title: Renal effects of the novel selective adenosine A1 receptor blocker SLV329 in experimental liver cirrhosis in rats.
abstract: 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.
authors.affiliation: Institute of Nutritional Science, University of Potsdam, Potsdam, Germany.
authors.forename: Berthold
authors.initials: B
authors.lastname: Hocher
authors.forename: Susi
authors.initials: S
authors.lastname: Heiden
authors.forename: Karoline
authors.initials: K
authors.lastname: von Websky
authors.forename: Ayman M
authors.initials: AM
authors.lastname: Arafat
authors.forename: Jan
authors.initials: J
authors.lastname: Rahnenführer
authors.forename: Markus
authors.initials: M
authors.lastname: Alter
authors.forename: Philipp
authors.initials: P
authors.lastname: Kalk
authors.forename: Dieter
authors.initials: D
authors.lastname: Ziegler
authors.forename: Yvan
authors.initials: Y
authors.lastname: Fischer
authors.forename: Thiemo
authors.initials: T
authors.lastname: Pfab
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D003404:Creatinine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D007677:Kidney Function Tests; D008106:Liver Cirrhosis, Experimental / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology / Q000652:urine; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D013853:Thioacetamide
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D043682:Receptor, Adenosine A1; D013853:Thioacetamide; D003404:Creatinine; D010727:Phosphoric Diester Hydrolases; C030986:pyrimidine