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Aim: The renin-angiotensin-aldosterone system (RAAS) plays important roles in oxidative stress and various gastroenterological mechanisms. Omapatrilat, an RAAS-acting agent, inhibits both neprilysin neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE) and may therefore affect protective mechanisms against gastric ulcer. Therefore, this study examined the gastroprotective role of omapatrilat in a mouse model of gastric ulcer induced by indomethacin to reveal pharmacological and biochemical changes resulting from omapatrilat treatment. Materials and Methods: Forty-two BALB/c mice were divided into seven groups: control, 40 mg/kg omapatrilat only, 25 mg/kg indomethacin only, indomethacin and 40 mg/kg famotidine, and three groups with indomethacin and 10-40 mg/kg omapatrilat. All chemicals were administered by oral gavage in 0.5 mL of 0.9% NaCl solution at the determined doses. Stomach ulcers were induced by indomethacin in mice treated with famotidine (40 mg/kg) and omapatrilat (10-40 mg/kg). Stomach tissue samples were examined macroscopically. Oxidative stress biomarkers of malondialdehyde (MDA), glutathione (GSH), NEP and ACE levels as well as superoxide dismutase (SOD) activity were measured. Results: The best antiulcer activity was measured with 40 mg/kg omapatrilat, where the gastric damage observed in the ulcer groups was significantly reversed, and gave the most similar results to the specific famotidine treatment. In relation with the increasing omapatrilat dose, SOD activity was corrected as well as GSH and MDA levels. Also the levels of ACE and NEP decreased back towards those measured in the control group. Therefore, these macroscopic and biochemical findings indicating reversal of gastrotoxicity and gastric ulcer indications demonstrate the role of omapatrilat’s NEP and ACE inhibition in indomethacin toxicity, and its strong gastroprotective potential. Conclusion: Dual inhibition of NEP and ACE by omapatrilat may suppress oxidative stress associated with indomethacin-induced gastric ulcer. Therefore, the protective effect of omapatrilat in the treatment of ulcers may lead to the search for new treatment strategies.

Copyright of Namık Kemal Tıp Dergisi is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

[Figure: see text]. [ABSTRACT FROM AUTHOR]

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.

In this study, we designed a suitable ester prodrug for omapatrilat to penetrate the blood-brain barrier and treat CNS diseases. Based on the ADMET properties, the methyl carboxylate ester of omapatrilat was chosen from among several prodrug structures. Sixteen methyl carboxylate esters were constructed for omapatrilat. The structure of brain carboxylesterase was derived via homology modeling, and molecular docking was used to determine the most potent stereoisomers against brain carboxylesterase. The top three stereoisomer complexes, and the apo form of the protein, were then considered using molecular dynamics simulation and MM/GBSA analysis. Following the simulation, structural analysis was performed using RMSD, RMSF, R g , and hydrogen bond analysis tools. Our data demonstrated that the prodrug of RSSR is a suitable structure for crossing the blood-brain barrier and binding to brain carboxylesterase. In addition, we found via QM/MM calculation that the catalytic reaction of the prodrug of RSSR against brain carboxylesterase occurs via two steps, including acylation and diacylation steps. Based on our findings, we propose a clinical trial of a methyl carboxylate ester prodrug of omapatrilat's RSSR for the treatment of brain diseases.Communicated by Ramaswamy H. Sarma.

The development of the promising agent sacubitril/valsartan, known as an angiotensin receptor blocker-neprilysin inhibitor ( ARNI), to improve heart failure ( HF) management, may benefit morbidity, mortality, and readmission rates in patients with HF. The PARADIGM- HF trial demonstrated that the ARNI can reduce morbidity and mortality in patients with heart failure with reduced ejection fraction ( HFr EF), while ongoing PARAMOUNT and PARAGON- HF trials determined whether the ARNI has morbidity and mortality benefits in patients with heart failure with preserved ejection fraction ( HFp EF). However, the risk of long-term side effects of the ARNI such as cognitive dysfunction or Alzheimer's disease ( AD) remains unknown. In fact, neprilysin ( NEP), encoded by NEP or MME gene, is a principal peptidase involved in the degradation of β-amyloid (Aβ) protein. Several studies have demonstrated that polymorphisms of the NEP gene may be associated with AD and cerebral amyloid angiopathy ( CAA). Pharmacogenomics, the study of variability in drug response due to genetic polymorphisms, can potentially explain the variability in the effect of the ARNI and their side effects. Therefore, we have attempted to highlight pharmacogenomic factors and potential long-term side effects of the ARNI. Physicians should carefully monitor elderly patients with genetic risk factors for AD and CAA. In the future, genetic testing and genomic testing for NEP polymorphisms may play an important role in monitoring long-term side effects in ARNI-treated HF patients. [ABSTRACT FROM AUTHOR]

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]

