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Dual ECE/NEP inhibition and ETA/B receptor antagonists: Two ways of inhibiting endogenous ET‐1 effects in resistance arteries
Author(s) -
Lemkens Pieter,
Nelissen Jelly,
Meens Merlijn JPMT,
Bost Jet GP,
Janssen Ben JA,
Schiffers Paul MH,
De Mey Jo GR
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.631.2
Endothelin‐1 (ET‐1), a 21 amino acid peptide, can be formed by endothelin converting enzyme (ECE) and neutral endopeptidases (NEP). The DOCA‐salt hypertension model is reported to display enhanced ET‐1 function. We investigated in isolated rat mesenteric resistance arteries (MA) whether (1) synthesis of endogenous ET‐1 can be inhibited by the dual ECE/NEP inhibitors phosphoramidon (PRD) and SOL‐1 and (2) the mixed ETA/B‐receptor antagonist bosentan (BOS) and PRD affect vasomotor responses to a candidate stimulus of ET‐1‐release (BJP 156, 1239, 2009). Vascular synthesis of ET‐1 was induced by thrombin (TRB, 5 IEU for 3 hours) in isolated MA from 16 week old WKY rats and monitored by RIA. Arterial contractile responses to K+ were recorded by myography. Incubation with TRB increased ET‐1 content in MA by 3‐fold. This increase was significantly reduced in the presence of PRD (10μM) or SOL‐1 (10μM). BOS (10 μM) as well as PRD (10 μM) reduced K+‐induced contractions in isolated MA of DOCA‐salt hypertensive rats, no effect of BOS was measured in MA of control rats. After removal of the endothelium, BOS had no effect on K+‐induced contractions in MA of DOCA‐salt hypertensive rats. Conclusion (1) PRD and SOL‐1 are effective in inhibiting ET‐1 synthesis and (2) in resistance arteries of DOCA‐salt hypertensive rats, endothelium‐derived ET‐1 enhances arterial smooth muscle tone. This study was performed within TIP project T2‐108