Effect of calmodulin-inhibitors and verapamil on the nephrotoxicity of cadmium in rat

Abstract

Recent reports indicate that calmodulin inhibitors (CIs) can modify cadmium (Cd) toxicity in rodents. Pretreatment with CIs prevents Cd-induced testicular damage in mice and reduces the severity of such damage in rats. On the other hand it has been suggested that the cellular transport of Cd can be partly inhibited by the calcium-channel inhibitor, verapamil. The aim of this study was to determine whether these inhibitors can prevent the toxic effects of Cd on the kidney which is the critical organ. For that purpose, we have examined the effects of two CIs (trifluoperazine and chlorpromazine) and of verapamil on the development of tubular damage in female Sprague-Dawley rats. The animals were injected subcutaneously 5 days a week for 8 weeks with cadmium chloride (1 mg Cd/kg), alone or in association with trifluoperazine (20 mg/kg), chlorpromazine (15 mg/kg) or verapamil (2×5 mg/kg). The development of renal dysfunction was followed by measuring the urinary excretion of the low molecular weight protein Clara cell protein (CC16). In Cd-treated rats, the urinary excretion of CC16 started to increase from 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 CC16 induced by Cd. The three inhibitors, by contrast, enhanced the accumulation of Cd in the liver and, at the exception of chlorpromazine, in the kidneys of Cd-treated rats. Although interfering with the metabolism of Cd, CIs and verapamil do not prevent renal damage in rats chronically exposed to this heavy metal.