omapatrilat and Diabetes-Mellitus--Type-2

The renin-angiotensin system plays an important role in the pathogenesis of diabetes-induced vascular and renal complications. Vasopeptidase inhibitors simultaneously inhibit angiotensin-converting enzyme (ACE) and neutral endopeptidase.. To compare the effectiveness of vasopeptidase inhibition and ACE inhibition in preventing hypertension, endothelial dysfunction and diabetic nephropathy in spontaneously diabetic Goto-Kakizaki (GK) rats.. Eight-week-old GK rats received omapatrilat (40 mg/kg) or enalapril (30 mg/kg) for 12 weeks, either during a normal-sodium or high-sodium diet (7% w/w). Blood pressure, arterial functions and renal morphology were determined.. Blood pressure and albuminuria were increased in GK rats compared to non-diabetic Wistar controls. Endothelium-dependent vascular relaxation in response to acetylcholine (ACh) and endothelium-independent vascular relaxation in response to sodium nitroprusside (SNP) were impaired in GK rats. Experiments with N-nitro-L-arginine methyl ester (L-NAME), diclofenac, and L-NAME + diclofenac suggested that cyclooxygenase and endothelium-derived hyperpolarizing factor components of endothelium-dependent vascular relaxation were also impaired. A high-sodium diet aggravated hypertension and diabetes-induced vascular and renal complications. Omapatrilat and enalapril normalized blood pressure and albuminuria during the normal-sodium diet, and effectively ameliorated diabetes-induced renal complications also during the high-sodium diet. However, omapatrilat improved endothelium-dependent relaxation to ACh to a greater extent (85 +/- 5%) than enalapril (68 +/- 6%, P < 0.05). Diclofenac pre-incubation eliminated this difference between omapatrilat and enalapril in ACh-induced vascular relaxation, suggesting that it was mediated, at least in part, via the cyclooxygenase pathway.. Despite comparable blood pressure-lowering and renoprotective properties, omapatrilat may be more effective in preventing vascular dysfunction during diabetes compared to enalapril in GK rats.

Topics: Acetylcholine; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Vessels; Diabetes Mellitus, Type 2; Diclofenac; Enalapril; Endothelium, Vascular; Kidney; Male; Metalloproteases; Neprilysin; NG-Nitroarginine Methyl Ester; Nitroprusside; Pyridines; Rats; Rats, Inbred Strains; Rats, Wistar; Sodium, Dietary; Thiazepines; Vasodilator Agents

In this study we examined diabetes- and hypertension-induced changes in cardiac structure and function in an animal model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We hypothesized that treatment with omapatrilat, a vasopeptidase inhibitor, which causes simultaneous inhibition of angiotensin converting enzyme and neutral endopeptidase, provides additional cardioprotective effects, during normal- as well as high sodium intake, compared to treatment with enalapril, a selective inhibitor of angiotensin converting enzyme. Fifty-two GK rats were randomized into 6 groups to receive either normal-sodium (NaCl 0.8%) or high-sodium (NaCl 6%) diet and enalapril, omapatrilat or vehicle for 12 weeks. The GK rats developed hypertension, cardiac hypertrophy and overexpression of cardiac natriuretic peptides and profibrotic connective tissue growth factor compared to nondiabetic Wistar rats. The high dietary sodium further increased the systolic blood pressure, and changed the mitral inflow pattern measured by echocardiography towards diastolic dysfunction. Enalapril and omapatrilat equally decreased the systolic blood pressure compared to the control group during normal- as well as high-sodium diet. Both drugs had beneficial cardioprotective effects, which were blunted by the high dietary sodium. Compared to enalapril, omapatrilat reduced the echocardiographically measured left ventricular mass during normal-sodium diet and improved the diastolic function during high-sodium diet in GK rats. Furthermore, omapatrilat reduced relative cardiac weight more effectively than enalapril during high sodium intake. Our results suggest that both the renin-angiotensin and the neutral endopeptidase system are involved in the pathogenesis of diabetic cardiomyopathy since vasopeptidase inhibition was shown to provide additional benefits in comparison with selective angiotensin converting enzyme inhibition alone.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Glucose; Blood Pressure; Body Weight; Cardiomegaly; Collagen; Diabetes Mellitus, Type 2; Echocardiography; Enalapril; Fibrosis; Heart; Insulin; Male; Metalloendopeptidases; Myocardium; Natriuretic Peptide, Brain; Organ Size; Protease Inhibitors; Pyridines; Random Allocation; Rats; Rats, Wistar; RNA, Messenger; Sodium Chloride, Dietary; 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