Comparison between the effect of bosentan and perindopril on diabetic angiopathy and nephropathy in streptozotocin-induced diabetic rats

ABSTRACT

Angiopathy and nephropathy are serious problems encountered in the management of diabetes, mellitus. There is accumulating literatrues describing some sort of hystological interaction between angiotensin II [ALI] and endothelins [ETs] in addition to their possible contributing roles in the pathogenesis of diabetic complications. In the present study, the angiotensin converting enzyme inhibitor [ACEI] perindopril to prevent or minimize the development of angiopathy [endothelial dysfunction] and nephropathy in a strepozotocininduced model of diabetes type I in albino rats. Animals were classified into six groups untreated healthy non diabetic [ND] control rats, healthy [ND] rats treated with perindopril [3 mg/kg/day], healthy [ND] rats treated with bosentan [100 mg/kg/day], untreated diabetic rats, and diabetic rats treated with either perindopril or bosentan in the same doses described before. Rats were rendered diabetic by a single injection, in the tail vein, of 55 mg/kg streptozotocin [STZ] after overnight fast. Treatment with bosentan and perindopril was continued for 16 weeks during which the 24[th] urine volume, urinary albumin content, urine and plasma levels of creatinine as well as systolic blood pressure [SBP] were assessed at the end of each 4 weeks. At the end of the 16[th] week rats were sacrificed and the kidneys were removed for examination of histopathological changes, while the thoracic aortae were removed for assessment of the vasorelaxant effect of acetylcholine [Ach]. Diabetic rats developed typical functional changes manifested by hyperglycemia, polyuria, albuminuria, elevated SBP, reduced response to vasorelaxant effect of ACh in addition to histopathological changes manifested by tubular dilatation, diffuse interstitial edema and decreased density of the brush border of epithelial cells. In the healthy [ND] animals, changes obtained in the different parameters studied were insignificant between the treated and non-treated groups. In diabetic animals, however; both perindopril and bosentan significantly reduced albuminuria and lowered elevated SBP. In addition both drugs improved creatinine clearance and relaxant response to ACh to a large extent. Perindopril was more potent with regard to the hypoalbuminuric effect and the effect on creatinine clearance, while bosentan-induced improvement of vascular reactivity to ACh was more significant. Different potencies of perindopril and bosentan in affecting certain studied parameters suggests that the two drugs work either through different mechanisms or through similar pathways but to different extents. The renoprotective and antiangiopathic effects of both drugs were independent of the blood glucose level because this parameter was not significantly altered by either treatment. In conclusion, it seems that both angiotensin II and endothelins play an important role in the pathogenesis of diabetic angiopathy and nephropathy with probable interaction between the two systems to augment the production of such pathological disorders. Therefore, ACELs and ET receptor antagonists are highly recommended in the management of diabetic and ET receptor antagonists are highly recommended in the management of diabetic complications