ENDOTHELIN-1 PRODUCTION AND AGONIST ACTIVITIES IN CULTURED PROSTATE-DERIVED CELLS - IMPLICATIONS FOR REGULATION OF ENDOTHELIN BIOACTIVITY AND BIOAVAILABILITY IN PROSTATIC HYPERPLASIA

BACKGROUND. Endothelin-l (ET-1) interacts with specific G-protein-coup led receptors to initiate short-term (contraction) and long-term (mito genesis) events in target cells. ET-1 is an abundant prostate secretor y protein that, in its biologically active form, elicits prostatic smo oth muscle contraction. The present study was designed to determine th e effects of ET-1 on prostate cell growth and to examine the regulatio n of endogenous ET-1 activity and bioavailability. METHODS. Primary cu ltures of prostate secretory epithelial (PE) and prostate fibromuscula r stromal (PS) cells were established from benign human prostate tissu e. RESULTS. In culture, PE cells secrete immunoreactive ET-1 (38.5 +/- 1.6 pg/ml/10(6) cells/24 hr) into the conditioned medium. Levels of i mmunoreactive ET-1 produced by PS cells were more than 10-fold lower. Endothelin-converting enzyme-1 (ECE-1) mRNA was detected in PE cells a nd not in PS cells; however, big ET-1 was the predominant immunoreacti ve ET-1 secretory product of PE cells. The ETB endothelin receptor was the predominant subtype in both PE and PS cells. Ln PS cells, but not PE cells, ET-1 induced significant inositol phosphate accumulation an d [H-3]-thymidine uptake. Agonist activity was inhibited by the ETB re ceptor selective antagonist, BQ 788. Intact PE cell monolayers secrete ET-1 through the apical surface, consistent with secretion of ET-1 in to the glandular lumen in vivo. CONCLUSIONS. On the basis of these fin dings, regulation of ET-1 activity and bioavailability appears to be t ightly regulated. Such findings have important implications in the pat hophysiology of prostate disease. (C) 1998 Wiley-Liss, Inc.