The renin-angiotensin-aldosterone system (RAAS) is an important pathway that contributes to the pathophysiology of acute liver injury due to paracetamol toxicity. Omapatrilat, a RAAS-acting agent, inhibits both angiotensin converting enzyme (ACE) and neprilysin/neutral endopeptidase (NEP). The aim of the present study was to investigate the hepatoprotective effects of omapatrilat and examine the role of ACE/NEP pathway on the physiopathology of paracetamol toxicity. A total of 56 BALB/c mice were separated into seven groups: Control, 40 mg/kg omapatrilat only, 400 mg/kg paracetamol only, paracetamol and 140 mg/kg N-acetylcysteine and three groups with paracetamol and 10-40 mg/kg omapatrilat. Blood and liver tissue samples were studied through histopathological imaging, alanine transaminase (ALT) and aspartate transaminase (AST) liver function tests and oxidant/antioxidant biomarker measurements including superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA). ACE and NEP activities were also measured. Histopathological analysis revealed that paracetamol toxicity resulted in a number of apoptotic and necrotic cells in liver tissue samples. By contrast, with 40 mg/kg omapatrilat administration in toxicity-induced mice, hepatocytes were significantly improved and exhibited similar appearance to the control group. Biochemical measurements also supported these histopathological results. Omapatrilat pretreatment provided a dose-dependent reduction in oxidative stress and reversed paracetamol toxicity indications by reducing ALT and AST activities, increasing SOD activity and GSH levels and reducing MDA levels. Dose-dependent increase of ACE and NEP enzymes in omapatrilat groups was also observed. The results demonstrated promotion of antioxidant activity by omapatrilat and suppression of oxidative stress associated with acute liver injury. These findings revealed the potential role of ACE/NEP pathway in paracetamol toxicity and hepatoprotective effects of omapatrilat against oxidative stress. [ABSTRACT FROM AUTHOR]

What is known and objective: Heart failure remains a leading cause of morbidity and mortality worldwide. Advanced therapies have prolonged survival in patients with advanced heart failure, but pharmacotherapeutic optimization remains the mainstay of treatment. It has been over 10 years since the last mortality-reducing medication has been approved by the Food and Drug Administration. This article reviews the background, current knowledge and data supporting the use of sacubitril/valsartan (Entresto®), the newly FDA-approved medication that dually inhibits angiotensin and neprilysin, in the treatment of heart failure. Methods: A literature search was performed (January 1980 to August 2015) using PubMed and the search terms were as follows: neprilysin inhibitor, heart failure, endopeptidase, natriuretic peptides, angiotensin, omapatrilat, LCZ696, valsartan and sacubitril. Peer-reviewed, published clinical trials, review articles, relevant treatment guidelines and prescribing information documents were identified and reviewed for relevance. Additionally, reference citations from publications identified were reviewed. Results and discussion: The inhibition of endopeptidases has been an area of extensive study for the treatment of heart failure. Previously published literature with the endopeptidase inhibitor omapatrilat failed to demonstrate a sufficient balance between clinical efficacy and safety to justify its approval. Omapatrilat blocked three pathways that break down bradykinin, leading to high rates of angioedema. Sacubitril, on the other hand, is metabolized to a form that is highly selective for neprilysin without possessing activity for the other two peptidases, ACE and APP. The combination of sacubitril with valsartan in a single formulation offers the benefit of concurrent blockade of the renin angiotensin aldosterone system and the inhibition of neprilysin while minimizing angioedema risk. When compared to ACE inhibitor therapy in systolic heart failure patients, sacubitril/valsartan demonstrated reductions in all-cause mortality and hospitalization due to heart failure while maintaining a similar safety profile. What is new and conclusion: A formulation that contains both sacubitril and valsartan was manufactured and approved by the FDA in July 2015 for the reduction of mortality and hospitalization in systolic heart failure patients. The new medication offers a potentially superior alternative to ACE inhibitor therapy in the management of systolic heart failure. The effects of treatment with sacubitril/valsartan in the setting of diastolic heart failure are currently under investigation in clinical trials. [ABSTRACT FROM AUTHOR]

Omapatrilat (OMA), which simultaneously inhibits the angiotensin-converting enzyme (ACE) and the neutral endopeptidase (neprilysin (NEP)), is widely used in experimental protocols related to hypertension and heart failure. The penetration of OMA across the blood-brain barrier (BBB) and the effects of ACE/NEP inhibition on the recovery from ischaemic stroke have not yet been investigated. Angiotensin (Ang) I injected intracerebroventricularly (ICV) or intravenously (IV) is converted to Ang II by ACE and induces an immediate increase in blood pressure. The pressor responses to OMA administered ICV, orally or IV were studied in male Wistar rats instrumented with an ICV and arterial and venous catheters. OMA infused ICV rapidly appeared in the systemic circulation and more effectively attenuated the systemic than the central pressor responses to Ang I. OMA administered orally (5, 25, 100 μmol/kg body weight) or IV (0.5, 1, 5, 25 μmol/kg body weight) completely abolished increases in blood pressure to IV Ang I up to 2 h after treatment. The pressor responses to ICV Ang I were not altered, indicating that systemically administered OMA does not cross the BBB. To study the effects of ACE and NEP inhibition in the brain on the recovery from ischaemic stroke, OMA was infused ICV over a 5-day period before and 24 h after the occlusion of the middle cerebral artery (MCAO) for 90 min. ICV application of OMA had no effect on infarction volume and marginally improved neurological outcome. We demonstrate for the first time that simultaneous inhibition of ACE and NEP in the brain tissue does not alter the recovery from ischaemic stroke. [ABSTRACT FROM AUTHOR]

