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Introduction: Ularitide is a synthetic form of renally derived natriuretic peptide (NP), urodilatin. Omapatrilat (OMA) is a Vasopeptidase inhibitor (VPI), acting by dual inhibition of both angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP), which degrades the NPs. Ularitide and OMA underwent evaluation for the management of hypertension and heart failure (HF). Aim: This study aimed to address the effect of ularitide and OMA in aortocaval fistula (ACF) –induced congestive heart failure (CHF) in rats under various conditions of compensation (of clinical severity). Experimental protocol: Volume-overload CHF was induced in male albino rats by creating an infrarenal ACF. One week after fistula induction, ACF rats were randomized to compensated (Com) and decompensated (Decom) ACF groups and each further subdivided into ACF, ularitide and OMA/ularitide treated ACF groups. Sham was used as control. All treatment protocols were started one week after infrarenal ACF induction and continued for further two weeks. Three weeks after shunt induction, all animals were underwent assessment of cardiorenal and humoral functions. Renal outcome was measured by glomerular filtration rate (GFR), fractional excretion of sodium (FNa), absolute urinary sodium excretion (UNaV), urine volume, plasma cystin C level and urinary cyclic 3′, 5′-guanosine monophosphate (cGMP). The humoral function was assessed by plasma renin activity (PRA), angiotensin II (Ang II), Aldosterone, and cGMP. Cardiac outcome was assessed by plasma atrial natriuretic peptide (ANP), N-terminal pro–brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) while total and relative heart, lung and liver weights were recorded. Results: Induction of AC shunt was associated with deteriorated renal and excretory functions, activation of renin angiotensin aldosterone system (RAAS), elevated ANP with renal resistance to ANP, (NT-proBNP) and (cTnT), pulmonary and systemic congestion and marked cardiac hypertrophy. These changes were exacerbated in Decom-ACF. Ularitide treatment of ACF rats was associated with natriuresis, diuresis, enhanced GFR with RAAS inhibition. This effect was evident in Com-ACF, maximized by OMA but attenuated in Decom-ACF, restored by OMA treatment. Ularitide/OMA treatment had antihypertrophic, decongestant effect with preserved renal function, resulted in a marked improvement of animals’ survival. Conclusion: OMA potentiates the cardiorenal actions of ularitide in ACF-induced Com CHF and restoring its effect in Decom ACF, by simultaneously inhibiting ACE and NEP. OMA and ularitide could provide an effective therapeutic strategy for CHF.

Introduction Ularitide is a synthetic form of renally derived natriuretic peptide (NP), urodilatin. Omapatrilat (OMA) is a Vasopeptidase inhibitor (VPI), acting by dual inhibition of both angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP), which degrades the NPs. Ularitide and OMA underwent evaluation for the management of hypertension and heart failure (HF). Aim This study aimed to address the effect of ularitide and OMA in aortocaval fistula (ACF) –induced congestive heart failure (CHF) in rats under various conditions of compensation (of clinical severity). Experimental protocol Volume-overload CHF was induced in male albino rats by creating an infrarenal ACF. One week after fistula induction, ACF rats were randomized to compensated (Com) and decompensated (Decom) ACF groups and each further subdivided into ACF, ularitide and OMA/ularitide treated ACF groups. Sham was used as control. All treatment protocols were started one week after infrarenal ACF induction and continued for further two weeks. Three weeks after shunt induction, all animals were underwent assessment of cardiorenal and humoral functions. Renal outcome was measured by glomerular filtration rate (GFR), fractional excretion of sodium ( F Na ), absolute urinary sodium excretion (U Na V), urine volume, plasma cystin C level and urinary cyclic 3′, 5′-guanosine monophosphate (cGMP). The humoral function was assessed by plasma renin activity (PRA), angiotensin II (Ang II), Aldosterone, and cGMP. Cardiac outcome was assessed by plasma atrial natriuretic peptide (ANP), N-terminal pro–brain natriuretic peptide (NT-proBNP ) and high-sensitivity cardiac troponin T (hs-cTnT) while total and relative heart, lung