omapatrilat and Hypertension--Renal

This study investigates the effects of chronic administration of omapatrilat (OMA) on blood pressure (BP), renal injury, and other variables in N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension and in the low-renin model produced by the simultaneous administration of L-NAME and deoxycorticosterone acetate (DOCA).. The control, DOCA, L-NAME, L-NAME + DOCA, L-NAME + OMA, and L-NAME + DOCA + OMA groups were used. Tail systolic BP was measured twice a week. After 4 weeks of treatment, mean arterial pressure (MAP), and metabolic, morphologic, and renal variables were measured.. The final values of MAP were 109 +/- 5.1 mm Hg for the control group, 113 +/- 3.0 mm Hg for DOCA, 175 +/- 3.7 mm Hg for L-NAME, 193 +/- 3.8 mm Hg for L-NAME + DOCA, 117 +/- 3.9 mm Hg for L-NAME + OMA, and 158 +/- 3.0 mm Hg for L-NAME + DOCA + OMA. The rats treated with L-NAME showed mild and scarce renal lesions, which were prevented by OMA treatment and the L-NAME + DOCA group showed proteinuria and hyaline arteriopathy, which were markedly attenuated in the L-NAME + DOCA + OMA group. Plasma urea and creatinine were significantly increased in the L-NAME + DOCA group, whereas these variables were not significantly greater in the L-NAME + DOCA + OMA group versus controls. The L-NAME + DOCA group showed relative renal and cardiac hypertrophy that was not observed in the L-NAME + DOCA + OMA group.. The simultaneous blockade of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE) completely prevents L-NAME hypertension. Our results also show that OMA attenuates the increased BP and the renal injury in L-NAME hypertensive rats treated with DOCA. Assuming that this is a low-renin model of hypertension, the protective effect of OMA may be due to an increase in vasodilator peptides produced by both ACE and NEP inhibition.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Creatinine; Desoxycorticosterone; Disease Models, Animal; Drinking; Eating; Enzyme Inhibitors; Hypertension, Renal; Kidney; Male; Natriuresis; NG-Nitroarginine Methyl Ester; Potassium; Pyridines; Rats; Rats, Wistar; Sodium; Thiazepines; Urea

Vasopeptidase inhibitors are a new class of compounds that inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase. This study determined whether treatment with the vasopeptidase inhibitor omapatrilat (OMA) produced different effects on renal and cardiovascular structure compared with inhibition of ACE by enalapril (ENP) in rats with two-kidney, one clip hypertension (2K1C).. Hypertensive 2K1C rats were randomized into four groups and studied for another 8 weeks: no treatment, OMA, ENP or ENP combined with the diuretic hydrochlorothiazide (ENP + HCTZ). Albuminuria, vascular and renal histology as well as glomerular expression of transforming growth factor-beta (TGF-beta) were determined at the end of the experiment.. OMA decreased blood pressure slightly better than ENP. However, combination of ENP with a diuretic lowered blood pressure equally effective as OMA. OMA was numerically more efficient in reducing cardiovascular and renal hypertensive changes compared with ENP. In contrast, the combination of ENP + HCTZ was as efficient as OMA. However, OMA lowered overexpression of TGF-beta in the non-clipped kidney better than ENP or ENP +HCTZ. Antihypertensive therapy surprisingly decreased renal function as shown by increased plasma creatinine and urea and decreased creatinine clearance.. OMA is marginally more potent compared with ENP alone in lowering blood pressure and preventing cardiovascular and renal injury. This effect may be due to slightly better blood pressure reduction because addition of HCTZ enhances the cardio- and nephroprotective capacity of ENP. In contrast, OMA reduces TGF-beta overexpression in the non-clipped kidney better than ENP or ENP + HCTZ. Therefore, vasopeptidase inhibition is not superior to ACE inhibition in the prevention of cardiovascular and renal damage Goldblatt hypertension.

Topics: Analysis of Variance; Animals; Biopsy, Needle; Blotting, Western; Disease Models, Animal; Enalapril; Enzyme-Linked Immunosorbent Assay; Hypertension, Renal; Immunohistochemistry; Male; Organ Size; Probability; Protease Inhibitors; Pyridines; Random Allocation; Rats; Rats, Inbred Strains; Reference Values; Renal Circulation; Survival Rate; Thiazepines

