Dual neural endopeptidase/endothelin-converting [corrected] 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

Research output: Contribution to journalJournal articleResearchpeer-review

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 μmol/l indomethacine), nitric oxide synthase inhibition (100 μmol/l N(ω)-L-nitro arginine methyl ester), and stimulation of the endothelium by 0.001-10 μmol/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
JournalJournal of Hypertension
Volume30
Issue number9
Pages (from-to)1799-1808
ISSN2167-1095
DOIs
Publication statusPublished - 2012

Keywords

  • Angiotensin-Converting Enzyme Inhibitors
  • Animals
  • Endothelium, Vascular
  • Hypertension
  • Mesenteric Arteries
  • Peptide Hydrolases
  • Protease Inhibitors
  • Rats
  • Rats, Inbred SHR
  • Rats, Inbred WKY

Fingerprint

Dive into the research topics of 'Dual neural endopeptidase/endothelin-converting [corrected] enzyme inhibition improves endothelial function in mesenteric resistance arteries of young spontaneously hypertensive rats'. Together they form a unique fingerprint.

Cite this