Heart failure remains a major concern across the globe as life expectancies and delivery of health care continue to improve. There has been a dearth of new developments in heart failure therapies in the last decade until last year, with the release of the results from the PARADIGM-HF Trial heralding the arrival of a promising new class of drug, ie, the angiotensin receptor-neprilysin inhibitor. In this review, we discuss the evolution of our incremental understanding of the neurohormonal mechanisms involved in the pathophysiology of heart failure, which has led to our success in modulating its various pathways. We start by examining the renin-angiotensin-aldosterone system, followed by the challenges of modulating the natriuretic peptide system. We then delve deeper into the pharmacology and mechanisms by which angiotensin receptor-neprilysin inhibitors achieve their significant cardiovascular benefits. Finally, we also consider the potential application of this new class of drug in other areas, such as heart failure with preserved ejection fraction, hypertension, patients with renal impairment, and following myocardial infarction. [ABSTRACT FROM AUTHOR]

Purpose New compounds with neprilysin or neutral endopeptidase (NEP) inhibiting activity are under clinical investigation in heart failure and hypertension. We investigated the effect of NEP inhibition on the functional vasomotor responses to a range of vasoactive peptides in human blood vessels. Methods Small human resistance arteries from patients with coronary artery disease and preserved left ventricular systolic function were studied. Thiorphan (a NEP inhibitor) was compared with captopril (an ACE inhibitor) and omapatrilat (a dual NEP-ACE inhibitor) with regard to their effects on the response of human arteries to key vasoactive peptides. Results As expected, both captopril and omapatrilat (but not thiorphan) inhibited the vasoconstrictor effect of angiotensin I (maximal response [SEM]: 27 ± 8% vehicle, 6 ± 2% captopril, 39 ± 10% thiorphan, 8 ± 7% omapatrilat, P < 0.05). Thiorphan, captopril, and omapatrilat all enhanced the vasodilator response to bradykinin (all P < 0.01). Omapatrilat markedly augmented the vasodilator action of adrenomedullin ( P < 0.05), whilst thiorphan and captopril did not. None of the three inhibitors studied affected the vasodilator action of c-type natriuretic peptide, calcitonin gene-related peptide, vasoactive intestinal polypeptide or substance P. Conclusions NEP inhibition with thiorphan modestly augmented the vasodilator action of bradykinin, but did not potentiate the response to adrenomedullin; dual ACE and NEP inhibition with omapatrilat, as expected, markedly augmented the response to bradykinin and also potentiated the effect of adrenomedullin. Thiorphan weakly enhanced the vasoconstrictor response to angiotensin I. Neither omapatrilat nor thiorphan had any effect on the action of a range of other vasoactive peptides including CNP. [ABSTRACT FROM AUTHOR]

The renin-angiotensin-aldosterone system (RAAS) is an important pathway that contributes to the pathophysiology of acute liver injury due to paracetamol toxicity. Omapatrilat, a RAAS-acting agent, inhibits both angiotensin converting enzyme (ACE) and neprilysin/neutral endopeptidase (NEP). The aim of the present study was to investigate the hepatoprotective effects of omapatrilat and examine the role of ACE/NEP pathway on the physiopathology of paracetamol toxicity. A total of 56 BALB/c mice were separated into seven groups: Control, 40 mg/kg omapatrilat only, 400 mg/kg paracetamol only, paracetamol and 140 mg/kg N-acetylcysteine and three groups with paracetamol and 10-40 mg/kg omapatrilat. Blood and liver tissue samples were studied through histopathological imaging, alanine transaminase (ALT) and aspartate transaminase (AST) liver function tests and oxidant/antioxidant biomarker measurements including superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA). ACE and NEP activities were also measured. Histopathological analysis revealed that paracetamol toxicity resulted in a number of apoptotic and necrotic cells in liver tissue samples. By contrast, with 40 mg/kg omapatrilat administration in toxicity-induced mice, hepatocytes were significantly improved and exhibited similar appearance to the control group. Biochemical measurements also supported these histopathological results. Omapatrilat pretreatment provided a dose-dependent reduction in oxidative stress and reversed paracetamol toxicity indications by reducing ALT and AST activities, increasing SOD activity and GSH levels and reducing MDA levels. Dose-dependent increase of ACE and NEP enzymes in omapatrilat groups was also observed. The results demonstrated promotion of antioxidant activity by omapatrilat and suppression of oxidative stress associated with acute liver injury. These findings revealed the potential role of ACE/NEP pathway in paracetamol toxicity and hepatoprotective effects of omapatrilat against oxidative stress., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020, Spandidos Publications.)