and liver weights were recorded. Results Induction of AC shunt was associated with deteriorated renal and excretory functions, activation of renin angiotensin aldosterone system (RAAS), elevated ANP with renal resistance to ANP, (NT-proBNP ) and (cTnT), pulmonary and systemic congestion and marked cardiac hypertrophy. These changes were exacerbated in Decom-ACF. Ularitide treatment of ACF rats was associated with natriuresis, diuresis, enhanced GFR with RAAS inhibition. This effect was evident in Com-ACF, maximized by OMA but attenuated in Decom-ACF, restored by OMA treatment. Ularitide/OMA treatment had antihypertrophic, decongestant effect with preserved renal function, resulted in a marked improvement of animals’ survival. Conclusion OMA potentiates the cardiorenal actions of ularitide in ACF-induced Com CHF and restoring its effect in Decom ACF, by simultaneously inhibiting ACE and NEP. OMA and ularitide could provide an effective therapeutic strategy for CHF. [ABSTRACT FROM AUTHOR]

Background: We studied whether vasopeptidase inhibition corrects the structure and function of the small arteries in experimental chronic renal insufficiency (CRI). Methods: After 5/6 nephrectomy (NX) surgery was performed on rats, there was a 14-week follow-up, allowing CRI to become established. Omapatrilat (40 mg/kg/day in chow) was then given for 8 weeks, and the small mesenteric arterial rings were investigated in vitro using wire and pressure myographs. Results: Plasma and ventricular B-type natriuretic peptide (BNP) concentrations were increased 2- to 2.7-fold, while systolic blood pressure (BP) increased by 32 mm Hg after NX. Omapatrilat treatment normalized the BNP and reduced the BP by 45 mm Hg in the NX rats. Endothelium-dependent vasorelaxation was impaired but the response to acetylcholine was normalized after omapatrilat treatment. Vasorelaxations induced by nitroprusside, isoprenaline and levcromakalim were enhanced after omapatrilat, and the responses were even more pronounced than in untreated sham-operated rats. Arterial wall thickness and wall-to-lumen ratio were increased after NX, whereas omapatrilat normalized these structural features and improved the strain-stress relationship in the small arteries; this suggests improved arterial elastic properties. Conclusion: Omapatrilat treatment reduced BP, normalized volume overload, improved vasorelaxation and corrected the dimensions and passive elastic properties of the small arteries in the NX rats. Therefore, we consider vasopeptidase inhibition to be an effective treatment for CRI-induced changes in the small arteries. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: The aim of the present study was to compare the preventive impact of treatment with a vasopeptidase inhibitor (VPI) with an angiotensin-receptor blocker (ARB) on left ventricular (LV) function and renal damage in rats with renal failure after 5/6 renal ablation (Nx). Methods: Rats ( n = 15-20, each group) underwent either sham-operation (Sham) or 5/6 renal ablation (Nx). Two additional groups of Nx-animals (groups Nx-VPI and Nx-ARB) were treated with the VPI ilepatril (AVE7688, 30 mg kg−1 d−1) or with the ARB olmesartan (10 mg kg−1 d−1). Animals were followed for 4 weeks. Results: Systolic blood pressure (SBP), LV hypertrophy (LVH) and LV end-diastolic pressure (LVEDP) were increased 4 weeks after Nx ( p < 0.05). LV pressure rise (+d P/d t/LVPmax), LV pressure fall (−d P/d t/LVPmax), and creatinine clearance decreased, while albuminuria and renal glomerulosclerosis index (GSI) increased with Nx ( p < 0.05, respectively). In comparison to Nx, treatment with both VPI and ARB normalized SBP, LVH, LVEDP, +d P/d t/LVPmax, and −d P/d t/LVPmax to Sham control levels. GSI, but not creatinine clearance, was also normalized in response to both treatments. The significant increase in albuminuria observed in Nx (+230-fold versus Sham, p < 0.0001) was partially reduced in Nx-VPI (+47-fold versus Sham, p < 0.0001) and fully abolished in Nx-ARB. Conclusions: Both ilepatril and olmesartan conferred strong cardiorenal protective effects in rats with renal failure. While cardioprotection was clearly comparable with both treatment regimens, the ARB provided a better protection against the increase in albuminuria, although renal function and structural kidney changes were similarly affected by the VIP and ARB. [ABSTRACT FROM AUTHOR]