Journal Article

Renal Effects of the Novel Selective Adenosine A1 Receptor Blocker SLV329 in Experimental Liver Cirrhosis in Rats

Fischer, Yvan, Hocher, Berthold, Heiden, Susi, Alter, Markus, Rahnenführer, Jan, Kalk, Philipp, Pfab, Thiemo, Ziegler, Dieter, Arafat, Ayman M., von Websky, Karoline

2011

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenosine / Adenosine A1 Receptor Antagonists - pharmacology / Adenosine A1 Receptor Antagonists - therapeutic use / Animals / Biology / Cirrhosis / Clearances / Creatinine / Creatinine - metabolism / Diuretics / Dose-Response Relationship, Drug / Excretion / Fibrosis / Franklin, Benjamin (1706-1790) / Furosemide / Glomerular filtration rate / Histology / Immunoblotting / Intravenous administration / Kaplan-Meier Estimate / Kidney - drug effects / Kidney - physiopathology / Kidney Function Tests / Liver / Liver cirrhosis / Liver Cirrhosis, Experimental - blood / Liver Cirrhosis, Experimental - drug therapy / Liver Cirrhosis, Experimental - physiopathology / Liver Cirrhosis, Experimental - urine / Male / Medicine / Nitric oxide / Nutrition / Phosphodiesterase Inhibitors - pharmacology / Phosphoric Diester Hydrolases - metabolism / Pyrimidines - pharmacology / Pyrimidines - therapeutic use / Rats / Rats, Wistar / Receptor, Adenosine A1 - metabolism / Receptors / Renal function / Rodents / Sodium / Thioacetamide