Dual neural peptidase/endothelin-converting enzyme inhibition improves endothelial function in mesenteric resistance arteries of young spontaneously hypertensive rats

Pieter Lemkens, Jelly Nelissen, Merlijn J. P. M. T. Meens, Ben J. A. Janssen, Paul M. H. Schiffers, Jo G. R. De Mey*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Web of Science)

Abstract

Background: Endothelin-1 (ET1) is a potent vasoconstrictor peptide with pro-mitogenic and pro-inflammatory properties and is therefore of interest in the development of endothelial dysfunction, endothelium-dependent flow-related remodeling, and hypertension-related remodeling. ET1 can be formed through cleavage of big ET1 by endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP). Method: We investigated whether the dual NEP/ECE inhibitor SOL1 improves resistance artery function and structure in 12 weeks old spontaneously hypertensive rats (SHRs) and whether arterial structural responses to decreased (-90%) or increased (+100%) blood flow are impaired in young SHRs. To this end two groups of SHRs received chronic 4-week treatment at two different time points (4-8 and 8-12 weeks) prior to the experiment. We compared in-vitro effects of cyclo-oxygenase inhibition (1 mu mol/l indomethacine), nitric oxide synthase inhibition (100 mu mol/l N-omega-L-nitro arginine methyl ester), and stimulation of the endothelium by 0.001-10 mu mol/l acetylcholine (ACh) in isolated third-order mesenteric arteries of SHRs and aged-matched Wistar-Kyoto (WKY) rats. Results: SOL1 had no effect on blood pressure in SHRs or WKY rats. ACh caused biphasic effects in mesenteric arteries of SHRs. The contractile component (endothelium-derived contractile factor) was absent in WKY and abolished by acute indomethacin administration or chronic SOL1 treatment. Endothelium-derived nitric oxide-type responses did not differ in both strains and were not influenced by SOL1 treatment. Endothelium-derived hyperpolarizing factor-type responses were severely impaired in SHRs as compared to WKY rats and were normalized by chronic SOL1 treatment. In first-order mesenteric arteries, outward flow-induced remodeling was impaired in SHRs. Chronic SOL1 treatment did not restore this response. Conclusion: Thus chronic SOL1 treatment during the development of hypertension in SHRs has no effect on blood pressure but improves several aspects of endothelium-dependent vasomotor responses but not arterial remodeling.
Original languageEnglish
Pages (from-to)1799-1808
JournalJournal of Hypertension
Volume30
Issue number9
DOIs
Publication statusPublished - Sep 2012

Keywords

  • arterial remodeling
  • endothelial function
  • hypertension
  • neural peptidase/endothelin-converting enzyme inhibition
  • resistance artery
  • spontaneously hypertensive rats
  • vascular structure

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