TY  - JOUR
A1  - Hocher, Berthold
A1  - Heiden, S.
A1  - von Websky, Karoline
A1  - Rahnenführer, Jörg
A1  - Kalk, Philipp
A1  - Pfab, T.
T1  - Dual endothelin-converting enzyme/neutral endopeptidase blockade in rats with D-galactosamine-induced liver failure
JF  - European journal of medical research : official organ "Deutsche AIDS-Gesellschaft"
N2  - Secondary activation of the endothelin system is thought to be involved in toxic liver injury. This study tested the hypothesis that dual endothelin-converting enzyme / neutral endopeptidase blockade might: be able to attenuate acute toxic liver injury.
 Male Sprague-Dawley rats were implanted with subcutaneous minipumps to deliver the novel compound SLV338 (10 mg/kg*d) or vehicle. Four days later they received two intraperitoneal injections of D-galactosamine (1.3 g/kg each) or vehicle at an interval of 12 hours. The animals were sacrificed 48 hours after the first injection.
 Injection of D-galactosamine resulted in very severe liver injury, reflected by strongly elevated plasma liver enzymes, hepatic necrosis and inflammation, and a mortality rate of 42.9 %. SLV338 treatment did not show any significant effect on the extent of acute liver injury as judged from plasma parameters, hepatic histology and mortality. Plasma measurements of SLV338 confirmed adequate drug delivery. Plasma concentrations of big endothelin-1 and endothelin-1 were significantly elevated in animals with liver injury (5-fold and 62-fold, respectively). Plasma endothelin-1 was significantly correlated with several markers of liver injury. SLV338 completely prevented the rise of plasma big endothelin-1 (p<0.05) and markedly attenuated the rise of endothelin-1 (p = 0.055).
 In conclusion, dual endothelin-converting enzyme / neutral endopeptidase blockade by SLV338 did not significantly attenuate D-galactosamine-induced acute liver injury, although it largely prevented the activation of the endothelin system. An evaluation of SLV338 in a less severe model of liver injury would be of interest, since very severe intoxication might not be relevantly amenable to pharmacological interventions.
KW  - endothelin
KW  - endothelin-converting enzyme
KW  - neutral endopeptidase
KW  - D-galactosamine
KW  - acute liver failure
Y1  - 2011
SN  - 0949-2321
VL  - 16
IS  - 6
SP  - 275
EP  - 279
PB  - Med. Scientific Publ. Holzapfel
CY  - München
ER  - 
TY  - JOUR
A1  - Schildroth, Janice
A1  - Rettig-Zimmermann, Juliane
A1  - Kalk, Philipp
A1  - Steege, Andreas
A1  - Faehling, Michael
A1  - Sendeski, Mauricio
A1  - Paliege, Alexander
A1  - Lai, En Yin
A1  - Bachmann, Sebastian
A1  - Persson, Pontus B.
A1  - Hocher, Berthold
A1  - Patzak, Andreas
T1  - Endothelin type A and B receptors in the control of afferent and efferent arterioles in mice
JF  - Nephrology, dialysis, transplantation
N2  - Background. Endothelin 1 contributes to renal blood flow control and pathogenesis of kidney diseases. The differential effects, however, of endothelin 1 (ET-1) on afferent (AA) and efferent arterioles (EA) remain to be established.
 Methods. We investigated endothelin type A and B receptor (ETA-R, ETB-R) functions in the control of AA and EA. Arterioles of ETB-R deficient, rescued mice [ETB (-/-)] and wild types [ETB(+/+)] were microperfused.
 Results. ET-1 constricted AA stronger than EA in ETB (-/-) and ETB(+/+) mice. Results in AA: ET-1 induced similar constrictions in ETB(-/-) and ETB(+/+) mice. BQ-123 (ETA-R antagonist) inhibited this response in both groups. ALA-ET-1 and IRL1620 (ETB-R agonists) had no effect on arteriolar diameter. L-NAME did neither affect basal diameters nor ET-1 responses. Results in EA: ET-1 constricted EA stronger in ETB(+/+) compared to ETB(-/-). BQ-123 inhibited the constriction completely only in ETB(-/-). ALA-ET-1 and IRL1620 constricted only arterioles of ETB(+/+) mice. L-NAME decreased basal diameter in ETB(+/+), but not in ETB(-/-) mice and increased the ET-1 response similarly in both groups. The L-NAME actions indicate a contribution of ETB-R in basal nitric oxide (NO) release in EA and suggest dilatory action of ETA-R in EA.
