Vessel and Target Cell Specific Actions of Endothelin-1 and
Endothelin-3 in Rat Liver.
Zhang, Jian X., Michael Bauer, and Mark G. Clemens.
Department of Surgery, The Johns Hopkins University School of
Medicine, Baltimore, Maryland 21287
APStracts 2:0055G, 1995.
We studied the sinusoidal and extrasinusoidal constrictor response of
hepatic microcircu lation to endothelin-1 (ET-1) and endothelin-3
(ET-3) and the possible role of Ito cells versus Kupffer cells or
endothelial cells in mediating this response using isolated rat
livers under high power intravital microscopy. Rats were pretreated
by injection of 2.6x108 fluorescent latex beads (1 [mu]m) i.v. 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 ETA receptor antagonist BQ-123 or ETB antagonist IRL
1038, or alternatively the perfused livers were infused with the ETB
agonist sarafotoxin 6c (S6c, 1 nM or 5 nM). Sinusoid diameters were
quantitated at the sites of Ito cells (identified by vitamin A
fluorescence) or Kupffer cells (phagocytosed 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 Kupffer cells nor endothelial cells only
(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 in spite of a 1.8 fold (ET-3) or 5.6 fold (5 nM
S6c) greater increase in total portal resistance compared to 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 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 ETA receptors on Ito cells while the
presinusoidal effects are at least in part mediated by ETB receptors,
most likely in portal venules.
Received 1 September 1994; accepted in final form 13 March 1995.
APS Manuscript Number G333-4.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 4 April 1995.