TY  - JOUR
A1  - Kalk, Philipp
A1  - Sharkovska, Yuliya
A1  - Kashina, Elena
A1  - von Websky, Karoline
A1  - Relle, Katharina
A1  - Pfab, Thiemo
A1  - Alter, Markus L.
A1  - Guillaume, Philippe
A1  - Provost, Daniel
A1  - Hoffmann, Katrin
A1  - Fischer, Yvan
A1  - Hocher, Berthold
T1  - Endothelin-Converting Enzyme/Neutral Endopeptidase Inhibitor SLV338
 Prevents Hypertensive Cardiac Remodeling in a Blood Pressure-Independent
 Manner
JF  - HYPERTENSION
N2  - 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-beta 1 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-beta 1 expression. (Hypertension. 2011;57:755-763.)
KW  - renovascular hypertension
KW  - cardiac remodeling
KW  - endothelin-converting enzyme
KW  - neutral endopeptidase
KW  - TGF-beta 1
Y1  - 2011
U6  - https://doi.org/10.1161/HYPERTENSIONAHA.110.163972
SN  - 0194-911X
VL  - 57
IS  - 4
SP  - 755
EP  - 763
PB  - LIPPINCOTT WILLIAMS & WILKINS
CY  - PHILADELPHIA
ER  -