Role of NK1 receptors on cisplatin-induced nephrotoxicity in the rat.
The role of NK1 receptors on the nephrotoxicity associated with cisplatin treatment was evaluated. Adult Sprague-Dawley male rats (300-400 g) were treated with saline (0.1 ml/100 g, i.p., every 8 h for 72 h) or the selective NK1 receptor antagonist (GR205171; 2 mg/kg, i.p., every 8 h for 72 h). Treatments were started 5 min before cisplatin (7.5 mg/kg, i.p., single dose). All evaluations were made from 72 h to 96 h after cisplatin. An oral load of 10 ml/kg of water was given at time 0 (72 h after cisplatin). Cisplatin reduced the urinary volume (-45%), creatinine clearance (>90%), lithium clearance (-76%) and urinary potassium excretion (-54%). Protein and sodium excretion was not affected by cisplatin. GR205171 prevented the reduction in urine volume induced by cisplatin. In addition, the decreases in creatinine and lithium clearances induced by cisplatin were also attenuated by the NK1 receptor antagonist. The clearance of creatinine averaged 0.57+/-0.2 ml/min in controls, 0.004+/-0.01 ml/min after cisplatin, and 0.09+/-0.02 ml/min after cisplatin + GR205171. The lithium clearance was 0.09+/-0.04 ml/min in controls, 0.02+/-0.01 ml/min after cisplatin and 0.06+/-0.01 ml/min after cisplatin + GR205171. Cisplatin induced marked necrosis, vacuolation and edema of proximal renal tubules; these changes were considerably reduced in GR205171-treated animals. These results indicate that treatment with a selective NK1 receptor antagonist ameliorated cisplatin-induced renal toxicity in rats, as evidenced by improvements in renal function and histology.
Alfieri
A B
AB
Department of Pharmacology, School of Pharmacy, Central University of Venezuela, Caracas.
Cubeddu
L X
LX
D000704:Analysis of Variance; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity* / Q000652:urine; D002945:Cisplatin / Q000633:toxicity* / Q000652:urine; D003404:Creatinine / Q000652:urine; D004347:Drug Interactions; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008094:Lithium / Q000652:urine; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology*
D000970:Antineoplastic Agents; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D013777:Tetrazoles; D008094:Lithium; D003404:Creatinine; C103207:vofopitant; D002945:Cisplatin