Sen Cui

PAF, rather than Histamine, Participates in Mouse Anaphylactic Hypotension

We determined the roles of platelet-activating factor (PAF) and histamine in anaphylactic hypotension in ovalbumin-sensitized anesthetized BALB/c mice. The effects of PAF and histamine on hemodynamic variables were studied by measuring the systemic arterial (Psa), portal venous (Ppv) and central venous (Pcv) pressures. Intravenous PAF evoked a biphasic Psa response, an initial rapid and transient drop followed by marked hypotension, accompanied by a decrease in Pcv. Histamine caused only mild systemic hypotension. Both agents similarly increased Ppv by approximately 4 cm H2O at high doses. After an injection of antigen, Psa initially increased slightly and then decreased from the baseline of 94 ± 1 mm Hg to 46 ± 1 mm Hg at 10 min after antigen administration, with Pcv decreasing by 2.5 cm H2O. Ppv increased by 3.5 cm H2O at 5 min after antigen injection. Pretreatment with either CV-6209 (PAF receptor antagonist, 1 mg/kg) or diphenhydramine (histamine H1 receptor antagonist, 20 mg/kg) significantly attenuated an antigen-induced decrease in Psa. The inhibitory action of CV-6209 was greater than that of diphenhydramine, and the combination of these 2 antagonists almost completely inhibited the anaphylactic hypotension. In contrast, the antigen-induced increase in Ppv was attenuated by CV-6209 alone but augmented by diphenhydramine. It is concluded that anaphylactic hypotension is mainly mediated by PAF and, to a lesser extent, by histamine in anesthetized BALB/c mice.

Hepatic pre-sinusoidal vessels contract in anaphylactic hypotension in rabbits

Aim:  The purpose of this study was to determine whether anaphylactic hypotension in rabbits is accompanied by hepatic venoconstriction, and the effects of anaphylaxis on hepatic segmental vascular resistances and liver weight in isolated perfused rabbit livers.

7-nitroindazole, but not L-NAME or aminoguanidine, attenuates anaphylactic hypotension in conscious rats.

The roles of NO and isozymes of NO synthase (NOS) are not known in anaphylactic hypotension of unanesthetized rats. Effects of inhibition of NOS, iNOS, and nNOS by NG-nitro-L-arginine methyl ester (L-NAME), aminoguanidine, and 7-nitroindazole, respectively, were determined on the antigen-induced systemic hypotension and portal hypertension in conscious Sprague-Dawley rats sensitized with the ovalbumin antigen. The MAP and portal venous pressure were directly and simultaneously measured. The control rats showed a decrease in MAP along with an increase in portal venous pressure but did not die within 48 h after antigen injection. In the rats pretreated with the nonselective NOS inhibitor L-NAME (10 mg/kg), MAP before and after antigen administration was significantly higher than that of the control rats, but the net decrease in MAP and increase in portal venous pressure were rather greater than those of the control, resulting in fatal outcome within 12 h after antigen administration. In contrast, pretreatment with the relatively selective nNOS inhibitor 7-nitroindazole (50 mg/kg) substantially attenuated anaphylactic hypotension over 20 min after antigen administration, whereas the relatively selective iNOS inhibitor aminoguanidine (100 mg/kg) did not affect it. In conclusion, in anaphylactic hypotension of unanesthetized rats, NO derived from nNOS, but not from iNOS, may be involved, and the nonselective NOS inhibitor L-NAME is lethal.

Mouse Hepatic Portal Venoconstrictive Response to Vasoconstrictors Is Much Weaker Than That in Rat

We previously reported that the portal venous pressure (PPV) response of perfused mouse livers to various vasoactive agents was much weaker than that of other mammals such as rat, rabbit, and guinea pigs. The purpose of this study was to determine the responsiveness of PPV in in vivo BALB/c mouse to intraportal injections of the 3 major vasoconstrictors of angiotensin II, norepinephrine, and endothelin-1 in comparison with that in Sprague-Dawley rats. In anesthetized spontaneously breathing animals, PPV, systemic arterial pressure, and central venous pressure were directly and continuously measured. The above-mentioned vasoconstrictors were injected into the portal vein as a bolus repetitively at the doses ranging 0.01-100 nmol/kg. A dose-dependent increase in systemic arterial pressure in response to each vasoconstrictor was observed similarly in both mice and rats. All vasoconstrictors also caused a dose-dependent increase in PPV in both species, but the peak levels in mouse did not reach higher than 7 mm Hg, whereas it reached as high as 15-24 mm Hg in rats. Immunostaining for α-smooth muscle actin revealed that smooth muscles were distributed substantially in portal venules of rat but scarcely in that of mouse. In conclusion, PPV response to various vasoconstrictors was limited in anesthetized BALB/c mice, as compared with the anesthetized Sprague-Dawley rats, presumably due to small amount of vascular smooth muscle in mouse portal venules.

