ISSN No. 1606-7754                   Vol.14 No.1  April 2006

Effect of some calcium channel blockers in experimentally induced diabetic nephropathy in rats
Wael Mohammed Yousef1, Adek Hussein Omar1, Naglaa Mohamed Ghanayem2, Moshira Mohamed Abd El-Wahed3, Mohamed Darwesh Morsy4
1 Departments of Clinical Pharmacology, 2 Medical Biochemistry, 3 Pathology, 4Physiology, Faculty of Medicine, Menoufiya University, Egypt

Abstract

The aim of this study was to investigate the role of amlodipine and diltiazem (calcium channel blockers) in the prevention and treatment of diabetic nephropathy in rats. Eighty male albino rats weighing (130-180 g) were used in this study. These animals were subdivided into five groups; Group I: control group, Group II: diabetic ischaemic rats treated with insulin for 12 weeks, Group III: diabetic ischaemic rats treated with insulin and captopril for 12 weeks, Group IV: diabetic ischaemic rats treated with insulin and diltiazem for 12 weeks, Group V: diabetic ischaemic rats treated with insulin and amlodipine for 12 weeks. At the end of the experiments, urine and blood samples were obtained for biochemical analysis and kidney samples were 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 urine volume and protein and serum creatinine. While renal ischaemia alone produced a significant increase in systolic blood pressure (SBP), BUN and serum creatinine, it produced a significant decrease in creatinine clearance. Combination of renal ischaemia with DM also produced a significant increase in rat kidney weight and BUN levels and a significant increase in K/B ratio, random blood glucose, 24-h urine volume and protein and creatinine concentration. Moreover, this combination produced a significant decrease in creatinine clearance. Insulin, when given alone produced a significant reduction of the enlarged rat kidney weight and elevated K/B ratio, blood glucose and 24-h urine volume. Treatment with diltiazem or amlodipine significantly lowered the elevated SBP and 24-h urine volume. Furthermore, treatment with captopril significantly lowered the elevated SBP, serum creatinine, K/B ratio and proteinuria. Light microscopic examination of kidneys 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 hyaline proteinaceous droplets within the glomeruli. Moreover, examination of the kidneys of ischaemic animals by light microscopy revealed focal tubular necrosis at multiple points along the nephron, and occlusion of tubular lamina by eosinophilic hyaline casts or pigmented granular casts particularly in distal tubules. There was an interstitial oedema and accumulation of leukocytes 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 and amlodipine ameliorated the signs of diabetic nephropathy. (Int J Diab Metab 14:39-49, 2006)

Keywords: Calcium channel blockers, diabetic nephropathy, diabetes mellitus, rat

Introduction

Diabetic nephropathy (DNP) is a major cause of illness and premature death in people with diabetes, largely through accompanying cardiovascular diseases and end-stage renal failure. It is a progressive disease ending in chronic renal insufficiency. Indeed, diabetic patients are several times as prone to kidney disease as non-diabetic people and the cumulative risk of diabetic nephropathy in type I and type II diabetes mellitus is about 30% to 50% after 25 years of the disease. Proteinuria heralds the onset of DNP and the worsening of proteinuria parallels progression of renal disease.1-3

There is increasing evidence that non-dihydropyridine calcium channel blockers (NDHPCCBs) seem to offer nephroprotection not seen with dihydropyridine calcium channel blockers (DHPCCBs) alone in terms of reducing proteinuria and slowing the progression of diabetic renal failure.4-7

The present study was designed to elucidate the beneficial effect of some calcium channel blockers (CCBs) in experimentally induced diabetic nephropathy (DNP) in rats. It also investigates the nephroprotective capacity of some CCBs especially diltiazem (non-dihydropyridine) and amlodipine (dihydropyridine) beyond their systemic blood pressure lowering effects.

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