Effects of platelet-activating factor and thromboxane A2 on isolated perfused guinea pig liver

https://doi.org/10.1016/j.prostaglandins.2003.11.002Get rights and content

Abstract

Lipid mediators, thromboxane A2 (TxA2) and platelet-activating factor (PAF), are potent vasoconstrictors, and have been implicated as mediators of liver diseases, such as ischemic-reperfusion injury. We determined the effects of a TxA2 analogue (U-46619) and PAF on the vascular resistance distribution and liver weight (wt) in isolated guinea pig livers perfused with blood via the portal vein. The sinusoidal pressure was measured by the double occlusion pressure (Pdo), and was used to determine the pre- (Rpre) and post-sinusoidal (Rpost) resistances. U-46619 and PAF concentration-dependently increased the hepatic total vascular resistance (Rt). The minimum concentration at which significant vasoconstriction occurs was 0.001 μM for PAF and 0.1 μM for U-46619. Moreover, the concentration of U-46619 required to increase Rt to the same magnitude is 100 times higher than PAF. Thus, the responsiveness to PAF was greater than that to U-46619. Both agents increased predominantly Rpre over Rpost. U-46619 caused a sustained liver weight loss. In contrast, PAF also caused liver weight loss at lower concentrations, but it produced liver weight gain at higher concentrations (2.5±0.3 per 10 g liver weight at 1 μM PAF), which was caused by substantial post-sinusoidal constriction and increased Pdo. In conclusion, both TxA2 and PAF contract predominantly the pre-sinusoidal veins. TxA2 causes liver weight loss, while PAF at high concentrations increases liver weight due to substantial post-sinusoidal constriction in isolated guinea pig livers.

Introduction

Both platelet-activating factor (PAF) and thromboxane A2 (TxA2) are lipid mediators with potent vasoactive actions, and are released by a variety of cells, including platelets, neutrophils, macrophages (e.g. Kupffer cells), monocytes, lymphocytes, endothelial, and smooth muscle cells, in response to various stimuli [1], [2]. Either substance is implicated as a mediator of various types of liver diseases, such as endotoxin liver injury [3], [4], [5], ischemia–reperfusion liver injury [6], [7], [8], [9], and hepatic resection [8], [9], [10]. The microcirculation of the hepatic sinusoid plays a crucial role in the integrity of liver function [11]. PAF and TxA2 may influence the sinusoidal circulation, as a result of its vasoconstrictive action. Indeed, an infusion of the TxA2 analogue into the isolated perfused rat liver increases portal vein pressure, indicative of constriction of the hepatic vasculature [12], [13]. PAF also causes an increase in the portal vein pressure in in vivo animals [14], [15] and isolated perfused livers [16], [17]. More recently, we have reported by measuring the sinusoidal pressure using the hepatic vascular occlusion methods in isolated blood-perfused canine livers that the TxA2 analogue predominantly contracts the post-sinusoidal veins [18], while PAF contracts similarly both the pre- and post-sinusoidal veins [19]. However, there might be species differences in the primary site of hepatic vasoconstriction, and the effects of these lipid mediators on the hepatic vessels of guinea pigs are not known. Therefore, we examined using the hepatic vascular occlusion methods the effects of PAF and a TxA2 mimetic of U-46619, on hepatic vascular resistance distribution and liver weight (wt) in isolated perfused guinea pig livers.

Section snippets

Materials and methods

Twenty-five male Hartley guinea pigs weighing 351±31 (S.D.) g were used in this study. The experiments conducted in the present study were approved by the Animal Research Committee of Kanazawa Medical University.

Effect of PAF on hepatic hemodynamic variables, liver weight, and bile flow

Fig. 1 shows a representative example of variables after an injection of PAF. Soon after an injection of PAF at 0.1 μM, vasoconstriction occurred, as evidenced by an increase in Ppv. Ppv increased from the baseline of 7.7±0.8 cmH2O to the peak of 34.0±7.8 cmH2O within 2–4 min after PAF injection. Phv and blood flow did not change because of the constant flow rate perfusion. The double occlusion maneuver performed at 4 min after PAF revealed that Pdo increased from the baseline value of 3.4±0.2 cmH2O

Discussion

The present study has shown that both PAF and U-46619 contract predominantly the pre-sinusoidal veins over the post-sinusoidal veins in isolated perfused guinea pig livers. U-46619 causes liver weight loss, while PAF at high concentrations increases liver weight due to substantial post-sinusoidal constriction.

We have recently reported using the same isolated guinea pig liver preparation that hepatic anaphylaxis induced by ovalbumin antigens causes marked venoconstriction and liver weight gain,

Acknowledgements

This work was supported by a grant for Collaborative Research from Kanazawa Medical University (C2003-1) and a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Sciences and Technology of Japan (No. 15591665).

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