Renal outcome in equipotent antihypertensive treatment with telmisartan, ramipril and in combination in SHR-SP rats.

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 between 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.

Dual endothelin-converting enzyme/neutral endopeptidase blockade in rats with D-galactosamine-induced liver failure.

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.

Impact of maternal body mass index on neonatal outcome.

INTRODUCTION: Maternal body mass index has an impact on maternal and fetal pregnancy outcome. An increased maternal BMI is known to be associated with admission of the newborn to a neonatal care unit. The reasons and impact of this admission on fetal outcome, however, are unknown so far. OBJECTIVE: The aim of our study was to investigate the impact of maternal BMI on maternal and fetal pregnancy outcome with special focus on the children admitted to a neonatal care unit. METHODS: A cohort of 2049 non-diabetic mothers giving birth in the Charite university hospital was prospectively studied. The impact of maternal BMI on maternal and fetal outcome parameters was tested using multivariate regression analysis. Outcome of children admitted to a neonatal ward (n = 505) was analysed. RESULTS: Increased maternal BMI was associated with an increased risk for hypertensive complications, peripheral edema, caesarean section, fetal macrosomia and admission of the newborn to a neonatal care unit, whereas decreased BMI was associated with preterm birth and lower birthweight. In the neonatal ward children from obese mothers are characterized by hypoglycaemia. They need less oxygen, and exhibit a shorter stay on the neonatal ward compared to children from normal weight mothers, whereas children from underweight mothers are characterized by lower umbilical blood pH and increased incidence of death corresponding to increased prevalence of preterm birth. CONCLUSION: Pregnancy outcome is worst in babies from mothers with low body mass index as compared to healthy weight mothers with respect to increased incidence of preterm birth, lower birth weight and increased neonate mortality on the neonatal ward. We demonstrate that the increased risk for neonatal admission in children from obese mothers does not necessarily indicate severe fetal impairment.

Renal phenotype of ET-1 transgenic mice is modulated by androgens.

INTRODUCTION: Activation of the endothelin (ET) system promotes inflammation and fibrosis in various tissues including the kidney. Male ET-1 transgenic mice are characterized by chronic kidney inflammation and renal scarring. We hypothesized that this renal phenotype might be modulated by androgens. Thus the aim of our study was to elucidate the impact of gonadectomy in ET-1 transgenic mice on kidney function and morphology. - METHODS: Male ET-1 transgenic mice at the age of 10 weeks were randomly allocated to the following groups: normal ET transgenic mice (ET; n = 17) and ET transgenic mice that underwent castration (ET + cas; n = 12). Study duration was 9 months. Creatinine clearance and protein excretion was monitored. At study end animals were sacrificed and kidneys were harvested for histology/immunhistochemistry. RESULTS: Castration significantly ameliorated glomerulosclerosis in ET-1 transgenic mice (ET glomerulosclerosis-score: 3.0 +/- 0.17 vs ET+cas: 2.4 +/- 0.17; p < 0.05) as well as renal perivascular fibrosis (ET fibrosis-score: 3.0 +/- 0.14 vs ET + cas: 2.2 +/- 0.14; p < 0.05). However, interstitial fibrosis and media/lumen-ratio of renal arteries remained unaffected by castration. Regarding inflammation, castration significantly reduced the number of CD4-positive cells in renal tissue of ET-1 transgenic mice (ET CD4-positive cells/10000 cells: 355 +/- 72 vs ET + cas: 147 +/- 28; p < 0.05). Renal tissue contents of CD8 positive cells as well as of macrophages were not affected by castration. Regarding kidney function castration significantly reduced proteinuria in ET-1 transgenic mice whereas creatinine clearance did not differ between study groups. CONCLUSION: Our study demonstrates that the renal histopathological phenotype in male ET-1 transgenic mice with regard to glomerulosclerosis, proteinuria, perivascular fibrosis and immune cell immigration is ameliorated by castration. We thus conclude that the effects of ET-1 overexpression on renal tissue injury are modulated by androgens.

Tissue specific activation of the endothelin system in severe acute liver failure.

The endothelin system has been implicated in the pathogenesis of acute liver failure. However, it has not yet been assessed in a tissue specific manner. - Acute liver failure was induced in rats by two intraperitoneal injections of galactosamine (1.3 g/kg, interval of 12 hours, n = 20). The animals were sacrificed after 48 hours. - Plasma measurements demonstrated that animals receiving galactosamine had a laboratory constellation of severe liver injury and they histologically presented with hepatic necrosis and inflammation. Plasma concentrations of endothelin-1 were elevated 60-fold in the animals receiving galactosamine (p = 0.005). In contrast endothelin-1 tissue contents were decreased in the kidneys and unchanged in the liver. Western blot analysis showed that animals receiving galactosamine had a significantly lower endothelin B receptor concentration in liver and kidney tissue, whereas no differences were detected for endothelin A receptors. - This study demonstrates that the local endothelin system of liver and kidneys is not responsible for the increase of plasma endothelin-1 concentrations in acute liver failure. Since it is well established that the endothelin B receptor acts as a clearance receptor, its decreased density might contribute to the strongly elevated plasma endothelin-1 concentrations seen in this model of acute liver injury.

