oxadiazoles and Proteinuria

Angiotensin receptor blockers (ARBs) are preferably used in hypertensive patients with CKD. Azilsartan is a strong antihypertensive ARB, but its antiproteinuric effects are not well understood. We compared the antiproteinuric effect of azilsartan and candesartan in CKD patients in an open-label, randomized, crossover trial.. A total of 111 patients were treated with 20 mg of azilsartan daily for 2 months as a run-in period. After the run-in period, patients were randomized into 2 arms and received either 20 mg of azilsartan or 8 mg of candesartan daily for 3 months in a crossover trial. The primary outcome was the percent change in urinary protein-to-Cr ratio (UPCR).. Ninety-five patients completed the trial. The mean age was 64.3 years. The estimated glomerular filtration rate (eGFR) and UPCR were 41.5 mL/min/1.73 m2 and 1.8 g/gCr, respectively. The baseline systolic and diastolic blood pressures were 131.4 and 71.0 mm Hg, respectively. The mean percent change in the UPCR was -3.8% in the azilsartan group and 30.8% in the candesartan group at the 1st endpoint (p = 0.0004), and 6.1% in the azilsartan group and 25.8% in the candesartan group at the 2nd (final) endpoint (p = 0.029). The incidence of adverse events, including eGFR levels and serum potassium levels, was not significantly different between the groups.. A 20 mg azilsartan dose had potent antiproteinuric effects compared with an 8 mg candesartan dose, without an increase in adverse events. Azilsartan may provide renal protection in addition to antihypertensive effects in CKD patients.

Topics: Angiotensin II Type 1 Receptor Blockers; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Biphenyl Compounds; Cross-Over Studies; Female; Humans; Male; Middle Aged; Oxadiazoles; Proteinuria; Renal Insufficiency, Chronic; Tetrazoles

We previously observed that high-dose angiotensin receptor blocker (ARB) can induce regression of existing glomerulosclerosis. We also found that proliferator-activated recepto-γ (PPARγ) agonist can attenuate glomerulosclerosis in a nondiabetic model of kidney disease, with specific protection of podocytes. We now assessed effects of combination therapy with ARB and pioglitazone on established glomerulosclerosis. Sprague-Dawley male rats underwent 5/6 nephrectomy (5/6 Nx) at week 0 and renal biopsy at week 8. Rats were randomized to groups with equal starting moderate glomerulosclerosis, and treated with ARB, PPARγ agonist (pioglitazone), combination or vehicle from weeks 8 to 12. Body weight, systolic blood pressure (SBP), and urinary protein (UP) were measured at intervals. In rats with established sclerosis, SBP, UP, and GS were equal in all groups at week 8 before treatment by study design. Untreated control rats had hypertension, decreased GFR, and progressive proteinuria and glomerulosclerosis at week 12. Only combination therapy significantly ameliorated hypertension and proteinuria. ARB alone or pioglitazone alone had only numerically lower SBP and UP than vehicle at week 12. Both pioglitazone alone and combination had significantly less decline in GFR than vehicle. Combination-induced regression of glomerulosclerosis in more rats from weeks 8 to 12 than ARB or pioglitazone alone. In parallel, combination treatment reduced plasminogen activator inhibitor-1 expression and macrophage infiltration, and preserved podocytes compared with vehicle. These results were linked to increased AT2 receptor and Mas1 mRNA in the combination group. PPARγ agonists in combination with ARB augment regression of glomerulosclerosis, with downregulation of injurious RAAS components vs PPARγ alone, with increased anti-fibrotic/healing RAAS components, enhanced podocyte preservation, and decreased inflammation and profibrotic mechanisms.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Blood Pressure; Creatinine; Disease Progression; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Kidney; Macrophages; Male; Oxadiazoles; Pioglitazone; Podocytes; PPAR gamma; Proteinuria; Proto-Oncogene Mas; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Thiazolidinediones

The pharmacological profile of a novel angiotensin II type 1 receptor blocker, azilsartan medoxomil, was compared with that of the potent angiotensin II receptor blocker olmesartan medoxomil. Azilsartan, the active metabolite of azilsartan medoxomil, inhibited the binding of [(125)I]-Sar(1)-I1e(8)-angiotensin II to angiotensin II type 1 receptors. Azilsartan medoxomil inhibited angiotensin II-induced pressor responses in rats, and its inhibitory effects lasted 24h after oral administration. The inhibitory effects of olmesartan medoxomil disappeared within 24h. ID(50) values were 0.12 and 0.55 mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In conscious spontaneously hypertensive rats (SHRs), oral administration of 0.1-1mg/kg azilsartan medoxomil significantly reduced blood pressure at all doses even 24h after dosing. Oral administration of 0.1-3mg/kg olmesartan medoxomil also reduced blood pressure; however, only the two highest doses significantly reduced blood pressure 24h after dosing. ED(25) values were 0.41 and 1.3mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In renal hypertensive dogs, oral administration of 0.1-1mg/kg azilsartan medoxomil reduced blood pressure more potently and persistently than that of 0.3-3mg/kg olmesartan medoxomil. In a 2-week study in SHRs, azilsartan medoxomil showed more stable antihypertensive effects than olmesartan medoxomil and improved the glucose infusion rate, an indicator of insulin sensitivity, more potently (≥ 10 times) than olmesartan medoxomil. Azilsartan medoxomil also exerted more potent antiproteinuric effects than olmesartan medoxomil in Wistar fatty rats. These results suggest that azilsartan medoxomil is a potent angiotensin II receptor blocker that has an attractive pharmacological profile as an antihypertensive agent.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Blood Glucose; Blood Pressure; CHO Cells; Cricetinae; Cricetulus; Dogs; Hypertension; Hypertension, Renal; Imidazoles; Insulin; Male; Olmesartan Medoxomil; Oxadiazoles; Protective Agents; Proteinuria; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Tetrazoles

The effects of the ATP-sensitive potassium (KATP) channel opener YM099, and the angiotensin-converting enzyme (ACE) inhibitor captopril, on the progression of renal disease in rats with surgical renal mass reduction (RMR) were evaluated. Rats were subtotal (5/6) nephrectomized by resection of the renal poles. After 2 weeks of RMR, rats were randomized to three groups and treated for 6 weeks: no treatment (n=9); YM099 at a dose of 0.3 mg/kg by daily oral administration (n=9); or captopril at a dose of 50 mg/kg by daily oral administration (n=9). Sham-operated rats were used as normal animals (n=9). In RMR rats with no treatment, proteinuria progressively developed. At 8 weeks after RMR, renal function as assessed by plasma creatinine (Pcr) and blood urea nitrogen (BUN) was impaired. Pharmacological activation of KATP channel opening by YM099 showed no beneficial effect on proteinuria and renal functional parameters. On the other hand, pharmacological ACE inhibition by captopril significantly attenuated proteinuria, and tended to inhibit the increases in Pcr and BUN; however, these effects were not statistically significant. The presents study indicates that YM099 exhibits no renoprotection with antiproteinuric effect in rats with progressive renal disease. These findings suggest that activation of KATP channel opening may play no role in the retardation of progressive renal disease.

Topics: Animals; Captopril; Cyclic N-Oxides; Kidney Diseases; Male; Oxadiazoles; Potassium Channels; Proteinuria; Rats; Rats, Sprague-Dawley

Topics: Benzyl Compounds; Blood Pressure; Diuresis; Edema; Female; Humans; Maternal-Fetal Exchange; Oxadiazoles; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Proteinuria; Uterus