Thromboxane receptor blockade attenuates the toxic effect of cyclosporine in experimental renal transplantation.
Renal dysfunction, manifested as a dose-dependent reduction in glomerular filtration rate (GFR), is a common complication of cyclosporine A (CyA) administration to laboratory animals and humans. We have recently shown that chronic CyA treatment in normal rats is associated with a selective increase in renal thromboxane A2 (TXA2) synthesis, which may play a role in GFR reduction. The present experiments were designed to investigate whether pharmacological inhibition of TXA2 activity could reduce CyA nephrotoxicity in a rat model of renal transplantation. To discriminate the possible biochemical changes due to rejection episodes from those due to CyA nephrotoxicity, we selected a model of renal isograft free of graft rejection processes. We demonstrated that oral CyA administration for 30 days to rats undergoing renal isograft is associated with the development of renal insufficiency, as indicated by a progressive increase in serum creatinine concentration and reduction in creatinine clearance. In the same animals, a parallel increase in the urinary excretion of TXB2 was found. Combination of the specific thromboxane receptor antagonist GR32191 with CyA treatment partially prevented the deterioration in renal function observed in animals given CyA alone, without modifying the urinary TXB2 excretion. In contrast, renal-isografted rats given GR32191 alone or vehicle alone for 30 days did not show any changes in serum creatinine, creatinine clearance, and urinary TXB2 excretion throughout the experimental period. Mild hypercellularity of the glomerular tuft was observed in isografted kidneys chronically exposed to either CyA or CyA plus GR32191.(ABSTRACT TRUNCATED AT 250 WORDS)
Rossini
M
M
Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy.
Belloni
A
A
Remuzzi
G
G
Perico
N
N
D000818:Animals; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D003524:Cyclosporins / Q000633:toxicity*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006538:Heptanoic Acids / Q000627:therapeutic use*; D016030:Kidney Transplantation; D008297:Male; D051381:Rats; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D013929:Thromboxane B2 / Q000652:urine
D001713:Biphenyl Compounds; D003524:Cyclosporins; D006538:Heptanoic Acids; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013929:Thromboxane B2; D013928:Thromboxane A2; C060013:vapiprost