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.