Background and Purpose: Inhibition of bradykinin metabolizing enzymes (BMEs) can cause acute angioedema, as demonstrated in a recent clinical trial in patients administered the antihypertensive, omapatrilat. However, the relative contribution of specific BMEs to this effect is unclear and confounded by the lack of a predictive pre-clinical model of angioedema.Experimental Approach: Rats were instrumented to record blood pressure and heart rate; inhibitors were infused for 35 min and bradykinin was infused during the last 5 min to elicit hypotension, as a functional marker of circulating bradykinin and relative angioedema risk.Key Results: In the presence of omapatrilat bradykinin produced dose-dependent hypotension, an effect abolished by B(2) blockade. In the presence of lisinopril (ACE inhibitor), but not candoxatril (NEP inhibitor) or apstatin (APP inhibitor), bradykinin also elicited hypotension. Lisinopril-mediated hypotension was unchanged with concomitant blockade of NEP or NEP/DPPIV (candoxatril+A-899301). However, hypotension was enhanced upon concomitant blockade of APP and further intensified in the presence of NEP inhibition to values not different from omapatrilat alone.Conclusions and Implications: We demonstrated that bradykinin is degraded in vivo with an enzyme rank-efficacy of ACE>APP>>NEP or DPPIV. These results suggest the effects of omapatrilat are mediated by inhibition of three BMEs, ACE/APP/NEP. However, dual inhibition of ACE/NEP or ACE/NEP/DPPIV elicits no increased risk of angioedema compared to ACE inhibition alone. Thus, novel BME inhibitors must display no activity against APP to avoid angioedema risk due to high prevalence of ACE inhibitor therapy in patients with diabetes and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to identify the mechanism(s) of omapatrilat degradation observed during dissolution from modified release (MR) tablet formulations containing colorants. The tablets were manufactured by a dry granulation process employing roller compaction. The colorants were added intragranularly and included red and yellow iron oxides and FD&C Blue No. 2 lake and dye. Dissolution studies in pH 6 or 6.8 media do not indicate any omapatrilat degradation in the absence of colorants. In the presence of colorants the degradation rate of omapatrilat in pH 6.8 media was in the following order: blue lake>blue lake+yellow iron oxide>yellow and red iron oxides. Higher degradation was observed with MR tablets formulated with indigo carmine (dye) as opposed to tablets formulated with aluminum oxide or aluminum hydroxide (dye substrate portion of lake). The inclusion of tartaric acid and the photostabilizer, uric acid, in omapatrilat MR tablets containing the blue lake reduced the degradation significantly. The dissolution instability observed at pH 6.8 in the MR tablet formulated with FD&C Blue No. 2 Lake was attributed to the dye component of the lake. The instability was more pronounced at higher pH and in the absence of a photostabilizer. [Copyright &y& Elsevier]

Abstract: The objective of this study was to determine whether adrenomedullin, a vasodilator peptide, modulates the process of cell death in cardiomyocytes and whether its effect would be enhanced by the endopeptidase inhibitor omapatrilat, which reduces adrenomedullin degradation. Further, we sought to determine whether the effect of adrenomedullin involved an action to preserve mitochondrial transmembrane potential (ΔΨ m). Cardiomyocytes in culture were treated with agents that interrupted the mitochondrial electron transport chain, inhibiting glycolysis and oxidative phosphorylation. Cell death was evaluated by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and ΔΨ m was assessed by fluorescent microscopy. Cytochrome c loss from mitochondria and appearance in cytosol was determined by Western blotting. Potassium cyanide (KCN) plus deoxyglucose or antimycin A, for 24 h, produced significant (p <0.01) concentration-dependent reductions in cell viability or increases in cell death. Adrenomedullin reduced cell death produced in this manner and the effect of adrenomedullin was enhanced by treatment with omapatrilat. In contrast, there was no additional reduction in cell death by lisinopril treatment. Omapatrilat plus adrenomedullin reduced the KCN plus deoxyglucose-induced increase in cytosolic cytochrome c. A likely mechanism centers on the ability of adrenomedullin plus omapatrilat to prevent the decline in mitochondrial ΔΨ m produced by KCN plus deoxyglucose treatment. In summary, adrenomedullin plus omapatrilat limited the decline in mitochondrial ΔΨ m that accompanies interruption of mitochondrial metabolism and limited the extent of cell death in cardiomyocytes treated with KCN plus deoxyglucose or antimycin. Adrenomedullin plus the endopeptidase inhibitor omapatrilat may be a useful strategy to protect cardiomyocytes from cell death, in conditions associated with impairment of mitochondrial function. [Copyright &y& Elsevier]

