Thromboxane receptor blockade attenuates chronic cyclosporine nephrotoxicity and improves survival in rats with renal isograft.
The question of whether pharmacological inhibition of the thromboxane A2 activity prevents cyclosporine-induced chronic renal dysfunction in a Lewis rat model of renal isograft was addressed. Transplanted animals were given a daily oral dose of cyclosporine (20 mg/kg; N = 15), cyclosporine (20 mg/kg) and the thromboxane A2 receptor antagonist GR32191 (3 mg/kg twice daily, by gavage; N = 15), or the vehicle alone (N = 12). Treatments were started the day of kidney transplant, and animals were monitored for 1 year. Cyclosporine-treated animals developed renal insufficiency, as documented by serum creatinine levels of 0.49 +/- 0.09, 0.95 +/- 0.12, and 1.38 +/- 0.15 mg/dL before and after 6 and 12 months of observation, respectively. Cyclosporine and GR32191 used in combination partially but significantly prevented the deterioration of renal function (serum creatinine, basal, 0.52 +/- 0.06; month 6, 0.68 +/- 0.04; month 12, 0.93 +/- 0.10 mg/dL). At the end of the study, GFR, as insulin clearance, was significantly lower in rats given cyclosporine (0.28 +/- 0.09 mL/min/100 g) than in rats given cyclosporine plus GR32191 (0.45 +/- 0.05 mL/min/100 g) or than in vehicle-treated animals (0.56 +/- 0.07 mL/min/100 g). Similar results were obtained for the effective RPF, measured as p-aminohippurate clearance. At the same time points, comparable to whole-blood cyclosporine levels were found in rats receiving cyclosporine alone and in those given cyclosporine plus GR32191. More than 50% of the animals on cyclosporine alone died from uremia before the end of the observation period. By contrast, rats receiving cyclosporine in combination with GR32191 had a prolonged survival.(ABSTRACT TRUNCATED AT 250 WORDS)
Perico
N
N
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Rossini
M
M
Imberti
O
O
Malanchini
B
B
Cornejo
R P
RP
Gaspari
F
F
Bertani
T
T
Remuzzi
G
G
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000097:blood / Q000633:toxicity*; D005919:Glomerular Filtration Rate; D006085:Graft Survival; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000139:chemically induced* / Q000517:prevention & control; D016030:Kidney Transplantation; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D017482:Receptors, Thromboxane; D012079:Renal Circulation; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D001713:Biphenyl Compounds; D006538:Heptanoic Acids; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013928:Thromboxane A2; D016572:Cyclosporine; D003404:Creatinine; C060013:vapiprost