The ability of prostaglandin E1 (PGE1) and nitric oxide (NO) donor compounds such as sodium nitroprusside (SNP), glyceryl trinitrate (GTN), and 3-morpholino-sydnonimine (SIN-1) to modulate the histamine- and bradykinin-induced increase in microvascular permeability have been investigated in rabbit skin. The effect of the NO synthesis inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) on the plasma exudation induced by histamine and bradykinin was also studied. Local edema formation was evaluated using [125I]human serum albumin. New Zealand white rabbits received an intravenous injection of [125I]human albumin followed immediately by the intradermal injection of edematogenic agents into the shaved dorsolateral skin. PGE1 (0.1 nmol/site) significantly potentiated both histamine- and bradykinin-induced edema. In contrast, SNP (0.4-400 nmol/site), SIN-1 (0.4-400 nmol/site), and GTN (0.4-40 nmol/site) did not affect the edematogenic response induced by either histamine or bradykinin. GTN (0.4-40 nmol/site) also had no effect on the increase in plasma exudation induced by histamine and bradykinin in the presence of PGE1. l-NAME (50-400 nmol/site), but not its enantiomer d-NAME, dose-dependently reduced the edema formation induced by a combination of either histamine or bradykinin with PGE1. This inhibition was significantly reversed by SNP (4-400 nmol/site) and by high doses (2.5 μmol/site) of l-arginine (but not by d-arginine). Our results thus demonstrate that PGE1, but not nitrovasodilators, can actually potentiate histamine- and bradykinin-induced edema in rabbit skin. This discrepancy cannot be explained by the lack of vasodilator activity of the nitrovasodilators since these were able to reverse the l-NAME-induced inhibition of the edema provoked by histamine. 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