Ruan, Zonghai, Toshishige Shibamoto, Tomohiro Shimo, Hideaki Tsuchida, Tomonobu Koizumi, and Matomo Nishio. NO, but not CO, attenuates anaphylaxis-induced postsinusoidal contraction and congestion in guinea pig liver. Am J Physiol Regul Integr Comp Physiol 286: R94-R100, 2004. First published October 2, 2003 10.1152/ ajpregu.00648.2002The pathophysiology of the hepatic vascular response to anaphylaxis in guinea pig is not known. We studied effects of anaphylaxis on hepatic vascular resistances and liver weight in isolated perfused livers derived from guinea pigs sensitized with ovalbumin. We also determined whether nitric oxide (NO) or carbon monoxide (CO) modulates the hepatic anaphylaxis. The livers were perfused portally and recirculatingly at constant flow with diluted blood. With the use of the double-occlusion technique to estimate the hepatic sinusoidal pressure (P do), portal venous resistance (Rpv) and hepatic venous resistance (Rhv) were calculated. An antigen injection caused venoconstriction characterized by an increase in R pv greater than Rhv and was accompanied by a large liver weight gain. Pretreatment with the NO synthase inhibitor N G -nitro-L-arginine methyl ester, but not the heme oxygenase inhibitor zinc protoporphyrin IX, potentiated the antigen-induced venoconstriction by increasing both R pv and Rhv (2.2-and 1.2-fold increase, respectively). In conclusion, anaphylaxis causes both pre-and postsinusoidal constriction in isolated guinea pig livers. However, the increases in postsinusoidal resistance and Pdo cause hepatic congestion. Endogenously produced NO, but not CO, modulates these responses. hepatic circulation; antigen; double occlusion pressure; hepatic vascular resistance 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, although there are other life-threatening effects, including bronchospasm, angioedema, and pulmonary edema (24). Cardiovascular manifestation includes a rapid and precipitous decrease in systemic arterial pressure with a concomitant decrease in cardiac output (5). Anaphylactic hypotension is primarily caused by alterations in the systemic circulation that influence blood flow to the heart because left ventricular function is relatively well preserved during anaphylactic shock (5). Peripheral circulatory collapse is ascribed to hypovolemia, which results from a plasma volume loss. The latter could be the result of vasodilation with the peripheral pooling in largecapacity splanchnic venous beds and increased vascular permeability with a shift of intravascular fluid to the extravascular space.In canine experimental models of anaphylactic shock, congestion of livers and the upstream splanchnic organs is important in the pathogenesis of circulatory collapse. Actually, eviscerated dogs did not develop anaphylactic shock (17). Enjeti et al. (5) reported that the severity of th...

There exist species differences in the hepatic vasculature between rat and guinea-pig. Basal pre-sinusoidal resistance in rat is greater than that in guinea-pig. Although noradrenaline predominantly contracts pre-sinusoidal vessels in both species, histamine causes predominant post-sinusoidal vasoconstriction in guinea-pig liver, while it has no vasoactive effects on rat liver.

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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...

1. The effects of the nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) on anaphylaxis-induced venoconstriction were examined in rat isolated livers perfused with blood-free solutions in order to clarify the role of NO in anaphylactic venoconstriction. 2. Rats were sensitized with ovalbumin (1 mg) and, 2 weeks later, livers were excised and perfused portally in a recirculating manner at a constant flow with Krebs'-Henseleit solution. The antigen (ovalbumin; 0.1 mg) was injected into the reservoir 10 min after pretreatment with L-NAME (100 micromol/L) or D-NAME (100 micromol/L) and changes in portal vein pressure (Ppv), hepatic vein pressure (Phv) and perfusate flow were monitored. In addition, concentrations of the stable metabolites of NO ( and ) were determined in the perfusate using an HPLC-Griess system. 3. The antigen caused hepatic venoconstriction, as evidenced by an increase in Ppv from a mean (SEM) baseline value of 7.7 +/- 0.1 cmH2O to a peak of 21.4 +/- 1.1 cmH2O at 3 min in D-NAME-pretreated livers. Pretreatment with L-NAME augmented anaphylactic venoconstriction, as reflected by a higher Ppv (27.4 +/- 0.8 cmH2O) after antigen than observed following D-NAME pretreatment. The addition of L-arginine, a precursor for the synthesis of NO, reversed the augmentation of anaphylactic venoconstricion by L-NAME. This suggests that hepatic anaphylaxis increased the production of NO, which consequently attenuated anaphylactic venoconstriction. However, perfusate NOx levels did not increase significantly after antigen in livers pretreated with either L-NAME or D-NAME. 4. In conclusion, L-NAME potentiates rat anaphylactic hepatic venoconstriction, suggesting that NO contributes to the attenuation of the venoconstriction. However, this functional evidence was not accompanied by corresponding changes in perfusate NOx concentrations.