Omapatrilat, a vasopeptidase inhibitor, inhibits both neutral endopeptidase and angiotensin-converting enzyme with similar potency. The aim of this study was to investigate whether omapatrilat prevents or reverses cardiovascular remodeling and hypertension in deoxycorticosterone acetate (DOCA)-salt rats. Male Wistar rats (313 ± 2 g, n=114) were uninephrectomized (UNX) with or without further treatment with DOCA and 1% NaCl in the drinking water. Compared with UNX control rats, DOCA-salt rats developed hypertension, cardiovascular hypertrophy, perivascular and interstitial cardiac fibrosis and inflammation, endothelial dysfunction, and the prolongation of ventricular action potential duration within four weeks. The administration of omapatrilat (40 mg/kg/day po) for two weeks commencing two weeks after surgery attenuated the development of cardiovascular hypertrophy, inflammation, fibrosis, and ventricular action potential prolongation. In contrast, omapatrilat treatment did not lower systolic blood pressure nor improve endothelial dysfunction. This study concludes that the renin-angiotensin-aldosterone, natriuretic peptide, and bradykinin systems are directly involved in the pathogenesis of cardiovascular remodeling in the DOCA-salt model of hypertension in rats, which may be independent of their effects on blood pressure. [ABSTRACT FROM AUTHOR]

Natriuretic peptides play an important role in sodium regulation and blood pressure (BP) control. We examined the effects of atrial natriuetic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) on human isolated resistance arteries and the mechanisms involved in vasorelaxation. Human subcutaneous resistance arteries were mounted in an isometric myograph and contracted with phenylephrine. CNP, but not ANP or BNP, relaxed arteries in a concentration dependent manner. The action of CNP was unaffected by removal of the endothelium, inhibition of nitric oxide synthase by NG-monomethyl-Larginine or inhibition of soluble guanylate cyclase by 1H-[1,2,4] oxadiazolo [4,3-alpha] quinoxalin-1-one. Blockade of cyclic GMP-dependent kinase by 8- bromoguanosine-3', 5'- cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-cGMPS) inhibited CNP relaxation. CNP relaxation was also inhibited by high potassium or iberiotoxin, indicating that it was due to opening of BKCa channels. Omapatrilat, a vasopeptidase inhibitor of neutral endopeptidase and angiotensin-converting enzyme, enhanced the effect of CNP and inhibited responses to Ang I. In summary, CNP, but not ANP or BNP, relaxes human resistance arteries by activating cyclic GMP-dependent kinase and BKCa. The effects of CNP are enhanced by vasopeptidase inhibition and this may contribute to the vasodilator effects of these agents in vivo. Since CNP is widely present in endothelium it may play a role in the regulation of peripheral resistance in man in physiological and pathological circumstances. [ABSTRACT FROM PUBLISHER]

The objective of the present study was to assess the cardioprotective effect of dual NEP–ACE inhibition in relation to endogenous cardiac bradykinin (BK), its active metabolite des-Arg9-BK, endogenous brain natriuretic peptides (BNP), and cGMP. Rats were treated with the dual metallopeptidase inhibitor, omapatrilat, or the ACE inhibitor, ramipril, for 7 d (1 mg·kg–1·d–1). Hearts were then isolated and subjected to a zero-flow ischemia and reperfusion (except controls), in the absence or presence of either a B2-receptor antagonist (Hoe-140), a B1-receptor antagonist (Lys-Leu8-des-Arg9-BK), or the GC-A/GC-B-receptor antagonist (HS-142-1). Chronic omapatrilat and ramipril increased the amount of endogenous BK collected upon reperfusion, but only ramipril increased that of des-Arg9-BK. Only omapatrilat increased both peak BNP and peak cGMP upon reperfusion, those increases being blocked by Hoe-140. Chronic omapatrilat (but not ramipril) decreased the total noradrenaline and lactate dehydrogenase release during the reperfusion period. Importantly, only omapatrilat improved the functional recovery of the ischemic reperfused heart, with a reduced left ventricular end-diastolic pressure, and improved developed left ventricular pressure. All cardio protective effects of omapatrilat were blocked by Hoe-140 and by HS-142-1, but not by the B1-receptor antagonist. In conclusion, a chronic treatment with a dual metallopeptidase inhibitor demonstrated a cardioprotective action not observed with an ACE inhibitor in a context of severe ischemia in rat isolated hearts, which was mediated by both endogenous BK and BNP. [ABSTRACT FROM AUTHOR]

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Omapatrilat inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). We compared the effects of omapatrilat (40 mg/kg/day, p.o.) to fosinopril (40 mg/kg/day, p.o.) on flow-induced vascular remodeling in New Zealand genetically hypertensive (GH) rats. Both drugs equally reduced blood pressure (BP) initially, but systolic BP and pulse pressure were reduced more by omapatrilat after 1 week. Carotid remodeling was induced by partial ligation of the left common carotid artery (LCA). There was little remodeling in untreated GH rats – measured as outer diameter to body weight (OD/BW vs. before ligation): 97 ± 1% of initial LCA (low flow) and 107 ± 3% of initial right common carotid artery (RCA, high flow). In contrast, OD/BW increased to 118 ± 5% (p < 0.05) of initial RCA after omapatrilat versus 108 ± 2% (p = 0.96) after fosinopril. The major change was increased RCA lumen area which was significantly larger in omapatrilat-treated animals (127% vs. control) than fosinopril-treated animals (103% vs. control). The increase in outward remodeling after omapatrilat treatment correlated weakly with vascular cGMP levels and decreased systolic BP. The results suggest that dual inhibition of NEP/ACE may have greater effects than ACE inhibition alone on vessel remodeling in hypertension. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