 Conclusions. ETA-R mediates vasoconstriction in AA and contributes to vasoconstriction in EA in this mouse model. ETB-R has no effect in AA but mediates basal NO release and constriction in EA. The stronger effect of ET-1 on AA supports observations of decreased glomerular filtration rate to ET-1 and indicates a potential contribution of ET-1 to the pathogenesis of kidney diseases.
KW  - endothelin
KW  - ETB receptor-deficient mouse
KW  - glomerular arterioles
KW  - renal haemodynamics
Y1  - 2011
U6  - https://doi.org/10.1093/ndt/gfq534
SN  - 0931-0509
VL  - 26
IS  - 3
SP  - 779
EP  - 789
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Tsuprykov, Oleg
A1  - Chaykovska, Lyubov
A1  - Kretschmer, Axel
A1  - Stasch, Johannes-Peter
A1  - Pfab, Thiemo
A1  - Krause-Relle, Katharina
A1  - Reichetzeder, Christoph
A1  - Kalk, Philipp
A1  - Adamski, Jerzy
A1  - Hocher, Berthold
T1  - Endothelin-1 overexpression improves renal function in eNOS knockout mice
JF  - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology
N2  - Background/Aims: To investigate the renal phenotype under conditions of an activated renal ET-1 system in the status of nitric oxide deficiency, we compared kidney function and morphology in wild-type, ET-1 transgenic (ET+/+), endothelial nitric oxide synthase knockout (eNOS-/-) and ET+/+eNOS-/- mice. Methods: We assessed blood pressure, parameters of renal morphology, plasma cystatin C, urinary protein excretion, expression of genes associated with glomerular filtration barrier and tissue remodeling, and plasma metabolites using metabolomics. Results: eNOS-/- and ET+/+eNOS-/- mice developed hypertension. Osteopontin, albumin and protein excretion were increased in eNOS-/- and restored in ET+/+eNOS-/- animals. All genetically modified mice developed renal interstitial fibrosis and glomerulosclerosis. Genes involved in tissue remodeling (serpinel, TIMP1, Collal, CCL2) were up-regulated in eNOS-/-, but not in ET+/+eNOS-/- mice. Plasma levels of free carnitine and acylcarnitines, amino acids, diacyl phosphatidylcholines, lysophosphatidylcholines and hexoses were descreased in eNOS-/- and were in the normal range in ET+/+eNOS-/- mice. Conclusion: eNOS-/- mice developed renal dysfunction, which was partially rescued by ET-1 overexpression in eNOS-/- mice. The metabolomics results suggest that ET-1 overexpression on top of eNOS knockout is associated with a functional recovery of mitochondria (rescue effect in 13-oxidation of fatty acids) and an increase in antioxidative properties (normalization of monounsaturated fatty acids levels). (C) 2015 The Author(s) Published by S. Karger AG, Basel
KW  - Chronic kidney disease
KW  - Endothelial nitric oxide synthase
KW  - Endothelin
KW  - Mice
KW  - Nitric oxide
Y1  - 2015
U6  - https://doi.org/10.1159/000438516
SN  - 1015-8987
SN  - 1421-9778
VL  - 37
IS  - 4
SP  - 1474
EP  - 1490
PB  - Karger
CY  - Basel
ER  - 
TY  - JOUR
A1  - Vignon-Zellweger, Nicolas
A1  - Relle, Katharina
A1  - Kienlen, Elodie
A1  - Alter, Markus L.
