Histamine paw edema of mice was increased and became H2-antagonist sensitive by co-injection of nitric oxide forming agents, but serotonin paw edema was decreased.

Nitric oxide (NO) surprisingly caused the opposite effect on histamine and serotonin edema. The local injection of acidified nitrite (0.3-30 micrograms/paw which correspond 10 micrograms-1 mg/kg) increased histamine edema of mice up to 45 +/- 4% and suppressed serotonin edema to 90 +/- 3%. Other NO-generators (nitroprusside sodium and hydroxylamine) showed similar effects. These results were in accordance with our previous data on endogenous NO. Methylene blue (MB, 30 ng/paw which corresponds to 1 microgram/kg) suppressed histamine edema (62 +/- 3%) and increased serotonin edema (43 +/- 3%) in normal mice, being reversed by acidified nitrite. This suggests the involvement of guanosine 3',5'-cyclic monophosphate (cGMP) formation for the action of NO. Histamine edema became sensitive to H2-antagonist, cimetidine, by co-injection of 30 micrograms/paw (which corresponds to 1 mg/kg) acidified nitrite (ED50 = 30 micrograms/kg versus >> 1 mg/kg). NO seemed to modify the histamine receptor(s) or tautomeric form of histamine. NO, O2- and other oxyradicals might finely control the vascular permeability together with inflammatory mediators.