@article{SharkovskaKalkvonWebskyetal.2011,
  author    = {Sharkovska, Yuliya and Kalk, Philipp and von Websky, Karoline and Relle, Katharina and Pfab, Thiemo and Alter, Markus L. and Fischer, Yvan and Hocher, Berthold},
  title     = {Renoprotective effects of combined endothelin-converting enzyme/neutral endopeptidase inhibitor SLV338 in acute and chronic experimental renal damage},
  series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion},
  volume    = {57},
  journal   = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion},
  number    = {7-8},
  publisher = {Clin Lab Publ., Verl. Klinisches Labor},
  address   = {Heidelberg},
  issn      = {1433-6510},
  pages     = {507 -- 515},
  year      = {2011},
  abstract  = {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.},
  language  = {en}
}
@article{SchmerbachKalkWengenmayeretal.2012,
  author    = {Schmerbach, K. and Kalk, Philipp. and Wengenmayer, Christina and Lucht, K. and Unger, T. and Hocher, Berthold and Thoene-Reineke, C.},
  title     = {Renal outcome in equipotent Antihypertensive Treatment with Telmisartan, Ramipril and in combination in SHR-SP Rats},
  series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion},
  volume    = {58},
  journal   = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion},
  number    = {7-8},
  publisher = {Clin Lab Publ., Verl. Klinisches Labor},
  address   = {Heidelberg},
  issn      = {1433-6510},
  doi       = {10.7754/Clin.Lab.2011.110622},
  pages     = {625 -- 633},
  year      = {2012},
  abstract  = {Background: The ONTARGET trial revealed an association of ACEI/ARB combination treatment (telmisartan and ramipril) with adverse renal outcome versus respective monotherapy; preclinical evidence regarding renal outcome in ACEI/ARB combination treatment is scarce. Methods: Spontaneously hypertensive stroke prone rats (SHR-SP) rats on a salt-rich diet were randomly allocated to 4 groups: SHR (untreated, n = 24), SHR + telmisartan (SHR-T, 2.39 +/- 0.69 mg/kg bw; n = 27), SHR + ramipril (SHR-R, 6.28 +/- 3.48 mg/kg bw; n = 27) and combination treatment (SHR-TR, 0.51 +/- 0.14 mg/kg bw; same dose for telmisartan and ramipril; n = 26). Study duration was 12 weeks, blood pressure was assessed weekly and doses were adjusted to maintain equal blood pressure. Finally, blood and urine samples were obtained and kidneys were harvested for histological studies. Results: Blood pressure in untreated rats rose to a maximum of 239 mmHg, whereas in all treatment groups it remained stable betvveen 140 and 150 mmHg. Mortality was 50\% in the untreated group, whereas all treatment groups survived completely. Renal function - as indicated by plasma urea and cystatin c - was significantly worse in SHR-TR animals compared to all other groups. With plasma creatinine a similar trend was observed. All treatment options significantly decreased albuminuria. Renal glomerulosclerosis was decreased by monotherapy, whereas combination therapy failed to have a significant effect. Interstitial fibrosis was decreased to a similar extent by all treatment options. Conclusions: ACEI/ARB combination treatment failed to render significant additional benefits on renal outcome in hypertensive rats when compared to monotherapy. Instead our data indicate that dual RAAS blockade might have an adverse effect on kidney function and histology when compared to monotherapy in salt-loaded SHR-SP.},
  language  = {en}
}