EFFECT OF CALMODULIN-INHIBITORS AND VERAPAMIL ON THE NEPHROTOXICITY OF CADMIUM IN RAT

Recent reports indicate that calmodulin inhibitors (CIs) can modify ca dmium (Cd) toxicity in rodents. Pretreatment with CIs prevents Cd-indu ced testicular damage in mice and reduces the severity of such damage in rats. On the other hand it has been suggested that the cellular tra nsport of Cd can be partly inhibited by the calcium-channel inhibitor, verapamil. The aim of this study was to determine whether these inhib itors can prevent the toxic effects of Cd on the kidney which is the c ritical organ. For that purpose, we have examined the effects of two C Is (trifluoperazine and chlorpromazine) and of verapamil on the develo pment of tubular damage in female Sprague-Dawley rats. The animals wer e injected subcutaneously 5 days a week for 8 weeks with cadmium chlor ide (1 mg Cd/kg), alone or in association with trifluoperazine (20 mg/ kg), chlorpromazine (15 mg/kg) or verapamil (2 x 5 mg/kg). The develop ment of renal dysfunction was followed by measuring the urinary excret ion of the low molecular weight protein Clara cell protein (CC16). In Cd-treated rats, the urinary excretion of CC16 started to increase fro m week 6 to reach at the end of experiment values more than 100-times above normal. CIs or verapamil did not influence the rise of urinary C C16 induced by Cd. The three inhibitors, by contrast, enhanced the acc umulation of Cd in the liver and, at the exception of chlorpromazine, in the kidneys of Cd-treated rats. Although interfering with the metab olism of Cd, CIs and verapamil do not prevent renal damage in rats chr onically exposed to this heavy metal. (C) 1998 Elsevier Science Irelan d Ltd. All rights reserved.