1 Intravenous injection of ioxaglate (4 g iodine kg
71), an iodinated radiographic contrast medium, caused a marked protein extravasation, pulmonary oedema and a decrease in the arterial partial oxygen pressure in rats. 2 All of these reactions to ioxaglate were reversed by the pretreatment with gabexate mesilate (10 and 50 mg kg
71, 5 min prior to injection) or nafamostat mesilate (3 and 10 mg kg 71 ), in which the inhibition was complete after injection of nafamostat mesilate (10 mg kg 71 ). 3 Both gabexate mesilate and nafamostat mesilate inhibited the activity of puri®ed human lung tryptase, although the latter compound was far more potent than the former. 4 Ioxaglate enhanced the nafamostat-sensitive protease activity in the extracellular¯uid of rat peritoneal mast cell suspensions. 5 Tryptase enhanced the permeability of protein through the monolayer of cultured human pulmonary arterial endothelial cells. Ioxaglate, when applied in combination with rat peritoneal mast cells, also produced the endothelial barrier dysfunction. These eects of tryptase and ioxaglate were reversed by nafamostat mesilate. 6 Consistent with these ®ndings, immuno¯uorescence morphological analysis revealed that tryptase or ioxaglate in combination with mast cells increased actin stress ®bre formation while decreasing VE-cadherin immunoreactivity. Both of these actions of tryptase and ioxaglate were reversed by nafamostat mesilate. 7 These ®ndings suggest that tryptase liberated from mast cells plays a crucial role in the ioxaglateinduced pulmonary dysfunction. In this respect, nafamostat mesilate may become a useful agent for the cure or prevention of severe adverse reactions to radiographic contrast media. British Journal of Pharmacology (2003) 138, 959 ± 967. doi:10.1038/sj.bjp.0705121 Keywords: Radiographic contrast media; vascular hyperactivity; pulmonary edema; endothelial barrier function; tryptase; actin stress ®bre; VE-cadherin Abbreviations: BSA, bovine serum albumin; HBSS, Hank's balanced salt solution; HPAECs, human pulmonary arterial endothelial cells; PAR-2, proteinase-activated receptor-2; PBS, phosphate buered saline; RCM, radiographic contrast media; t-Boc-Phe-Ser-Arg-
IntroductionIn spite of increasing use of radiographic contrast media (RCM), no eective prevention or therapy for the anaphylactoid reactions, including bronchospasm, dyspnea, laryngeal oedema and pulmonary oedema accompanying respiratory distress, induced by the intravascular injection of RCM has yet been established. The pulmonary oedema is a serious lifethreatening adverse event, although the incidence is rare. The RCM-induced pulmonary oedema is a non-cardiogenic type and appears to be related to the increase in pulmonary vascular permeability subsequent to the activation of in¯ammatory cascade or the release of a variety of chemical mediators (Bouachour et al., 1991). Although the precise mechanisms underlying the RCM-induced vascular hyperpermeability or pulmonary dysfunction remain to be clari®ed, several lines of evidence have suggested that ...
