Prevention of cyclosporin nephrotoxicity with a platelet-activating factor (PAF) antagonist.
BACKGROUND
Cyclosporin (CsA) is a potent immunosuppressive drug whose main side-effect is nephrotoxicity. In the kidney, CsA induces vasoconstriction with a decrease in renal blood flow (RBF) and glomerular filtration rate (GFR) and a significant increase in renal vascular resistance (RVR). CsA enhances platelet-activating factor (PAF) synthesis in mesangial cells in vitro. PAF, a secondary mediator of anaphylaxis and inflammation, exhibits vasoactive properties in the kidney similar to those of CsA.


METHODS
The in situ autoperfused rat kidney model was used to investigate whether PAF plays a role in the haemodynamic injury induced by CsA.


RESULTS
In this model, CsA (40 mg/kg and 20 mg/kg i.v.) induced a significant decrease in RBF and in GFR and an increase in RVR. BN 52021, a potent and specific PAF antagonist (20 mg/kg i.v. bolus dose) induced a significant increase in GFR (137 +/- 32% of initial value, P < 0.05). BN 52021 (20 and 10 mg/kg) also significantly prevented the decline in RBF and GFR induced by CsA.


CONCLUSIONS
We have demonstrated that the PAF antagonist BN 52021 can minimize the alteration of renal function induced by CsA.
Bagnis
C
C
Department of Nephrology, Hôpital Pitié Salpêtrière, Paris, France.
Deray
G
G
Dubois
M
M
Pirotzky
E
E
Jacquiaud
C
C
Baghos
W
W
Aupetit
B
B
Braquet
P
P
Jacobs
C
C
D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage / Q000633:toxicity*; D004224:Diterpenes; D004333:Drug Administration Routes; D046934:Ginkgolides; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000633:toxicity*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D010477:Perfusion; D010936:Plant Extracts / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000633:toxicity; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D004224:Diterpenes; D046934:Ginkgolides; D007166:Immunosuppressive Agents; D007783:Lactones; D010936:Plant Extracts; D010972:Platelet Activating Factor; C022131:cremophor; D011092:Polyethylene Glycols; D016572:Cyclosporine; C045856:ginkgolide B