This plasma concentration was able to cause strong short-term effects on diuresis and saliuresis when administered intravenously as shown in Table 2. A steady-state is usually reached in the course of long-term diuretic therapy by means of compensatory mechanisms of tubular reabsorption. This explains why the 24-hour urine volume and electrolyte excretion in week 16 is not different between the groups of the cirrhosis model. However, when looking at mean water intake over 8 weeks, as a putative NVP-BEZ235 surrogate of diuresis, the effects of furosemide and SLV329 can be detected. It would have been interesting to evaluate fractional sodium excretion and free water clearance. This was not done due to limited plasma quantities. SLV329 does not affect the expression of hepatic or renal adenosine receptors in cirrhotic animals. The expression of A2R seems to be reduced in cirrhotic animals, independent of the treatment group. As yet, there are no reports on the expression of A2R in cirrhotic liver tissue. However, it is known, that hepatic A2R play an active role in the pathogenesis of hepatic fibrosis. It is a limitation of this study that adenosine receptor expression was evaluated only in liver and kidney homogenates by Western blot. Immunohistochemistry or radioligand binding experiments might give further detailed information. The beneficial effects of SLV329 in the cirrhosis model cannot be explained by morphological effects since SLV329 did not relevantly influence the degree of liver fibrosis, kidney histology or expression of hepatic or renal adenosine receptors. Animal studies suggest that liver cirrhosis activates the hepatorenal reflex via A1R, leading to renal water and sodium retention. Animal and human studies suggest that a resetting of the tubuloglomerular feedback contributes to the pathophysiology of kidney impairment in liver cirrhosis. Thus, inhibition of both the hepatorenal reflex and the tubuloglomerular feedback might explain the higher rate of creatinine clearance in the animals treated with SLV329. In addition to the effect on creatinine clearance, yet unknown effects of SLV329 might contribute to the reduction of mortality. As an addition to the present study it would be interesting to study liver cirrhosis in the established murine A1R knockout model. The ability of A1R antagonists to induce diuresis and natriuresis while not compromising glomerular filtration rate has become an attractive therapeutic option for the treatment of other fluid retention disorders, e.g. in kidney disease and heart failure, especially in conditions associated with diuretic resistance. The preexisting experience with this class of drugs for other indications might facilitate the future translation of the results of this study to clinical application.