Production and effects of endothelin-1 in rat pancreatic stellate cells.
BACKGROUND
Proliferation and matrix synthesis of activated pancreatic stellate cells (PSCs) participate in the development of chronic pancreatitis. Besides other substances, endothelin-1 (ET-1) may influence the activation process of PSCs. Until now, ET-1 has not been studied in this particular cell type.


OBJECTIVE
To characterize PSCs in rat pancreas with respect to expression of ET(A)-receptors, production of ET-1, and physiological effects induced by ET-1 during PSC activation.


METHODS
Immunocytochemical and ELISA techniques and cDNA microarray analysis were used. Physiologic effects were characterized by single cell measurements of free cytosolic Ca2+-concentration and of PSC contractility on collagen lattices.


RESULTS
Activation of PSCs in vitro, as assessed by alpha-smooth muscle actin expression, was accompanied by the de novo expression of ET(A)-receptors and synthesis of ET-1 mRNA and protein. Cytosolic Ca2+-concentration was increased upon ET-1 stimulation in activated but not in quiescent PSCs. Contractility of activated PSCs was significantly reduced by the selective ET(A)-receptor antagonist BQ123 but not by the ET(B)-receptor antagonist IRL-1038.


CONCLUSIONS
The results suggest that ET-1 may act as a paracrine and autocrine factor for activated PSCs and may mediate contractions of activated, but not quiescent, PSCs.
Klonowski-Stumpe
Hanne
H
Clinic of Gastroenterology, Hepatology and Infectiology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. Hanne.Klonowski-Stumpe@uni-duesseldorf.de
Reinehr
Roland
R
Fischer
Richard
R
Warskulat
Ulrich
U
Lüthen
Reinhard
R
Häussinger
Dieter
D
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology*; D016232:Endothelins / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C077420:Cys(11)-Cys(15)-endothelin-1 (11-21); C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium