title: Dual NEP/ECE inhibition improves endothelial function in mesenteric resistance arteries of 32-week-old SHR.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Lemkens
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Leon Ja
authors.initials: LJ
authors.lastname: Spijkers
authors.affiliation: Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.|Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.|Department of Medical Specialties-Cardiology, University of Geneva, Geneva, Switzerland.
authors.forename: Merlijn J
authors.initials: MJ
authors.lastname: Meens
authors.affiliation: Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: Jelly
authors.initials: J
authors.lastname: Nelissen
authors.affiliation: Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: Ben
authors.initials: B
authors.lastname: Janssen
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Stephan Lm
authors.initials: SL
authors.lastname: Peters
authors.affiliation: Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
authors.forename: Paul Mh
authors.initials: PM
authors.lastname: Schiffers
authors.affiliation: Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.|Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Jo Gr
authors.initials: JG
authors.lastname: De Mey
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000818:Animals; D001552:Benzazepines / Q000627:therapeutic use; D000077300:Bosentan; D000072396:Endothelin-Converting Enzymes / Q000037:antagonists & inhibitors*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006830:Hydralazine / Q000627:therapeutic use; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology*; D019808:Losartan / Q000627:therapeutic use; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology*; D009119:Muscle Contraction / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000627:therapeutic use; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D013449:Sulfonamides / Q000627:therapeutic use; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: C577035:2-((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; D047228:Angiotensin II Type 1 Receptor Blockers; D001552:Benzazepines; D004791:Enzyme Inhibitors; D011480:Protease Inhibitors; D013449:Sulfonamides; D006830:Hydralazine; D052250:Nitric Oxide Synthase Type III; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes; D019808:Losartan; D000077300:Bosentan; D019331:NG-Nitroarginine Methyl Ester