possible reno- and vascufoprotective of drugs that inhibit the renin angiotensin system in diabetic rats

ABSTRACT

Aim: The renin angiotensin system [RAS] plays an important role in the development of diabetic renovascular pathology characteristic of diabetic nephropathy [DN]. Through inhibition of RAS by different mechanisms, angiotensin-converting enzyme inhibitors [ACEIs] and angiotensin II type 1 receptor blockers [ARBs] could slow the progression of diabetic renovascular disease. Thus, the present study was undertaken to test the hypothesis that a combination of an ACEI [fosinopril] and an ARB [candesartan] could exert additive reno- and vasculoprotective effects in uninephrectomized [UNE], streptozotocin [STZ] -induced diabetic rats. Material and Fifty male albino rats weighing 150-200 g were used in the present study. Rats were divided into five groups [each of ten rats]; ten rats of them were taken as normal sham-operated group. The remaining forty rats were subjected to left unilateral nephrectomy and then three weeks later, diabetes was induced by a single intravenous injection of STZ. The UNE STZ - diabetic rats were further subdivided into control rats that were given no additional treatment but insulin s.c., UNE STZ -diabetic rats treated with fosinopril in addition to insulin for 16 weeks, UNE STZ - diabetic rats treated with candesartan in addition to insulin for 16 weeks and the fifth group was UNE STZ -diabetic rats treated with a combination of fosinopril and candesartan in addition to insulin for 16 weeks. UNE STZ - diabetic rats exhibited the characteristic features of diabetic renal disease including increased BP, plasma creatinine [PCr], urinary albumin excretion [UAE], kidney weight [KW], BG and glycosylated hemoglobin [HbAIc] together with decreased urinary creatinine [UCr] and creatinine clearance [CrCI]. Furthermore, control rats showed significant elevations in plasma transforming growth factor-beta 1 [TGF-D 1] and in renal malondialdehyde [MDA] associated with significant reduction in renal reduced glutathione [GSH]. Edothalial dysfunction [ED] of renal arteries isolated from STZ-diabetic rats, evidenced by a significant decrease in percentage of maximal relaxation in response to acetylcholine [ACH], has been also demonstrated. Oral administration of fosinopril or candesartan for 16 weeks in UNE STZ diabetic rats produced significant decreases in KW,BP, PCr,UAE, plasma TGED1 and renal MDA concentration together with significant increase in UCr, CrC 1 and renal GSH concentration. Vasculoprotective effect of fosinopril and candesartan has been also found, evidenced by a significant increase in the percentage of maximal relaxation in response to Ach in renal arteries isolated from UNR STZ-diabetic rats treated with fosinopril or candesartan Treatment of UNE diabetic rats with a combination of an ACEI [Fosinopril] and an ARB [candesartan] improved most of the estimated biochemical parameters as well as BP more significantly than either drug alone, but the combination of both drugs did not result in a significant difference in the percentage of maximal relaxation in response to Ach in renal arteries compared to either drug given alone. Conclusions: the results of the present study demonstrated that ACEIs and ARBs have a comparable degree of reno- and vasculoprotection in UNE STZ- induced diabetic rats Moreover, the present study demonstrated an additive renoprotective effect of combination therapy with ACEIs and ARBs over monotherapy with either class alone