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 - TY - JOUR A1 - Hocher, Berthold A1 - Heiden, Susi A1 - von Websky, Karoline A1 - Arafat, Ayman M. A1 - Rahnenführer, Jan A1 - Alter, Markus L. A1 - Kalk, Philipp A1 - Ziegler, Dieter A1 - Fischer, Yvan A1 - Pfab, Thiemo T1 - Renal effects of the novel selective adenosine A(1) receptor blocker SLV329 in experimental liver cirrhosis in rats JF - PLoS one N2 - Liver cirrhosis is often complicated by an impaired renal excretion of water and sodium. Diuretics tend to further deteriorate renal function. It is unknown whether chronic selective adenosine A(1) receptor blockade, via inhibition of the hepatorenal reflex and the tubuloglomerular feedback, might exert diuretic and natriuretic effects without a reduction of the glomerular filtration rate. In healthy animals intravenous treatment with the novel A(1) receptor antagonist SLV329 resulted in a strong dose-dependent diuretic (up to 3.4-fold) and natriuretic (up to 13.5-fold) effect without affecting creatinine clearance. Male Wistar rats with thioacetamide-induced liver cirrhosis received SLV329, vehicle or furosemide for 12 weeks. The creatinine clearance of cirrhotic animals decreased significantly (-36.5%, p < 0.05), especially in those receiving furosemide (-41.9%, p < 0.01). SLV329 was able to prevent this decline of creatinine clearance. Mortality was significantly lower in cirrhotic animals treated with SLV329 in comparison to animals treated with furosemide (17% vs. 54%, p < 0.05). SLV329 did not relevantly influence the degree of liver fibrosis, kidney histology or expression of hepatic or renal adenosine receptors. In conclusion, chronic treatment with SLV329 prevented the decrease of creatinine clearance in a rat model of liver cirrhosis. Further studies will have to establish whether adenosine A(1) receptor antagonists are clinically beneficial at different stages of liver cirrhosis. Y1 - 2011 U6 - https://doi.org/10.1371/journal.pone.0017891 SN - 1932-6203 VL - 6 IS - 3 PB - PLoS CY - San Fransisco ER - TY - JOUR A1 - Sharkovska, Yuliya A1 - Kalk, Philipp A1 - von Websky, Karoline A1 - Relle, Katharina A1 - Pfab, Thiemo A1 - Alter, Markus L. A1 - Fischer, Yvan A1 - Hocher, Berthold T1 - Renoprotective effects of combined endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 in acute and chronic experimental renal damage JF - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion N2 - Background: Acute kidney injury (AKI) as well as chronic renal failure are associated with a huge mortality/morbidity. However, so far no drugs have been approved for the treatment of acute kidney failure and only a few for the treatment of chronic kidney disease (CKD). We analysed the effect of SLV 338, a neutral endopeptidase (NEP)/endothelin converting enzyme (ECE)-inhibitor in animal models of acute kidney failure as well as chronic renal failure. Methods: Acute renal failure was induced in male Wistar rats by uninephrectomy and clamping of the remaining kidney for 55 minutes. SLV338 (total dose: 4.9 mg/kg) or vehicle was continuously infused for 2 hours (starting 20 minutes prior to clamping). Sham operated animals served as controls. Plasma creatinine was measured at baseline and day 2 and 8 after renal ischemia-reperfusion. Hypertensive renal damage was induced in male Sprague Dawley rats by nitric oxide deficiency using L-NAME (50 mg/kg per day, added to drinking water for 4 weeks). One group was treated over the same time period with SLV338 (30 mg/kg per day, mixed with food). Systolic blood pressure was monitored weekly. At study end, urine and blood samples were collected and kidneys were harvested. Results: Acute renal ischemia-reperfusion caused a 5-fold plasma creatinine elevation (day 2), which was significantly attenuated by more than 50 % in animals treated with SLV338 (p < 0.05). Renal failure was accompanied by a 67 % mortality in vehicle-treated rats, but only 20 % after SLV338 treatment (p = 0.03 compared to sham controls). Chronic L-NAME administration caused hypertension, urinary albumin excretion, glomerulosclerosis, renal arterial remodelling, and renal interstitial fibrosis. Treatment with SLV338 did not significantly affect blood pressure, but abolished renal tissue damage (interstitial fibrosis, glomerulosclerosis, renal arterial remodelling (p < 0.05 versus L-NAME group in each case). Conclusions: The dual ECE/NEP inhibitor SLV338 preserves kidney function and reduces mortality in severe acute ischemic renal failure. Moreover, combined ECE/NEP inhibition prevents hypertensive renal tissue damage in a blood pressure independent manner in L-NAME-treated rats. KW - Renal failure KW - endothelin-converting enzyme KW - neutral endopeptidase Y1 - 2011 SN - 1433-6510 VL - 57 IS - 7-8 SP - 507 EP - 515 PB - Clin Lab Publ., Verl. Klinisches Labor CY - Heidelberg ER -