Kinetics of tachyphylaxis to mediators of acute inflammation.

The kinetics of vascular leakage and tachyphylaxis induced by histamine and bradykinin were examined in rabbit skin and were compared with the kinetics of tachyphylaxis of neutrophil accumulation in lesions induced with the chemotaxin formylmethionyl-leucyl-phenylalanine (FMLP). Maximal leakage of 125I-human serum albumin occurred during the first 5 min after injection of bradykinin and from 10 to 20 min after injection of histamine. Tachyphylaxis developed within 30 min of injection of bradykinin and 1 hr after injection of histamine. For both agents, there was a linear regression of sensitivity with time from 8 hr to 4 days, with normal sensitivity estimated to return at 4.6 days for bradykinin and 4.7 days for histamine. Marked cross-desensitization occurred between the two agents, and lesions initiated with the chemotaxin FMLP were desensitized to restimulation with a mixture of histamine and bradykinin. Initiation of lesions with histamine and bradykinin did not diminish the accumulation of neutrophils when lesions were restimulated with FMLP. The kinetics of tachyphylaxis of neutrophil accumulation in lesions stimulated with FMLP exhibited a linear regression of sensitivity on time between 4 days and 10 days, with estimated resensitization at 11.9 days. Histamine and bradykinin induce enhanced vascular permeability when endothelial cells in post-capillary venules contract following stimulation of their membrane receptors for these agents. We have recently proposed that the migration of neutrophils into acute inflammatory lesions is regulated by a mechanism coupled to chemotaxin receptors which may be similarly located on endothelial cells within the lesions. The present experiments indicate that expression of receptors for vascular permeability agents and the chemotaxin FMLP are independent events with distinct kinetics.