Vessel- and target cell-specific actions of endothelin-1 and endothelin-3 in rat liver
Zhang, J.X.; Bauer, M.; Clemens, M.G.
American Journal of Physiology 269(2 Pt 1): G269-G277
1995
ISSN/ISBN: 0002-9513 PMID: 7653568 Document Number: 444421
We studied the sinusoidal and extrasinusoidal constrictor response of hepatic microcirculation to endothelin-1 (ET-1) and endothelin-3 (ET-3) and the possible role of Ito cells vs. Kupffer cells or endothelial cells in mediating this response, using isolated rat livers under high-power intravital microscopy. Rats were pretreated by injection of 2.6 times 10-8 fluorescent latex beads (1 mu-m) intravenously to label Kupffer cells. Three hours later livers were isolated and perfused before and during the infusion of 1 nM ET-1 or ET-3 with or without the endothelin type A (ETA) receptor antagonist BQ-123 or ET-B antagonist IRL-1038. Alternatively, the perfused livers were infused with the ETB agonist sarafotoxin 6c (S6c, 1 or 5 nM). Sinusoid diameters were quantitated at the sites of Ito cells (identified by vitamin A fluorescence) or Kupffer cells (phagoeytosed fluorescent latex beads) or where neither cell type was found (endothelial cells). ET-1 was found to induce significant sinusoid constriction at the sites of Ito cells (13.21 +- 0.58 mu-m control vs. 10.47 +- 0.48 mu-m during ET-1 infusion) but not at the sites of Kupffer cells or endothelial cells (13.26 +- 0.79 vs. 12.92 +- 0.61 mu-m and 12.20 +- 0.71 vs. 11.98 +- 0.40 mu-m, respectively), whereas neither ET-3 nor S6c had any effect on sinusoid narrowing, despite a 1.8-fold (ET-3) or 5.6-fold (5 nM S6c) greater increase in total portal resistance compared with ET-1. BQ-123 inhibited the sinusoidal constriction (12.07 +- 0.59 vs. 11.28 +- 0.47 mu-m during ET-1 perfusion) but not the portal pressure response to ET- 1. Conversely, IRL- 1038 inhibited the portal pressure but not the sinusoidal response to ET-1. These results suggest that the effects of exogenous ET-1 on sinusoidal constriction in normal livers are predominately mediated by contraction of Ito cells, with little contribution by Kupffer cells, and the ET-1-induced sinusoid constriction is mediated by ET-A receptors on Ito cells, whereas the presinusoidal effects are at least in part mediated by ET-B receptors, most likely in portal venules.