: BackgroundRecent reports suggest that existing antihypertensive agents may not have sufficient efficacy to control blood pressure (BP) in many patients. Omapatrilat, an agent under development, has been shown to have significantly greater antihypertensive efficacy than existing agents, but may also carry increased risk of angioedema. We compared the efficacy and safety of omapatrilat to a representative angiotensin-converting enzyme (ACE) inhibitor, enalapril.: MethodsThe Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial is a multicenter, randomized, double-blind, active-controlled, 24-week trial in 25,302 patients with untreated or uncontrolled hypertension conducted in 3298 office-based sites in 12 countries. Subjects were randomized to omapatrilat 10 mg or enalapril 5 mg as initial therapy for hypertension (group 1, n = 9292), replacement for existing antihypertensive therapy (group 2, n =11,224), or in addition to existing antihypertensive therapy (group 3, n = 4751). Study drug was force-titrated at week 2 and electively titrated at weeks 4 and 6 to a maximum of omapatrilat 80 mg or enalapril 40 mg once daily. At weeks 8 and 16, adjunctive antihypertensive medications were added electively to achieve target BP.: ResultsOmapatrilat reduced systolic BP 3.6 mm Hg more than enalapril at week 8, and was associated with less use of adjunctive antihypertensive therapy by week 24 (19% v 27%; P < 0.001 for both comparisons). Subjects randomized to omapatrilat were more likely to reach BP target, regardless of demographics or comorbid conditions and whether omapatrilat was used as initial therapy, replacement for existing therapy, or in addition to existing therapy. Angioedema was more frequent with omapatrilat than enalapril (2.17% v 0.68%). Two omapatrilat-treated subjects experienced angioedema with airway compromise, which was successfully treated.: ConclusionsOmapatrilat provided broadly superior antihypertensive efficacy when used in a setting resembling clinical practice. Angioedema was more common than with enalapril but life-threatening angioedema was rare. The risk–benefit profile for omapatrilat in clinical use therefore appears likely to be favorable in appropriate patients. [Copyright &y& Elsevier]

Vasopeptidase inhibitors simultaneously inhibit both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The aim of this study was to determine the cardiorenal effects of the vasopeptidase inhibitor omapatrilat in the transgenic m(Ren-2)27 rat which exhibits fulminant hypertension and severe organ pathology. At 6 weeks of age, male Ren-2 rats were randomized to receive no treatment (N = 10), the ACE inhibitor fosinopril 10 mg/kg/day (N = 10), or omapatrilat 10 mg/kg/day (N = 10) or 40 mg/kg/day (N = 10) by daily gavage for 24 weeks. Various cardiorenal functional and structural parameters were assessed. Compared to controls, all treatment groups reduced hypertension in control Ren-2 rats, with both doses of omapatrilat reducing systolic blood pressure significantly more than fosinopril (control, 178 ± 3 mmHg; fosinopril 10 mg/kg/day, 130 ± 4 mmHg; omapatrilat 10 mg/kg/day, 110 ± 3 mmHg; omapatrilat 40 mg/kg/day, 91 ± 3 mmHg). Omapatrilat dose-dependently reduced cardiac hypertrophy, caused a greater inhibition of renal ACE than fosinopril, and was the only treatment to inhibit renal NEP. Attenuation of albuminuria, glomerulosclerosis and cardiorenal fibrosis occurred to a similar degree with omapatrilat and fosinopril. Omapatrilat confers cardiorenal protection in the hypertensive Ren-2 rat. Although inhibition of tissue NEP may contribute to the superior blood pressure reduction by omapatrilat, overall, the results are consistent with the central role that angiotensin II plays in renal and cardiac fibrosis in this model of hypertension. [ABSTRACT FROM AUTHOR]

