Production and effects of endothelin-1 in rat pancreatic stellate cells.

Abstract

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. 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. 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. 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. 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.