Effect of some calcium channel blockers in experimentally induced diabetic nephropathy in rats

Abstract

The aim of this study was to investigate the role of amlodipine and diltiazem (calcium channel blockers) in the preventionand treatment of diabetic nephropathy in rats. Eighty male albino rats weighing (130-180 g) were used in this study. Theseanimals were subdivided into five groups; Group I: control group, Group II: diabetic ischaemic rats treated with insulin for 12weeks, Group III: diabetic ischaemic rats treated with insulin and captopril for 12 weeks, Group IV: diabetic ischaemic ratstreated with insulin and diltiazem for 12 weeks, Group V: diabetic ischaemic rats treated with insulin and amlodipine for 12weeks. At the end of the experiments, urine and blood samples were obtained for biochemical analysis and kidney sampleswere taken for histopathological evaluation. Diabetes mellitus (DM) produced a significant increase in rat kidney weight,creatinine clearance and a highly significant increase in kidney/body weight (K/B) ratio, random blood glucose, 24 h urinevolume and protein and serum creatinine. While renal ischaemia alone produced a significant increase in systolic bloodpressure (SBP), BUN and serum creatinine, it produced a significant decrease in creatinine clearance. Combination of renalischaemia with DM also produced a significant increase in rat kidney weight and BUN levels and a significant increase inK/B ratio, random blood glucose, 24-h urine volume and protein and creatinine concentration. Moreover, this combinationproduced a significant decrease in creatinine clearance. Insulin, when given alone produced a significant reduction of theenlarged rat kidney weight and elevated K/B ratio, blood glucose and 24-h urine volume. Treatment with diltiazem oramlodipine significantly lowered the elevated SBP and 24-h urine volume. Furthermore, treatment with captoprilsignificantly lowered the elevated SBP, serum creatinine, K/B ratio and proteinuria. Light microscopic examination ofkidneys from diabetic animals revealed glomerulopathy characterized by thickening of the glomerular basement membrane,mesangial matrix expansion, arteriole hyalinosis and large proteinaceous deposits occluding capillary loops and hyalineproteinaceous droplets within the glomeruli. Moreover, examination of the kidneys of ischaemic animals by light microscopyrevealed focal tubular necrosis at multiple points along the nephron, and occlusion of tubular lamina by eosinophilic hyalinecasts or pigmented granular casts particularly in distal tubules. There was an interstitial oedema and accumulation ofleukocytes within the dilated vasa recta. Treatment with insulin alone did not reverse the histopathological changes.Treatment with captopril did not reverse the morphological changes in the glomeruli and the casts did not disappear.However, treatment with diltiazem and amlodipine improved many histopathological changes. In conclusion, diltiazem andamlodipine ameliorated the signs of diabetic nephropathy. (Int J Diab Metab 14:39-49, 2006)