Endothelin-1 Gene Expression in Endothelial Cells Is Potently Inhibited by a Vasodilator, Dilazep

DOI PubMed 61 References
  • SHRESTHA Balaram
    Department of Cardiology, Tokyo Women’s Medical University
  • HIDAI Chiaki
    Department of Cardiology, Tokyo Women’s Medical University Second Department of Physiology, Nihon University School of Medicine
  • IKEDA Hiromi
    Department of Cardiology, Tokyo Women’s Medical University
  • OKADA-OHNO Masako
    Department of Cardiology, Tokyo Women’s Medical University
  • KASANUKI Hiroshi
    Department of Cardiology, Tokyo Women’s Medical University
  • KAWANA Masatoshi
    Department of Cardiology, Tokyo Women’s Medical University

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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±74.5 pg/ml, p <0.001) and 24 h (38.8±9.8 vs. 5,075±52.0 pg/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 μmol/l). DZ suppressed PpET-1 transcription in confluent HUVEC at 3 h (0.41±0.11 vs. 1, p <0.0001). DZ strongly inhibited PpET-1 transcription after 1 h of thrombin (TH) treatment (0.30±0.01 vs. 1.51±0.03, p <0.0001). Transfection experiments using the 5 kb ET-1 promoter-luciferase plasmid revealed that DZ strongly suppressed ET-1 promoter activity by 99% (p <0.01). DZ potently inhibited ET-1 gene expression at the transcription level in serum- or TH-treated endothelial cells. (Hypertens Res 2004; 27: 409-415)

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