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