A1  - Seider, Patrick
A1  - Sharkovska, Juliya
A1  - Heiden, Susi
A1  - Kalk, Philipp
A1  - Schwab, Karima
A1  - Albrecht-Kuepper, Barbara
A1  - Theuring, Franz
A1  - Stasch, Johannes-Peter
A1  - Hocher, Berthold
T1  - Endothelin-1 overexpression restores diastolic function in eNOS knockout mice
JF  - Journal of hypertension
N2  - Background The cardiac nitric oxide and endothelin-1 (ET-1) systems are closely linked and play a critical role in cardiac physiology. The balance between both systems is often disturbed in cardiovascular diseases. To define the cardiac effect of excessive ET-1 in a status of nitric oxide deficiency, we compared left ventricular function and morphology in wild-type mice, ET-1 transgenic (ET+/+) mice, endothelial nitric oxide synthase knockout (eNOS(-/-)) mice, and ET(+/+)eNOS(-/-) mice.
 Methods and results eNOS(-/-) and ET(+/+)eNOS(-/-) mice developed high blood pressure compared with wild-type and ET+/+ mice. Left ventricular catheterization showed that eNOS(-/-) mice, but not ET(+/+)eNOS(-/-), developed diastolic dysfunction characterized by increased end-diastolic pressure and relaxation constant tau. To elucidate the causal molecular mechanisms driving the rescue of diastolic function in ET(+/+)eNOS(-/-) mice, the cardiac proteome was analyzed. Two-dimensional gel electrophoresis coupled to mass spectrometry offers an appropriate hypothesis-free approach. ET-1 overexpression on an eNOS(-/-) background led to an elevated abundance and change in posttranslational state of antioxidant enzymes (e. g., peroxiredoxin-6, glutathione S-transferase mu 2, and heat shock protein beta 7). In contrast to ET(+/+)eNOS(-/-) mice, eNOS(-/-) mice showed an elevated abundance of proteins responsible for sarcomere disassembly (e. g., cofilin-1 and cofilin-2). In ET(+/+)eNOS(-/-) mice, glycolysis was favored at the expense of fatty acid oxidation.
 Conclusion eNOS(-/-) mice developed diastolic dysfunction; this was rescued by ET-1 transgenic overexpression. This study furthermore suggests that cardiac ET-1 overexpression in case of eNOS deficiency causes specifically the regulation of proteins playing a role in oxidative stress, myocytes contractility, and energy metabolism.
KW  - cardiovascular diseases
KW  - endothelin
KW  - nitric oxide
Y1  - 2011
U6  - https://doi.org/10.1097/HJH.0b013e3283450770
SN  - 0263-6352
SN  - 1473-5598
VL  - 29
IS  - 5
SP  - 961
EP  - 970
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  - 
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  - Haumann, Hannah
A1  - Rahnenführer, Jan
A1  - Reichetzeder, Christoph
A1  - Kalk, Philipp
A1  - Pfab, Thiemo
A1  - Tsuprykov, Oleg
A1  - Winter, Stefan
A1  - Hofmann, Ute
A1  - Li, Jian
A1  - Püschel, Gerhard Paul
A1  - Lang, Florian
A1  - Schuppan, Detlef
A1  - Schwab, Matthias
A1  - Schaeffeler, Elke
T1  - Maternal eNOS deficiency determines a fatty liver phenotype of the offspring in a sex dependent manner
JF  - Epigenetics : the official journal of the DNA Methylation Society
N2  - Maternal environmental factors can impact on the phenotype of the offspring via the induction of epigenetic adaptive mechanisms. The advanced fetal programming hypothesis proposes that maternal genetic variants may influence the offspring's phenotype indirectly via epigenetic modification, despite the absence of a primary genetic defect. To test this hypothesis, heterozygous female eNOS knockout mice and wild type mice were bred with male wild type mice. We then assessed the impact of maternal eNOS deficiency on the liver phenotype of wild type offspring. Birth weight of male wild type offspring born to female heterozygous eNOS knockout mice was reduced compared to offspring of wild type mice. Moreover, the offspring displayed a sex specific liver phenotype, with an increased liver weight, due to steatosis. This was accompanied by sex specific differences in expression and DNA methylation of distinct genes. Liver global DNA methylation was significantly enhanced in both male and female offspring. Also, hepatic parameters of carbohydrate metabolism were reduced in male and female offspring. In addition, male mice displayed reductions in various amino acids in the liver. Maternal genetic alterations, such as partial deletion of the eNOS gene, can affect liver metabolism of wild type offspring without transmission of the intrinsic defect. This occurs in a sex specific way, with more detrimental effects in females. This finding demonstrates that a maternal genetic defect can epigenetically alter the phenotype of the offspring, without inheritance of the defect itself. Importantly, these acquired epigenetic phenotypic changes can persist into adulthood.