Effects of Hct on L-NAME-induced potentiation of anaphylactic presinusoidal constriction in perfused rat livers.

Effects of hematocrit (Hct) on NG-nitro-L-arginine methyl ester (L-NAME)-induced modulation of anaphylactic venoconstriction were determined in isolated perfused rat livers. The rats were sensitized with ovalbumin (1 mg), and the livers were excised 2 weeks later and perfused portally and recirculat-ingly under constant flow at Hct of 0%, 5%, 16%, and 22%. The hepatic sinusoidal pressure was estimated via the double occlusion pressure (Pdo), and the presinusoidal resistance (Rpre) and the postsinusoidal resistance (Rhv) were calculated. The antigen of ovalbumin 0.1 mg was injected into the reservoir at 10 minutes after pretreatment with L-NAME (100 μM) or D-NAME (100 μM). Perfusate viscosity, a determinant of vascular resistance and shear stress, was increased in parallel with Hct. In the D-NAME groups, antigen caused predominant presinusoidal constriction. The magnitude of venoconstriction was significantly smaller at Hct 0% than at Hct 5% to 22%, whereas no significant differences were found among Hct 5% to 22%. L-NAME potentiated the antigen-induced increase in Rpre, but not in Rpost at Hct 5% to 22% as compared with D-NAME. But the augmentative effects of L-NAME were similar in magnitude among Hct 5% to 22%. These findings suggest that hepatic anaphylaxis increases production of nitric oxide, which consequently attenuates anaphylactic presinusoidal constriction in rat livers, and that these effects are independent of perfusate Hct or viscosity in blood-perfused rat livers.

Oxygen consumption, assessed with the oxygen absorption spectrophotometer, decreases independently of venoconstriction during hepatic anaphylaxis in perfused rat liver

ABSTRACT Anaphylactic shock is accompanied by a decrease in oxygen consumption. However, it is not well known whether oxygen consumption decreases during local anaphylactic reaction in liver. We determined the effects of anaphylaxis and norepinephrine on oxygen consumption in isolated rat livers perfused portally and recirculatingly at constant flow with blood (hematocrit, 12%). Oxygen consumption was continuously measured by monitoring the portal-hepatic venous oxygen saturation differences using the absorption spectrophotometer, the probes of which were built in perfusion lines. Hepatic anaphylaxis was induced by an injection of ovalbumin (0.01 or 0.1 mg) into the perfusate of the isolated liver of the rat sensitized with subcutaneous ovalbumin (1 mg). Hepatic venoconstriction and liver weight loss were similarly observed in response to norepinephrine (0.01-10 &mgr;mol L−1) and anaphylaxis. However, hepatic anaphylaxis reduced oxygen consumption, whereas norepinephrine increased it. There was a possibility that anaphylactic venoconstriction could reduce the perfused surface area, resulting in decreased oxygen consumption. However, pretreatment with a vasodilator of sodium nitroprusside substantially attenuated venoconstriction but not the decrease in oxygen consumption during anaphylaxis. Thus, we conclude that local hepatic anaphylaxis decreases oxygen consumption independently of venoconstriction in isolated blood-perfused rat livers.

Exercise training attenuates anaphylactic venoconstriction in rat perfused liver, but does not affect anaphylactic hypotension in conscious rats.

1. Exercise training attenuates circulatory shock due to haemorrhage, endotoxin or heatstroke. However, it remains unknown whether exercise training attenuates anaphylactic shock. Hepatic venoconstriction is involved in rat anaphylactic hypotension. In the present study, we determined the effects of exercise training on both anaphylaxis‐induced segmental venoconstriction in rat perfused livers and systemic anaphylaxis in conscious rats. The role of nitric oxide (NO) in the effect of exercise on the venoconstriction of perfused livers was also examined.

NG-nitro-L-arginine methyl ester potentiates anaphylactic venoconstriction in rat perfused livers

1 The effects of the nitric oxide (NO) synthase inhibitor NG‐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 mmol/L) or d‐NAME (100 mmol/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.

Anaphylactic hepatic venoconstriction is attenuated by nitric oxide released via shear stress-dependent and -independent mechanisms in Guinea pig.

1. The role of shear stress in nitric oxide (NO)‐mediated attenuation of anaphylactic venoconstriction was studied using an isolated ovalbumin‐sensitized guinea pig liver.