Thromboxane A2 from Kupffer cells contributes to the hyperresponsiveness of hepatic portal circulation to endothelin-1 in endotoxemic rats.
We examined the role of thromboxane A2 (TXA2) in LPS-induced hyperresponsiveness of hepatic portal circulation to endothelins (ETs) and whether Kupffer cells are the primary source of TXA2 release in response to ET-1 in endotoxemia. After 6 h of LPS (1 mg/kg body wt ip) or saline (control), liver was isolated and perfused with recirculating Krebs-Henseleit bicarbonate buffer at a constant flow rate (100 ml.min(-1).kg body wt(-1)). ET-1 (10 pmol/min) was infused for 10 min. Portal pressure (PP) was continuously monitored during perfusion. Perfusate was sampled for enzyme immunoassay of thromboxane B2 (TXB2; the stable metabolite of TXA2) and lactate dehydrogenase (LDH) assay. ET-1 infusion resulted in a significantly greater increase of PP in the LPS group than in controls. Both TXA2 synthase inhibitor furegrelate (Fureg) and TXA2 receptor antagonist SQ-29548 (SQ) substantially blocked enhanced increase of PP in the LPS group (4.9 +/- 0.4 vs. 3.6 +/- 0.5 vs. 2.6 +/- 0.6 mmHg for LPS alone, LPS + Fureg, and LPS + SQ, respectively; P < 0.05) while having no significant effect on controls. GdCl3 for inhibition of Kupffer cells had similar effects (4.9 +/- 0.4 mmHg vs. 2.9 +/- 0.4 mmHg for LPS alone and GdCl3 + LPS, respectively; P < 0.05). In addition, the attenuated PP after ET-1 was found concomitantly with significantly decreased releases of TXB2 and LDH in LPS rats treated with Fureg, SQ, and GdCl3 (886.6 +/- 73.4 vs. 110.8 +/- 0.8 vs. 114.8 +/- 54.7 vs. 135.2 +/- 45.2 pg/ml, respectively; P < 0.05). After 6 h of LPS, Kupffer cells in isolated cell preparations released a significant amount of TXA2 in response to ET-1. These results clearly indicate that hyperresponsiveness of hepatic portal circulation to ET-1 in endotoxemia is mediated at least in part by TXA2-induced receptor activation, and Kupffer cells are likely the primary source of increased TXA2 release.
Xu
Hongzhi
H
Department of Biology, University of North Carolina at Charlotte, 9201 Univ. City Blvd., Charlotte, NC 28223, USA.
Korneszczuk
Katarzyna
K
Karaa
Amel
A
Lin
Tian
T
Clemens
Mark G
MG
Zhang
Jian X
JX
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019332:Endothelin-1 / Q000494:pharmacology / Q000502:physiology*; D019446:Endotoxemia / Q000503:physiopathology*; D005231:Fatty Acids, Unsaturated; D005682:Gadolinium / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology; D007728:Kupffer Cells / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides; D008099:Liver / Q000098:blood supply* / Q000503:physiopathology; D008297:Male; D017082:Portal Pressure / Q000187:drug effects; D011168:Portal System / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000502:physiology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D001572:Benzofurans; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019332:Endothelin-1; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D008070:Lipopolysaccharides; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; C045749:SQ 29548; D005682:Gadolinium; D013930:Thromboxane-A Synthase; C039936:furegrelate; C038958:gadolinium chloride