KW  - Epigenetics
KW  - eNOS
KW  - Fetal programming
KW  - fatty liver
KW  - metabolism
Y1  - 2016
U6  - https://doi.org/10.1080/15592294.2016.1184800
SN  - 1559-2294
SN  - 1559-2308
VL  - 11
SP  - 539
EP  - 552
PB  - Routledge, Taylor & Francis Group
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Li, Jian
A1  - Lu, Yong Ping
A1  - Reichetzeder, Christoph
A1  - Kalk, Philipp
A1  - Kleuser, Burkhard
A1  - Adamski, Jerzy
A1  - Hocher, Berthold
T1  - Maternal PCaaC38:6 is Associated With Preterm Birth - a Risk Factor for Early and Late Adverse Outcome of the Offspring
JF  - Journal of European public policy
N2  - Background/Aims: Preterm birth (PTB) and low birth weight (LBW) significantly influence mortality and morbidity of the offspring in early life and also have long-term consequences in later life. A better understanding of the molecular mechanisms of preterm birth could provide new insights regarding putative preventive strategies. Metabolomics provides a powerful analytic tool to readout complex interactions between genetics, environment and health and may serve to identify relevant biomarkers. In this study, the association between 163 targeted maternal blood metabolites and gestational age was investigated in order to find candidate biomarkers for PTB. Methods: Five hundred twenty-three women were included into this observational study. Maternal blood was obtained before delivery. The concentration of 163 maternal serum metabolites was measured by flow injection tandem mass spectrometry. To find putative biomarkers for preterm birth, a three-step analysis was designed: bivariate correlation analysis followed by multivariable regression analysis and a comparison of mean values among gestational age groups. Results: Bivariate correlation analysis showed that 2 acylcarnitines (C16:2, C2), 1 amino acids (xLeu), 8 diacyl-PCs (PCaaC36:4, PCaaC38:4, PCaaC38:5, PCaaC38:6, PCaaC40:4, PCaaC40:5, PCaaC40:6, PCaaC42:4), and 1 Acylalkyl-PCs (PCaeC40:5) were inversely correlated with gestational age. Multivariable regression analysis confounded for PTB history, maternal body mass index (BMI) before pregnancy, systolic blood pressure at the third trimester, and maternal body weight at the third trimester, showed that the diacyl-PC PCaaC38:6 was the only metabolite inversely correlated with gestational age. Conclusions: Maternal blood concentrations of PCaaC38:6 are independently associated with gestational age. (C) 2016 The Author(s) Published by S. Karger AG, Basel
KW  - Metabolomics
KW  - PCaaC38:6
KW  - Biomarker
KW  - Preterm birth
Y1  - 2016
U6  - https://doi.org/10.1159/000443428
SN  - 1420-4096
SN  - 1423-0143
VL  - 41
SP  - 250
EP  - 257
PB  - Karger
CY  - Basel
ER  - 
TY  - JOUR
A1  - Sharkovska, Yuliya
A1  - Kalk, Philipp
A1  - Lawrenz, Bettina
A1  - Godes, Michael
A1  - Hoffmann, Linda Sarah
A1  - Wellkisch, Kathrin
A1  - Geschka, Sandra
A1  - Relle, Katharina
A1  - Hocher, Berthold
A1  - Stasch, Johannes-Peter
T1  - Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low- renin and high-renin models
N2  - Objectives The nitric oxide-soluble guanylate cyclase (sGC)-cGMP signal transduction pathway is impaired in different cardiovascular diseases, including pulmonary hypertension, heart failure and arterial hypertension. Riociguat is a novel stimulator of soluble guanylate cyclase (sGC). However, little is known about the effects of sGC stimulators in experimental models of hypertension. We thus investigated the cardio-renal protective effects of riociguat in low- renin and high-renin rat models of hypertension. Methods The vasorelaxant effect of riociguat was tested in vitro on isolated saphenous artery rings of normal and nitrate tolerant rabbits. The