Aims. Although ACE inhibitors slow progression of diabetic renal disease, the mortality and morbidity is still high. As other hormonal factors are involved, inhibition of vasopeptidases could further reduce progression. We studied dual inhibition of angiotensin converting enzyme and neutral endopeptidase in a model of progressive diabetic renal injury. The major endpoints were reductions in systemic blood pressure, albuminuria and renal structural injury. Methods. Diabetic spontaneously hypertensive rats were treated with the ACE inhibitor perindopril (mg·kg-1·day-1) or the vasopeptidase inhibitor omapatrilat at doses of 10 (oma10) and 40 (oma40) mg·kg-1·day-1 for 32 weeks. In vivo ACE and NEP inhibition was quantitated by in vitro autoradiography. Renal structural injury was assessed by measurement of the glomerulosclerotic (GS) index and tubulointerstitial area (TI). The expression of transforming growth factor β, β-inducible gene-h3 and nephrin were also quantitated. Results. Despite a similar reduction in blood pressure by perindopril and oma10, greater attenuation of albuminuria was afforded by oma10, with a complete amelioration observed with oma40. Oma40 lead to a 33% reduction in renal NEP binding and this was associated with less albuminuria and prevention of GS, TI area and overexpression of TGFβ and βig-h3. Diabetes-associated reduction in nephrin expression was restored by both drugs. Conclusion/Interpretation. These findings suggest that other vasoactive mechanisms in addition to angiotensin II are important in the prevention of diabetic nephropathy, and that vasopeptidase inhibition might confer an advantage over blockade of the RAS alone in the treatment of diabetic renal disease. [ABSTRACT FROM AUTHOR]

Background: Omapatrilat has potent enzymatic inhibitory effects on the angiotensin-converting enzyme and neutral endopeptidase. The prolonged effects of this inhibition on systemic and regional hemodynamics, cardiovascular mass, and hydroxyproline concentration in spontaneously hypertensive rats were studied. The contribution of endogenous bradykinin on the cardiovascular actions of omapatrilat in this genetic model of hypertension was also investigated.Methods and Results: Systemic and regional hemodynamics (radionuclide-labeled microspheres), left and right ventricular and aortic masses, and hydroxyproline concentration were determined in 35-week-old spontaneously hypertensive rats after 12 weeks of treatment with omapatrilat (40 mg/kg/day), with and without the bradykinin receptor antagonist icatibant (500 microg/kg/day). Omapatrilat decreased mean arterial pressure, reducing total peripheral resistance as well as decreased left ventricular and aortic mass indices. It also induced a profound renovasodilation associated with a decrease renal vascular resistance that markedly increased renal blood flow. Coronary hemodynamics and left ventricular hydroxyproline concentration remained unaltered. Concomitant blockade of bradykinin receptors partially attenuated the hypotensive effect of omapatrilat and its effect on aortic mass; and icatibant did not influence the renovasodilation.Conclusion: Omapatrilat produced profoundly beneficial effects on systemic and renal hemodynamics, as well as on left ventricular and aortic masses, without any effect on coronary hemodynamics. These effects of omapatrilat on arterial pressure and aortic mass, but not on renal hemodynamics and left ventricular mass, may have been at least partially mediated through the action of bradykinin. [ABSTRACT FROM AUTHOR]

Omapatrilat inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). ACE inhibitors have been shown to inhibit atherosclerosis in apoE-deficient mice and in several other animal models but failed in low-density lipoprotein (LDL) receptor-deficient mice despite effective inhibition of the renin-angiotensin-aldosterone system. The aim of the present study was to examine the effect of omapatrilat on atherogenesis in diabetic and nondiabetic LDL receptor-deficient mice. LDL receptor-deficient male mice were randomly divided into 4 groups (n = 11 each). Diabetes was induced in 2 groups by low-dose STZ, the other 2 groups served as nondiabetic controls. Omapatrilat (70 mg/kg/day) was administered to one of the diabetic and to one of the nondiabetic groups. The diabetic and the nondiabetic mice were sacrificed after 3 and 5 weeks, respectively. The aortae were examined and the atherosclerotic plaque area was measured. The atherosclerotic plaque area was significantly smaller in the omapatrilat-treated mice, both diabetic and nondiabetic, as compared to nontreated controls. The mean plaque area of omapatrilat-treated nondiabetic mice was 9357 ± 7293 μm 2 , versus 71977 ± 34610 μm 2 in the nontreated mice ( P = .002). In the diabetic animals, the plaque area was 8887 ± 5386 μm 2 and 23220 ± 10400 μm 2 , respectively for treated and nontreated mice ( P = .001). Plasma lipids were increased by omapatrilat: Mean plasma cholesterol in treated mice, diabetic and nondiabetic combined, was 39.31 ± 6.00 mmol/L, versus 33.12 ± 7.64 mmol/L in the nontreated animals ( P = .008). The corresponding combined mean values of triglycerides were 4.83 ± 1.93 versus 3.00 ± 1.26 mmol/L ( P = .02). Omapatrilat treatment did not affect weight or plasma glucose levels. Treatment with omapatrilat inhibits atherogenesis in diabetic as well as nondiabetic LDL receptor-deficient mice despite an increase in plasma lipids, suggesting a direct effect on the arterial wall. [ABSTRACT FROM AUTHOR]

: BackgroundThis study investigates the effects of chronic administration of omapatrilat (OMA) on blood pressure (BP), renal injury, and other variables in Nω-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).: MethodsThe 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.: ResultsThe 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.: ConclusionsThe 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. [Copyright &y& Elsevier]

