Effect of Calcium Channel Blocker on Apoptosis in Cyclosporine Nephrotoxicity

Koo, J R; Lee, Y H; Kim, Y S; Cha, D R; Cho, W Y; Kwon, Y J; Kim, A R; Won, N H; Kim, H K

Abstract

BACKGROUNDS: Calcium channel blocker has been widely used to prevent cyclosporine nephrotoxicity. Considering the major role of calcium in apoptosis, this study was performed to evaluate the effect of calcium channel blocker(verapamil) on apoptosis after verifying the role of apoptosis in cyclosporinee nephrotoxicity. METHOD: 30 Sprague-Dawley rats were divided into6groupsasfollows. 1)Group C: Polyoxyethylatedcastoroil(cyclosporinevehicle) 650mg/kg/day/subcutaneously (SC) for 7 days. 2)Group S4: Cyclosporine 50mg/kg/ day/SC for 4 days. 3)Group S7: Cyclosporine 50mg/ kg/day/SC for 7 days. 4)Group VS4: Cyclosporinse 50mg/kg/day/SC and verapamil 0.1mg/kg/ 12hour/SC for 4 days. 5)Group VS7: Cyclosporine 50mg/kg/day /SC and verapamil 0.1mg/kg/12hour/SC for 7 days. 6) Group R: Recovery 4 days after cyclosporine 50mg/ kg/day/SC for 7 days. Then the number and pattern of apoptosis in kidney were evaluated by in situ end labelling method and hematoxylin-eosin stain. RESULT: 1) The systolic blood pressure were increased in S4, S7 and VS4, VS7 groups as compared with C and R group. 2) The serum creatinine concentration were increased and creatinine clearance were decreased in S4, S7 and VS4, VS7, R groups as compared with C group. But fractional sodium excretion were all less than 1% without significant difference between groups 3) In hematoxylin-eosin stain, tubular vacuolization was increased in S4 and S7 groups with no evidence of necrosis. And verapamil had no effect on degree of tubular vacuolization. 4) The number and pattern of apoptosis were as follows Tubular cell apoptosis was maximal in S7 group and decreased in R and VS7 groups. On the contrary, interstitial cell apoptosis was minimal in S7 group and increased in R group. Verapamil had no effect on interstitial cell apoptosis. And there were only few apoptotic cells in glomeruli and vessels. 5) The number of tubular cell apoptosis was weakly correlated with systolic blood pressure.
CONCLUSIONS
Apoptosis probably has some role in cyclosporine induced tubular damage and decreased by verapamil. So inhibition of apoptosis may be a possible preventive mechanism of calcium channel blocker in cyclosporine nephrotoxicity.