Inhibition of nitric oxide synthases causes systemic hypertension and renal injury in rats. Our objective was to examine whether omapatrilat, a vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase, could induce better regression of renal injury than ACE inhibitor alone. Ten groups of rats were studied. They were fed either a normal (0.8% NaCl) or a high (4% NaCl) sodium diet. Eight of these groups received NG-nitro-L-arginine methyl ester (L-NAME, 20 mg x kg(-1) x d(-1)) in their drinking water. After 4 weeks, 1 group on each diet was killed and considered the L-NAME group, whereas the others received L-NAME alone, captopril (200 mg x kg(-1) x d(-1)) plus L-NAME, or omapatrilat (80 mg x kg(-1) x d(-1)) plus L-NAME for 4 additional weeks. In rats receiving L-NAME alone for 8 weeks, the mortality rate was approximately 90%, irrespective of the diet. In contrast, all rats survived in the captopril and the omapatrilat groups. In rats fed a normal-sodium diet, captopril and omapatrilat normalized systolic blood pressure and induced a complete regression of renal injury. Creatinine clearance and proteinuria were also normalized. In the high-sodium-diet groups, both treatments were less efficient: blood pressure remained elevated, and the regression of renal fibrosis was only partial. Although proteinuria decreased significantly with captopril or omapatrilat, creatinine clearance remained lower than in the controls. These results demonstrate that, in nitric oxide-deficient rats fed a normal-sodium diet, ACE and vasopeptidase inhibitors exhibit a marked renoprotective effect, whereas these treatments are less efficient in rats fed a high-sodium diet.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Vessels; Captopril; Cyclic GMP; Endothelin-1; Enzyme Inhibitors; Fibrosis; Hypertension, Renal; Kidney; Male; Neprilysin; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Protease Inhibitors; Pyridines; Rats; Rats, Sprague-Dawley; Sodium Chloride; Survival Rate; Thiazepines

Hypertension is the main risk factor for the progression of kidney damage in diabetes mellitus. The aim of the present work is to compare the effect of the treatment with irbesartan (IRBE) and omapatrilat (OMA), in obese Zucker rats (OZR).. A group of 45 OZR were uninephrectomized to accelerate renal damage, and divided into three groups: two experimental groups (IRBE and OMA) treated with 50 and 40 mg/kg/d, respectively; and the control group (CG). At the end of the 8-month follow-up period, animals were killed and the remnant kidney was removed for histologic study and to evaluate the transforming growth factor-beta1 (TGF-beta1) expression.. Both therapies reduced blood pressure (BP) versus CG (P <.001). Moreover, systolic BP was significantly lower in the OMA group than in the IRBE group (P <.001). Also, both treatments significantly lowered the urinary albumin excretion (P <.001). The OMA treatment exhibited lower values than the IRBE treatment (P <.05). The kidney TGF-beta1 expression was reduced by both treatments to a similar level. The correlation between systolic BP and glomerulosclerosis (GS) is very high (r = 0.90; P <.0001). Also, a high correlation was observed between GS and proteinuria (r = 0.79, P <.0001). The correlation between systolic BP and proteinuria was weaker (r = 0.69; P <.01).. These data suggest that both therapies are effective in ameliorating the progression of renal damage in this experimental model. Omapatrilat affords greater long-term renoprotection than irbesartan, mainly due to its potent effect in reducing systolic BP.

Topics: Albuminuria; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Hypertension, Renal; Irbesartan; Kidney; Nephrectomy; Pyridines; Rats; Rats, Zucker; Tetrazoles; Thiazepines; Transforming Growth Factor beta; Transforming Growth Factor beta1

Vasopeptidase inhibitors are a new class of cardiovascular compounds that inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The aim of the present study was to explore the effects of omapatrilat, a vasopeptidase inhibitor, on renal function and pathology in subtotally nephrectomized (STNx) rats.. STNx rats were randomized to four groups and treated for 12 weeks: no treatment (N = 14); omapatrilat at a low dose of 10 mg/kg (L, N = 12) and at a high dose of 40 mg/kg (H, N = 10); or an ACE inhibitor, fosinopril, at a dose of 10 mg/kg (N = 12). Sham-operated rats were used as control animals (N = 12).. Elevated blood pressure in STNx rats (174 +/- 9 mm Hg) was reduced by omapatrilat in a dose-dependent manner (L, 121 +/- 3 mm Hg; H, 110 +/- 3 mm Hg) and by fosinopril (149 +/- 5 mm Hg). Proteinuria in STNx rats (246 +/- 73 mg/day) was reduced by treatment with fosinopril (88 +/- 21 mg/day) and was normalized by treatment with omapatrilat (L, 30 +/- 4 mg/day; H, 20 +/- 2 mg/day vs. control 25 +/- 1 mg/day). Decreased glomerular filtration rates, elevated plasma urea and creatinine and glomerulosclerosis, and tubulointerstitial fibrosis were ameliorated by omapatrilat and fosinopril to a similar degree. Compared with fosinopril, omapatrilat treatment was associated with increased plasma renin activity and decreased renal ACE and NEP binding in a dose-dependent manner.. These findings suggest that vasopeptidase inhibition may provide a useful strategy for the treatment of progressive renal disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autoradiography; Blood Pressure; Creatinine; Disease Models, Animal; Fosinopril; Glomerular Filtration Rate; Heart Failure; Hypertension, Renal; Kidney; Male; Nephrectomy; Neprilysin; Organ Size; Peptidyl-Dipeptidase A; Proteinuria; Pyridines; Rats; Rats, Sprague-Dawley; Renal Insufficiency; Renin; Thiazepines; Urea