cardiovascular in-vivo effects of sGC stimulation were evaluated in hypertensive renin-transgenic rats treated with the nitric oxide-synthase inhibitor N- nitro-L-arginine methyl ester (L-NAME) (high-renin model) and in rats with 5/6 nephrectomy (low-renin model). Results In both animal models, riociguat treatment improved survival and normalized blood pressure. Moreover, in the L-NAME study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight and lower cardiac interstitial fibrosis, and reduced renal target organ damage as indicated by lower plasma creatinine and urea, less glomerulosclerosis and less renal interstitial fibrosis. In the 5/6 nephrectomy study part, riociguat reduced cardiac target organ damage as indicated by lower plasma ANP, lower relative left ventricular weight, lower myocyte diameter and lower arterial media/lumen ratio, and reduced renal target organ damage as indicated by improved creatinine clearance and less renal interstitial fibrosis. Conclusion We demonstrate for the first time that the novel sGC stimulator riociguat shows in two independent models of hypertension a potent protection against cardiac and renal target organ damage. J Hypertens 28: 1666-1675 (c) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
Y1  - 2010
UR  - http://journals.lww.com/jhypertension/pages/default.aspx
U6  - https://doi.org/10.1097/Hjh.0b013e32833b558c
SN  - 0263-6352
ER  - 
TY  - JOUR
A1  - Hocher, Berthold
A1  - Schlemm, Ludwig
A1  - Haumann, Hannah
A1  - Li, Jian
A1  - Rahnenführer, Jan
A1  - Guthmann, Florian
A1  - Bamberg, Christian
A1  - Kalk, Philipp
A1  - Pfab, Thiemo
A1  - Chen, You-Peng
T1  - Offspring sex determines the impact of the maternal ACE I/D polymorphism on maternal glycaemic control during the last weeks of pregnancy
JF  - Journal of the renin angiotensin aldosterone system
N2  - Hypothesis/Introduction: We recently demonstrated that fetal sex may affect maternal glycaemic control in genetically prone mothers. We tested the hypothesis that fetal sex/fetal Y/X chromosomes might affect maternal glycaemic control during pregnancy depending on the maternal angiotensin converting enzyme (ACE) I/D polymorphism.
 Material and methods: One thousand, three hundred and thirty-two Caucasian women without pre-existing diabetes and pre-existing hypertension with singleton pregnancies delivering consecutively at the Charite obstetrics department were genotyped. Glycaemic control was analysed by measuring total glycated haemoglobin at birth. Correction for confounding factors and multiple testing was done.
 Results: Maternal ACE I/D polymorphism showed significant interaction with fetal sex concerning maternal total glycated haemoglobin. Total glycated haemoglobin in DD mothers delivering boys was 6.42 +/- 0.70% vs. 6.21 +/- 0.66% in DD mother delivering girls (p < 0.005), whereas the II carrying mothers showed the opposite effect. II mothers delivering a girl had a higher (p = 0.044) total glycated haemoglobin at birth (6.40 +/- 0.80%) compared to II mothers delivering boys (6.21 +/- 0.81%). There was no interaction of the ACE I/D polymorphism and fetal sex with respect to new onset proteinuria, new onset edema and pregnancy-induced hypertension.
 Conclusions: Maternal glycaemic control during the last weeks of pregnancy seems to be influenced by an interaction of the ACE I/D genotyp and fetal sex.
KW  - ACE I/D polymorphism
KW  - pregnancy
KW  - fetal sex
KW  - pregnancy induced diabetes
KW  - total glycated hemoglobin
KW  - glycemic control during pregnancy
Y1  - 2011
U6  - https://doi.org/10.1177/1470320310387843
SN  - 1470-3203
VL  - 12
IS  - 3
SP  - 254
EP  - 261
PB  - Sage Publ.
CY  - London
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  -