Mast cells and other cells such as macrophages have been shown to mediate systemic anaphylaxis. We determined the roles of mast cells and Kupffer cells in hepatic and systemic anaphylaxis of rats. Roles of mast cells were examined by using the mast cell-deficient white spotting (Ws/Ws) rat; the Ws/Ws and wild type (ϩ/ϩ) rats were sensitized with ovalbumin (1 mg). Roles of Kupffer cells were examined by depleting Kupffer cells using gadolinium chloride or liposome-encapsulated dichloromethylene diphosphonate in the Ws/Ws and Sprague-Dawley rats. An intravenous injection of 0.6 mg ovalbumin caused substantial anaphylactic hypotension in both the Ws/Ws and ϩ/ϩ rats; however, the occurrence was delayed in the Ws/Ws rats. After antigen, portal venous pressure increased by 13.1 cmH 2O in the ϩ/ϩ rats, while it increased only by 5.7 cmH2O in the Ws/Ws rats. In response to antigen, the isolated perfused liver of the Ws/Ws rats also showed weak venoconstriction, the magnitude of which was one tenth as large as that of the ϩ/ϩ rats, indicating that hepatic anaphylaxis was primarily due to mast cells. In contrast, Kupffer cell depletion did not attenuate anaphylactic hepatic venoconstriction in isolated perfused livers. In conclusion, mast cells are involved mainly in anaphylactic hepatic presinusoidal portal venoconstriction but only in the early stage of anaphylactic systemic hypotension in rats. Macrophages, including Kupffer cells, do not participate in rat hepatic anaphylactic venoconstriction. blood pressure; hemodynamics; macrophages; anaphylactic shock; hepatic circulation ANAPHYLAXIS IS AN IMMEDIATE, type-1 hypersensitivity reaction that occurs after exposure of sensitized organisms and tissues to sensitizing antigen. The most common life-threatening feature of acute anaphylaxis is cardiovascular collapse and shock (29). Although anaphylaxis is classically mediated by histamine released in response to antigen cross-linking of IgE bound to high-affinity Ig-E receptors, FcεRI, on mast cells, both human and rodent studies indicate that this classical pathway does not account for all anaphylactic responses (3,10,21,26). Indeed, systemic anaphylaxis can be induced in genetically mast cell-deficient mice (13, 15). Moreover, lethal active anaphylactic shock was as likely to develop in mast cell-deficient W/W V as in normal mice (1,13,15,31). In contrast to mice, the role of mast cells in anaphylactic hypotension is not clear for rats: Nishida et al. (22) reported the lack of anaphylactic hypotension in the genetically mast cell-deficient rats "white spotting"; Ws/Ws (23) sensitized with the nematode Nippostrongylus brasiliensis, whereas Guo et al. (12) found similar hypotensive responses in both mast cell-deficient Ws/Ws and their wild-type (ϩ/ϩ) control rats. Thus, the necessary participation of mast cells in anaphylactic hypotension in rats is now being seriously questioned.On the other hand, two distinctive pathways of systemic anaphylaxis have been demonstrated in mice (11, 30): one mediated by mast cells, IgE, FcεRI...