Effect of calcium antagonism by nifedipine and chlorpromazine on acute N-(3,5-dichlorophenyl)succinimide-induced nephrotoxicity in Fischer 344 rats.
The nephrotoxicity induced by a wide variety of chemical compounds can be attenuated by agents which modify calcium ion (Ca2+) movement across membranes or calcium-dependent processes. The purpose of this study was to examine the ability of nifedipine, a calcium channel blocking drug, and chlorpromazine (CPZ), an antagonist of many calcium-dependent processes, to attenuate the nephrotoxicity induced by the agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) or its metabolite N-(3,5-dichlorophenyl)-2-hydroxysuccinimide (NDHS). Male Fischer 344 rats (4 rats per group) were pretreated intraperitoneally (i.p.) with nifedipine (0.25 or 0.50 mg/kg), CPZ (1.0 or 5.0 mg/kg) or vehicle 1 h before NDPS (0.4 mmol/kg), NDHS (0.1 mmol/kg) or vehicle (sesame oil, 2.5 ml/kg). In separate experiments, rats were pretreated with nifedipine (0.25 or 0.50 mg/kg/day, i.p.) starting 2 days before NDPS or NDPS vehicle and continuing throughout the experiment. Renal function was monitored at 24 and 48 h. Nifedipine (single or multiple treatments) and CPZ (1.0 mg/kg) were ineffective in substantially altering NDPS (0.4 mmol/kg)-induced nephrotoxicity. However, CPZ (5.0 mg/kg) markedly attenuated all aspects of NDPS-induced nephropathy. Also, CPZ (5.0 mg/kg) partially protected against NDHS (0.1 mmol/kg)-induced renal effects. These results demonstrate the inability of the calcium channel blocker nifedipine to attenuate NDPS nephrotoxicity. Attenuation of NDPS nephrotoxicity by CPZ could suggest that CPZ is antagonizing calcium influx into renal tissue and/or renal intracellular calcium-dependent processes to modify the renal response to NDPS. However, the inability of CPZ to markedly attenuate NDHS nephrotoxicity could indicate that CPZ protected against NDPS nephrotoxicity by inhibiting biotransformation of the parent compound to its toxic chemical species.
Rankin
G O
GO
Department of Pharmacology, Marshall University School of Medicine, Huntington, WV 25755-9310.
Valentovic
M A
MA
Teets
V J
VJ
Nicoll
D W
DW
Sutherland
C H
CH
Brown
P I
PI
D000818:Animals; D002746:Chlorpromazine / Q000627:therapeutic use*; D004231:Diuresis / Q000187:drug effects; D005659:Fungicides, Industrial / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000633:toxicity; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009543:Nifedipine / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013388:Succinimides / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000633:toxicity; D010130:p-Aminohippuric Acid / Q000378:metabolism
D005659:Fungicides, Industrial; D013388:Succinimides; C007352:N-(3,5-dichlorophenyl)succinimide; D009543:Nifedipine; D002746:Chlorpromazine; D010130:p-Aminohippuric Acid