eprosartan and Diabetic-Nephropathies

Candesartan is a novel high-affinity type 1 AT(1)-receptor blocker characterized by prolonged binding to and slow dissociation from the receptor. Pharmacokinetic properties of candesartan explain its pronounced and lengthy (24-36 hours) antihypertensive action which does not depend on patients sex, age and body mass. Long term use of candesartan has been associated with regression of left ventricular hypertrophy, renoprotective effect and lowered risk of stroke. Candesartan is well tolerated. All these features make the drug suitable for wide application in the management of hypertension. Preliminary results suggest that candesartan can be useful in the treatment of diabetic nephropathy.

Topics: Acrylates; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Diabetic Nephropathies; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Tetrazoles; Thiophenes; Valine; Valsartan

Diabetic nephropathy becomes the single most frequent cause of end-stage renal disease. The present study aimed therefore to investigate possible protective effect of eprosartan, an angiotensin II type 1 receptor blocker, on high-fat diet/streptozotocin-induced early diabetic nephropathy in rats and various mechanisms underlie this effect. Male Wistar rats with type 2 diabetes induced by high-fat diet/streptozotocin were treated with eprosartan at the dose levels of 30 and 60mg/kg daily for 5 weeks. Eprosartan induced a nephroprotective effect as evident by the significant decrease in serum creatinine, urea, total cholesterol, triglycerides and glucose levels, urinary albumin excretion and kidney index as well as renal levels of malondialdehyde and nitric oxide products (nitrite/nitrate), in addition to angiotensin II, inducible nitric oxide synthase, transforming growth factor-β1 and collagen IV expressions with a concurrent increase in renal levels of reduced glutathione and catalase activity compared to diabetic untreated rats. Histopathological examination confirmed the renoprotective effect of eprosartan. In conclusion, eprosartan protects rats against high-fat diet/streptozotocin-induced early diabetic nephropathy possibly, in part, through its antioxidant effect as well as by abrogating the overexpression of angiotensin II, inducible nitric oxide synthase, transforming growth factor-β1 and collagen IV.

Topics: Acrylates; Angiotensin II; Animals; Blood Glucose; Catalase; Cholesterol; Collagen Type IV; Diabetic Nephropathies; Diet, High-Fat; Gene Expression Regulation, Enzymologic; Glutathione; Imidazoles; Kidney; Male; Malondialdehyde; Nitrates; Nitric Oxide Synthase Type II; Nitrites; Rats; Rats, Wistar; RNA, Messenger; Streptozocin; Thiophenes; Transforming Growth Factor beta1; Triglycerides

We have previously reported that hyperglycemia in healthy human subjects increased the renal vasodilator response to the angiotensin-converting enzyme inhibitor captopril. This observation raised intriguing possibilities relevant to the pathogenesis of nephropathy in patients with diabetes mellitus. To ascertain whether the effect of captopril was indeed mediated by a reduction in angiotensin II (Ang II) formation, we performed another study in which an Ang II antagonist, eprosartan, was used in place of captopril. Nine healthy subjects were studied in high sodium balance (ie, sodium intake 200 mmol/d). On the first day, the subjects received 600 mg eprosartan orally, and renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured. Glucose was infused intravenously on the second and third study days to increase plasma glucose to a level below the threshold for glycosuria ( approximately 8.8 mmol/L). Eprosartan at a dose of 600 mg or placebo was administered randomly on the second or third study day 1 hour after initiation of glucose infusion. RPF increased (by 76+/-7 mL. min(-1). 1.73 m(-2), P<0.01) in response to sustained moderate hyperglycemia and then increased further (by 147+/-15 mL. min(-1). 1. 73 m(-2), P<0.01) when eprosartan was administered during hyperglycemia. Eprosartan, conversely, did not affect RPF and GFR in normoglycemic subjects. GFR was not affected by either hyperglycemia or eprosartan. Neither plasma renin activity nor plasma Ang II concentration changed during hyperglycemia, suggesting that the hormonal responses responsible for the enhanced renal vasodilator response to eprosartan occurred within the kidney. The enhancement of the renal vasodilator effect of eprosartan during hyperglycemia is consistent with activation of the intrarenal renin-angiotensin system.

Topics: Acrylates; Adult; Angiotensin II; Diabetic Nephropathies; Glomerular Filtration Rate; Hemodynamics; Humans; Hyperglycemia; Imidazoles; Kidney; Male; Middle Aged; Renal Circulation; Renin; Renin-Angiotensin System; Thiophenes