Influence of nonsteroidal anti-inflammatory drugs on calcium efflux in isolated rat renal cortex mitochondria and aspects of the mechanisms involved.
In the present study we investigated the influence of several nonsteroidal anti-inflammatory drugs on calcium efflux in isolated rat renal cortex mitochondria in order to assess their potential to disrupt cell calcium homeostasis, as well as aspects of the mechanisms associated with oxidation of mitochondrial pyridine nucleotides (NAD(P)H) and with inhibition of the process by cyclosporin A (CsA). Calcium efflux was estimated with arsenazo III as an indicator and the redox state of NAD(P)H was monitored fluorimetrically at the 366/450 nm excitation/emission wavelength pair. Dipyrone, paracetamol and ibuprofen did not induce calcium efflux even at 1 mM, piroxicam and salicylate were poor inducers, while diclofenac sodium and mefenamic acid were potent inducers releasing calcium even at 20 microM and 10 microM, respectively. In the presence of 10 microM calcium, CsA had no appreciable effect while in the presence of 30 microM calcium it delayed calcium efflux. Oxidation of mitochondrial NAD(P)H, concomitant with calcium efflux and inhibited by CsA, was observed only in the presence of 30 microM calcium. The results suggest that diclofenac sodium and mefenamic acid induce calcium efflux in mitochondria through both a mechanism intrinsic to the mitochondrial membrane permeability transition and a mechanism including the electroneutral Ca2+/nH+ porter.
Departamento de Física e Química, Faculdade de Ciências Farmacêuticas-USP, Ribeirão Preto S.P., Brazil.
A A
AA
Pigoso
S A
SA
Uyemura
A C
AC
Santos
T
T
Rodrigues
F E
FE
Mingatto
C
C
Curti
D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D004008:Diclofenac / Q000633:toxicity; D004177:Dipyrone / Q000633:toxicity; D007052:Ibuprofen / Q000633:toxicity; D066298:In Vitro Techniques; D017136:Ion Transport / Q000187:drug effects; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008528:Mefenamic Acid / Q000633:toxicity; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010894:Piroxicam / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D020156:Salicylic Acid / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009243:NAD; D010894:Piroxicam; D004008:Diclofenac; D000082:Acetaminophen; D008528:Mefenamic Acid; D009249:NADP; D004177:Dipyrone; D016572:Cyclosporine; D020156:Salicylic Acid; D002118:Calcium; D007052:Ibuprofen