, did not cause leakage of FITC-dextran; neither did it enhance PAF-induced leakage. PAF-induced leakage was completely inhibited by prior treatment with the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one (ODQ, 10 microM). 8-bromoguanosine 3',5'-cyclic monophosphate (8-br-cGMP) did not reverse this inhibition by ODQ although this cell permeable cGMP analog was able to completely reverse arteriolar vasoconstriction produced by ODQ. These results indicate that PAF-induced leakage of FITC-dextran in the hamster cheek pouch microcirculation requires an intact NO/cGMP pathway, although NO production does not cause PAF-induced leakage. This supports the hypothesis that NO plays an obligatory role in PAF-induced leakage.
Klabunde
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Department of Biomedical Sciences, I-304, College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA. klabunde@ohio.edu
Anderson
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D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D002610:Cheek / Q000098:blood supply; D006224:Cricetinae; D003911:Dextrans / Q000493:pharmacokinetics; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D008297:Male; D008647:Mesocricetus; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D003911:Dextrans; D020030:Nitric Oxide Donors; D010972:Platelet Activating Factor; C110881:S-nitro-N-acetylpenicillamine; D014665:Vasodilator Agents; C015219:fluorescein isothiocyanate dextran; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D010396:Penicillamine; D016650:Fluorescein-5-isothiocyanate