Effects of a selective adenosine A1 receptor antagonist on the development of cyclosporin nephrotoxicity.
1. The clinical application of cyclosporin as an immunosuppressive agent is limited by its nephrotoxicity. 2. The effect of FK453, a selective A1-receptor antagonist, administered twice daily to rats at a dose of 100 mg kg-1 was assessed on the development of nephrotoxicity induced by cyclosporin (10 mg kg-1 i.p. daily) administered for 14 days. The effects of nifedipine administered twice daily (0.3 mg kg-1 s.c.) for 14 days, on cyclosporin nephrotoxicity were also studied. 3. Cyclosporin induced a 46.58% and 35.78% decline in glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) respectively and a reduction of 16.69% in filtration fraction (FF). Co-administration of FK453 resulted in falls of 30.5%, 18.59% and 14.7% in GFR, ERPF and FF respectively, the former two significantly less than the falls seen with cyclosporin (CyA) alone (P < 0.05 vs CyA, ANOVA). 4. Nifedipine appeared to have a more pronounced protective effect resulting in a decline of only 20.91% in GFR, with no significant change in ERPF (increase of 0.93%) when co-administered with CyA. 5. These observations indicate adenosine plays a minor role in the pathophysiology of CyA nephrotoxicity.
Balakrishnan
V S
VS
Institute of Nephrology, University of Wales College of Medicine, Cardiff.
von Ruhland
C J
CJ
Griffiths
D F
DF
Coles
G A
GA
Williams
J D
JD
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016572:Cyclosporine / Q000633:toxicity*; D004347:Drug Interactions; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D058914:Purinergic Antagonists; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017596:Renal Plasma Flow, Effective / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D007166:Immunosuppressive Agents; D058914:Purinergic Antagonists; D011720:Pyrazoles; D011725:Pyridines; D014665:Vasodilator Agents; C077100:FK 453; D016572:Cyclosporine; D009543:Nifedipine