Abstract-Apolipoprotein E-deficient (apoE(−/−)) mice fed on Western diet are characterized by increased vascular resistance and atherosclerosis. Previously, we have shown that chronic angiotensin (Ang)(1-7) treatment ameliorates endothelial dysfunction in apoE(−/−) mice. However, the mechanism of Ang(1-7) on vasoconstrictor response to Ang II is unknown. To examine Ang(1-7) function, we used apoE(−/−) and wildtype mice fed on Western diet that were treated via osmotic minipumps either with Ang(1-7) (82 μg/kg per hour) or saline for 6 weeks. We show that Ang II-induced renal pressor response was significantly increased in apoE(−/−) compared with wildtype mice. This apoE(−/−)specific response is attributed to reactive oxygen species-mediated p38 mitogen-activated protein kinase activation and subsequent phosphorylation of myosin light chain (MLC 20 ), causing renal vasoconstriction. Here, we provide evidence that chronic Ang(1-7) treatment attenuated the renal pressor response to Ang II in apoE(−/−) mice to wildtype levels. Ang(1-7) treatment significantly decreased renal inducible nicotinamide adenine dinucleotide phosphate subunit p47phox levels and, thus, reactive oxygen species production that in turn causes decreased p38 mitogenactivated protein kinase activity. The latter has been confirmed by administration of a specific p38 mitogenactivated protein kinase inhibitor SB203580 (5 μmol/L), causing a reduced renal pressor response to Ang II in apoE(−/−) but not in apoE(−/−) mice treated with Ang(1-7). Moreover, Ang(1-7) treatment had no effect in Mas(−/−)/apoE(−/−) doubleknockout mice confirming the specificity of Ang (1-

Telmisartan plus propranolol reduces liver fibrosis and bile duct proliferation in the PSC-like Abcb4 (-/-) mouse model, even when started at late stages of fibrosis, and may thus represent a novel therapeutic option for cholestatic liver diseases such as PSC.

Summary:Four immunochemical methods for digoxin assay were used to analyse control samples, 33 amniotic fluid samples, 57 samples from digitalis-treated, non-pregnant women, 90 pregnancy serum samples, and 72 samples of fetal or neonatal serum with or without digoxin therapy. One hundred and five samples were also submitted to ultrafiltration before analysis.Three methods (RIA, TD X , AMERLITE) showed practically the same precision, while the precision of the DELFIA was markedly inferior. In the analysis of serum samples from digoxin-treated, non-pregnant women, RIA and TD X gave practically the same values, whereas AMERLITE and DELFIA gave significantly higher values.Pregnancy serum and fetal serum contain "digoxin-like immunoreactive factors", and the qualitative and quantitative effects of these interfering factors are different for each of the four methods. The greatest sensitivity to "digoxin-like immunoreactive factors" is shown by TD X and DELFIA, while the lowest interference by "digoxin-like immunoreactive factors" is found in the analysis of ultrafiltered samples, using the TD X method.The composition of the "digoxin-like immunoreactive factors" in pregnancy serum and in fetal serum is altered by digoxin therapy, and these changes have different effects on the various analytical methods. The concentration of "digoxin-like immunoreactive factors" in the serum of fetuses receiving digoxin is markedly lower than that of healthy fetuses.For the reliable monitoring of digoxin therapy in the maternal and fetal circulation, the blood samples must be submitted to ültrafiltration before analysis.

No abstract