Dual NEP/ECE inhibition improves endothelial function in mesenteric resistance arteries of 32-week-old SHR

Hypertens Res. 2017 Aug;40(8):738-745. doi: 10.1038/hr.2017.38. Epub 2017 Mar 16.


Endothelin 1 (ET-1), a potent vasoconstrictor, pro-mitogenic and pro-inflammatory peptide, may promote development of endothelial dysfunction and arterial remodeling. ET-1 can be formed through cleavage of big-ET-1 by endothelin-converting enzyme (ECE) or neutral endopeptidase (NEP). We investigated whether chronic treatment with the novel dual NEP/ECE inhibitor SOL1 improves functional and structural properties of resistance-sized arteries of 32-week-old male spontaneously hypertensive rats (SHR). SHR received a chronic 4-week treatment with SOL1, losartan or hydralazine. We then compared effects of inhibition of NO synthase (NOS) (100 μM l-NAME), blockade of ETA- and ETB-receptors (10 μM bosentan) and stimulation of the endothelium with 0.001-10 μM acetylcholine (ACh) in isolated third-order mesenteric resistance arteries. Losartan and hydralazine significantly lowered blood pressure. Losartan decreased the media-to-lumen ratio of resistance arteries. l-NAME (1) increased arterial contractile responses to K+ (5.9-40 mM) in the losartan, SOL1 and vehicle group and (2) increased the sensitivity to phenylephrine (PHE; 0.16-20 μM) in the SOL1 group but not in the losartan, hydralazine and vehicle group. Relaxing responses to ACh in the absence or presence of l-NAME during contractions induced by either 10 μM PHE or 40 mM K+ were not altered by any in vivo treatment. Acute treatment with bosentan did, however, significantly improve maximal relaxing responses involving endothelium-derived nitric oxide and -hyperpolarizing factors in the SOL1 group but not in the losartan, hydralazine or vehicle group. Thus, chronic inhibition of NEP/ECE improved basal endothelial function but did not alter blood pressure, resistance artery structure and stimulated endothelium-dependent relaxing responses in 32-week-old SHR.

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Animals
  • Benzazepines / therapeutic use
  • Bosentan
  • Endothelin-Converting Enzymes / antagonists & inhibitors*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiopathology*
  • Enzyme Inhibitors / therapeutic use*
  • Hydralazine / therapeutic use
  • Hypertension / drug therapy*
  • Hypertension / physiopathology*
  • Losartan / therapeutic use
  • Mesenteric Arteries / drug effects
  • Mesenteric Arteries / physiopathology*
  • Muscle Contraction / drug effects
  • NG-Nitroarginine Methyl Ester / therapeutic use
  • Neprilysin / antagonists & inhibitors*
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Protease Inhibitors / therapeutic use*
  • Rats
  • Rats, Inbred SHR
  • Sulfonamides / therapeutic use
  • Vascular Resistance / drug effects


  • 2-((1-(((1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)amino)carbonyl)cyclopentyl)methyl)-4-((3-(methylamino)propyl)(methyl)amino)-4-oxobutanoic acid
  • Angiotensin II Type 1 Receptor Blockers
  • Benzazepines
  • Enzyme Inhibitors
  • Protease Inhibitors
  • Sulfonamides
  • Hydralazine
  • Nitric Oxide Synthase Type III
  • Neprilysin
  • Endothelin-Converting Enzymes
  • Losartan
  • Bosentan
  • NG-Nitroarginine Methyl Ester