Perfusion of 6-hydroxydopamine through the rat knee joint causes an increase in plasma extravasation by activation of sympathetic neuron terminals. Similarly, the increase in plasma extravasation in the rat knee joint produced by the inflammatory mediator bradykinin is dependent on the sympathetic post-ganglion neuron. There is evidence that both 6-hydroxydopamine and bradykinin release a number of mediators, some of which appear to enhance plasma extravasation and some which inhibit it. We attempted to determine the nature of inhibitory factor(s) by co-infusing trypsin (which rapidly cleaves peptides) with 6-hydroxydopamine. We observed a marked enhancement of 6-hydroxydopamine-induced plasma extravasation by trypsin. This effect appeared to be specific to neurogenic plasma extravasation since trypsin alone had little effect on plasma extravasation and trypsin did not affect non-neurogenic plasma extravasation (that produced by platelet activating factor). Taken together, the data suggests that 6-hydroxydopamine not only releases mediators from the sympathetic neuron that produce plasma extravasation, but also an inhibitor(s) of plasma extravasation that is peptide in nature.