Protective effect of procaine hydrochloride on cisplatin-induced alterations in rat kidney.
Efforts have been made to reduce the undesirable side effects of cisplatin, mainly nephro- and neurotoxicity, but their reduction is usually accompanied by a concomitant inhibition of antitumor activity. The local anesthetic procaine hydrochloride (P.HCl) improves the therapeutic index of cisplatin not only by the reduction of its nephro- and hemotoxicity, but also by an increase of its antitumor activity. We therefore investigated the effects of a combined treatment of cisplatin and P.HCl on rat kidneys and compared this to kidneys from rats treated with a toxic dose of cisplatin or P.HCl alone. Treatment with a saline solution was used as control. Dehydrogenase activities [succinate dehydrogenase (SDH) and NADPH diaphorase reaction demonstrating nitric oxide synthase (NOS/NADPHd)] and phosphatase activities [K -nitrophenyl phosphatase (K pNPPase), alkaline phosphatase (AlPase) and acid phosphatase (AcPase)] were studied on cryostatic sections of kidneys from controls and treated rats. Evidence of heavy morphological damage and altered AlPase and AcPase activities induced by cisplatin were observed in the S3 segment of the proximal tubules. In addition, SDH and K pNPPase activities showed some changes in the distal tubule cells. The NOS/NADPHd activity in macula densa was drastically reduced. Combined treatment of cisplatin and P.HCl greatly attenuated morphological alterations of the rat kidney and reduced the changes in enzyme activities, except for NOS/NADPHd activity, compared to the cisplatin-treated group of animals. The study indicates that, in cisplatin-induced nephrotoxicity, a significant role is played by enzyme activities, in particular K pNPPase and NOS/NADPHd, and that P.HCl can mitigate the nephrotoxicity of cisplatin, possibly by influencing some enzyme activities involved in important renal metabolic pathways.
Fenoglio
Carla
C
Dipartimento di Biologia Animale, Università di Pavia, 27100 Pavia, Italy. fenoglio@unipv.it
Boicelli
Clodomiro Andrea
CA
Ottone
Massimo
M
Addario
Concetta
C
Chiari
Patrizia
P
Viale
Maurizio
M
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D004338:Drug Combinations; D004847:Epithelial Cells / Q000187:drug effects / Q000648:ultrastructure; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000648:ultrastructure; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D007679:Kidney Medulla / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011343:Procaine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D004338:Drug Combinations; D011343:Procaine; D010088:Oxidoreductases; D019001:Nitric Oxide Synthase; D010744:Phosphoric Monoester Hydrolases; D002945:Cisplatin