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


METHODS
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.


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.


CONCLUSIONS
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.
Kalk
P
P
Department of Pharmacology and Toxicology, Center for Cardiovascular Research, Charité, Campus Mitte, Hessische Strasse 3-4, 10115 Berlin, Germany.
Eggert
B
B
Relle
K
K
Godes
M
M
Heiden
S
S
Sharkovska
Y
Y
Fischer
Y
Y
Ziegler
D
D
Bielenberg
G-W
GW
Hocher
B
B
D000241:Adenosine / Q000494:pharmacology; D058916:Adenosine A1 Receptor Antagonists; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D003510:Cyclohexanes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004719:Endomyocardial Fibrosis / Q000503:physiopathology / Q000517:prevention & control*; D005353:Fibronectins / Q000378:metabolism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009392:Nephrectomy / Q000379:methods; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism / Q000502:physiology; D020889:Rolipram / Q000494:pharmacology; D020298:U937 Cells; D014970:Xanthines / Q000494:pharmacology
D058916:Adenosine A1 Receptor Antagonists; D024042:Collagen Type I; D024061:Collagen Type III; D003510:Cyclohexanes; D005353:Fibronectins; D006574:Heterocyclic Compounds, 2-Ring; D043682:Receptor, Adenosine A1; C523961:SLV320 compound; D014970:Xanthines; C051360:1,3-dipropyl-8-cyclopentylxanthine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003402:Creatine Kinase; D020889:Rolipram; D000241:Adenosine