The adenosine A1 receptor antagonist SLV320 reduces myocardial fibrosis in rats with 5/6 nephrectomy without affecting blood pressure.

BACKGROUND AND PURPOSE: Myocardial fibrosis is an unwanted effect associated with chronic renal failure. The adenosine system is involved in cardiac and renal function. Therefore, we investigated the novel selective adenosine A(1) receptor antagonist SLV320 focusing on its potential in preventing cardiomyopathy in rats with 5/6 nephrectomy. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were allocated to 4 groups of 12 rats each: 5/6 nephrectomy (5/6 NX), 5/6 NX plus SLV320 (10 mg kg(-1) d(-1) mixed with food), sham and sham plus SLV320. Study duration was 12 weeks, blood pressure was assessed repeatedly. At study end kidney function was assessed, blood samples and hearts were taken for histology/immunohistochemistry. Pharmacological properties of SLV320 were assessed using receptor binding and enzyme assays and in vivo. KEY RESULTS: SLV320 is a selective and potent adenosine A(1) antagonist in vitro (Ki=1 nM) with a selectivity factor of at least 200 versus other adenosine receptor subtypes. Functional A(1) antagonism was demonstrated in vivo. In rats with 5/6 NX SLV320 significantly decreased albuminuria by about 50%, but did not alter glomerular filtration rate (GFR). SLV320 normalized cardiac collagen I+III contents in 5/6 NX rats. SLV320 prevented nephrectomy-dependent rise in plasma levels of creatinine kinase (CK), ALT and AST. Blood pressure did not differ between study groups. CONCLUSION: SLV320 suppresses cardiac fibrosis and attenuates albuminuria without affecting blood pressure in rats with 5/6 nephrectomy, indicating that selective A(1) receptor antagonists may be beneficial in uraemic cardiomyopathy.

High-protein nutrition during pregnancy and lactation programs blood pressure, food efficiency, and body weight of the offspring in a sex-dependent manner.

Maternal low-protein diet during pregnancy is a risk factor for cardiovascular disease of the offspring in later life. The impact of high-protein diet during pregnancy on the cardiovascular phenotype of the offspring, however, is still unknown. We examined the influence of a high-protein diet during pregnancy and lactation on the renal, hemodynamic, and metabolic phenotype of the F1 generation. Female Wistar rats were either fed a normal protein diet (20% protein: NP) or an isocaloric high-protein diet (40% protein: HP) throughout pregnancy and lactation. At weaning, the offspring were fed with standard diet, and they were allocated according to sex and maternal diet to four groups: normal-protein male (NPm, n = 25), normal-protein female (NPf, n = 19), high-protein male (HPm, n = 24), high-protein female (HPf, n = 29). During the experiment (22 wk), the animals were characterized by repeated measurement of body weight, food intake, blood pressure, glucose tolerance, energy expenditure, and kidney function. At the end of the study period histomorphological analyses of the kidneys and weight measurement of reproductive fat pads were conducted. There were no differences in birth weight between the study groups. No influence of maternal diet on energy expenditure, glucose tolerance, and plasma lipid levels was detected. Blood pressure and glomerulosclerosis were elevated in male offspring only, whereas female offspring were characterized by an increased food efficiency, higher body weight, and increased fat pads. Our study demonstrates that a high-protein diet during pregnancy and lactation in rats programs blood pressure, food efficiency, and body weight of the offspring in a sex-dependent manner.

Immobilization of babirusa (Babyrousa babyrussa) with xylazine and tiletamine/zolazepam and reversal with yohimbine and flumazenil.

Twelve babirusa (Babyrousa babyrussa) (four females/eight males) were immobilized 30 times during a 4-yr interval. Significantly higher premedication and immobilizing doses were needed for females than for males (P < 0.05). An i.m. preanesthetic xylazine dose of 1.88 +/- 0.37 mg/kg (range = 1.20-2.12 mg/kg) was used for females and 1.22 +/- 0.16 mg/kg (range = 0.82-1.43 mg/kg) for males. After xylazine, the animals were induced with i.m. tiletamine/zolazepam; females received 2.20 +/- 0.47 mg/kg (range = 1.78-3.33 mg/kg) and males received 1.71 +/- 0.34 mg/kg (range = 1.08-2.05 mg/kg). Anesthesia was reversed with yohimbine (0.14 +/- 0.03 mg/kg; range = 0.07-0.20 mg/kg) and flumazenil (1 mg flumazenil/20 mg zolazepam) either i.m. or i.v. This anesthetic combination produced smooth induction, good relaxation, and sufficient immobilization to perform routine diagnostic and therapeutic procedures (venipuncture, hoof and tusk trims, transportation, radiographs, ultrasound examination, weight determinations, and skin biopsies). Supplemental ketamine HCl or isoflurane was administered to two animals to effectively deepen or prolong the anesthetic plane, with no resultant adverse effects.