Abstract
Endothelin-1 (ET-1) is considered to be involved in various cardiovascular and renal disorders. The objective of this study was to investigate whether a vasodilator and antiplatelet agent, 1,4-bis[3-(3,4,5-trimethoxybenzoyloxy) propyl]perhydro-1,4-diazepine dihydrochloride monohydrate (dilazep, DZ), has an ET-1-inhibiting effect in vitro. Bovine aortic endothelial cells (BAEC) and human umbilical vein endothelial cells (HUVEC) pretreated with fetal calf serum were treated with DZ and preproET-1 (PpET-1) transcription was evaluated by Northern blot analysis. ET-1 peptide release in culture medium was evaluated by radioimmunoassay. The effect of DZ on the ET-1 promoter/enhancer apparatus was evaluated in transfection experiments using -5 kb ET-1 promoter/enhancer constructs. Modest inhibition of PpET-1 gene transcription was detected after 30 min of DZ treatment (0.56+/-0.19 vs. 1 , p<0.01) and more marked inhibition was seen at 24 h (0.04+/-0.04 vs. 1, p<0.0001). ET-1 peptide release was suppressed strongly after 3 h (382.5+/-2.9 vs. 673.5+/-74.5pg/ml, p< 0.001) and 24 h (38.8+/-9.8 vs. 5,075+/-52.0pg/ml, p<0.0001). DZ potently inhibited PpET-1 transcription in a concentration-dependent manner (0.42+/-0.18 vs. 1, p<0.001, at 100...Continue Reading
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