title: Endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 prevents hypertensive cardiac remodeling in a blood pressure-independent manner.
abstract: Hypertensive heart disease is a major contributor to cardiovascular mortality. Endothelin is a potent vasoconstrictive and profibrotic mediator produced by the endothelin-converting enzyme (ECE), whereas natriuretic peptides, degraded by the neutral endopeptidase (NEP), have diuretic, vasodilatory, and antifibrotic properties. Thus, combined ECE/NEP inhibition may halt hypertensive cardiac remodeling. This study examined effects of SLV338, a novel ECE/NEP inhibitor, on cardiac protection in experimental renovascular hypertension (2-kidney, 1-clip [2K1C]). Male rats were allocated to 5 groups: sham-operated rats, untreated animals with 2K1C, 2K1C animals treated with oral SLV338 (30 and 100 mg/kg per day), and 2K1C animals treated with oral losartan (20 mg/kg per day). Treatment duration was 12 weeks. Blood pressure was assessed every 4 weeks. At study end, hearts were taken for histology/computer-aided histomorphometry/immunohistochemistry. Pharmacological properties of SLV338 are described. SLV338 is a dual ECE/NEP inhibitor, as demonstrated both in vitro and in vivo. In the 2K1C study, losartan lowered blood pressure by ≤46 mm Hg, whereas both dosages of SLV338 had no effect. However, SLV338 (both dosages) completely normalized cardiac interstitial fibrosis, perivascular fibrosis, myocyte diameter, and media:lumen ratio of cardiac arteries, as did losartan. Cardiac transforming growth factor-β1 expression was significantly enhanced in untreated 2K1C rats versus controls, whereas treatment with SLV338 and losartan prevented this effect. Taken together, dual ECE/NEP inhibitor SLV338 prevents cardiac remodeling to the same extent as losartan, but in a blood pressure-independent manner, in a rat model of renovascular hypertension. This effect is at least partially mediated via suppression of cardiac transforming growth factor-β1 expression.
authors.affiliation: Department of Nephrology, Charité, Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kalk
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Sharkovska
authors.forename: Elena
authors.initials: E
authors.lastname: Kashina
authors.forename: Karoline
authors.initials: K
authors.lastname: von Websky
authors.forename: Katharina
authors.initials: K
authors.lastname: Relle
authors.forename: Thiemo
authors.initials: T
authors.lastname: Pfab
authors.forename: Markus
authors.initials: M
authors.lastname: Alter
authors.forename: Philippe
authors.initials: P
authors.lastname: Guillaume
authors.forename: Daniel
authors.initials: D
authors.lastname: Provost
authors.forename: Katrin
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Yvan
authors.initials: Y
authors.lastname: Fischer
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001794:Blood Pressure / Q000187:drug effects*; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006978:Hypertension, Renovascular / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D009206:Myocardium / Q000378:metabolism; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D053773:Transforming Growth Factor beta1; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes; D019808:Losartan