At the American College of Cardiology in March two major trials were presented. The publicity surrounding the two could not have been more different. The LIFE demonstrated clear superiority of losartan-based therapy over atenolol-based therapy for the treatment of hypertension. It was published the same week in the Lancet and received major press coverage all over the world.The OVERTURE (Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events) study in contrast received a subdued reception, very little publicity and is yet to be published. 5770 NYHA class II–IV heart failure patients (LVEF≤30%, recent heart failure hospital admission) were randomised and uptitrated to either 10 mg BD of Enalapril or 40 mg once a day Omapatrilat. The primary end-point of all cause mortality or heart failure related hospitalisation did not differ significantly: 914/2884 for Enalapril and 914/2886 for Omapatrilat (hazard ratio 0.94, CI’s 0.86–1.03, P=0.187) . Mortality was also similar: 509 for Enalapril and 477 for Omapatrilat (hazard ratio 0.94, CI’s 0.83–1.07, P=0.339). Omapatrilat was as good as Enalapril but not better. The worrying trend was however, that angioedema was more common with Omapatrilat; 24 (0.8%) versus 14 cases (0.5%).The OCTAVE (Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) study was also presented at this time. 25,267 hypertensives were randomised to Omapatrilat or enalapril and a difference of approximately 3 mmHg in favour of Omapatrilat was seen. Significantly more cases of angioedema were seen with Omapatrilat, 274 (2.17%) compared to 86 (0.68%) with enalapril. Overall death rates were similar, 0.18% for enalapril and 0.15% for Omapatrilat. All adverse events were similar, 51.0% for Omapatrilat and 50.4% for enalapril. The rates of angioedema were much higher in blacks, 5.54% for Ompatrilat and 1.62% for enalapril and for smokers, 3.93% for Omapatrilat and 0.81% for enalapril. We were left with a drug that was, for heart failure, not superior to an ACE inhibitor already off patent, and, as an anti-hypertensive, with an angioedema rate more than double that of an ACE inhibitor in a large head to head comparison. The medical community will be watching to make sure these data are published in full in the medical literature in a timely fashion, in the order of end-points specified in the protocol and with appropriate emphasis on the logical points of presentation. [ABSTRACT FROM AUTHOR]

Background: Omapatrilat, a new vasopeptidase inhibitor, inhibits the activity of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP). Because these two enzymes participate in the degradation of the vasodilator and natriuretic peptide, angiotensin-(1-7) [Ang-(1-7)], we assessed whether omapatrilat treatment is associated with changes in the plasma and urinary excretion rates of the angiotensins.Methods: We investigated in spontaneously hypertensive rats (SHR) (0.24 kg body weight) the effect of omapatrilat on plasma and urinary concentrations of angiotensin (Ang) I, Ang II and Ang-(1-7) during 17 days of administration of either the drug (N = 15, 100 micromol/kg/day) or vehicle (N = 14) in the drinking water. Hemodynamic and renal excretory function studies were associated with histological examination of the expression of Ang-(1-7) in the kidneys of both vehicle and omapatrilat-treated SHRs.Results: Omapatrilat induced a sustained lowering of systolic blood pressure (-68 mm Hg) without changes in cardiac rate. The mild positive water balance produced by omapatrilat did not cause natriuresis or kaliuresis, although it was associated with a significant decrease in urine osmolality. Blood pressure normalization was accompanied by increases in plasma Ang I (2969%), Ang II (57%), and Ang-(1-7) (163%) levels, paralleling pronounced increases in urinary excretion rates of Ang I and Ang-(1-7) but not Ang II. Detection of Ang-(1-7) immunostaining in the kidneys of five other SHR exposed either to vehicle (N = 3) or omapatrilat (N = 2) ascertained the source of the Ang-(1-7) found in the urine. Intense Ang-(1-7) staining, more pronounced in omapatrilat-treated SHR, was found in renal proximal tubules throughout the outer and inner regions of the renal cortex and the thick ascending loop of Henle, whereas no Ang-(1-7)-positive immunostaining was found in glomeruli and distal tubules.Conclusions: Omapatrilat antihypertensive effects caused significant activation of the renin-angiotensin system associated with increases in urinary excretion rates of Ang I and Ang-(1-7). Combined studies of Ang-(1-7) metabolism in urine and immunohistochemical studies in the kidney revealed the existence of an intrarenal source, which may account for the pronounced increase in the excretion rate of the vasodilator heptapeptide. These findings provide further evidence for a contribution of Ang-(1-7) to the regulation of renal function and blood pressure. [ABSTRACT FROM AUTHOR]

Considerable attention has recently focused on the vasopeptidase inhibitors (VPI), a new class of drug that combines angiotensin-converting enzyme (ACE) inhibitor activity with inhibition of natriuretic peptide breakdown. In theory, a drug with these properties may be beneficial both in hypertension and in heart failure. Whilst the efficacy of VPIs in hypertension has been consistently demonstrated in pre-clinical and clinical studies, the role of VPIs, if any, in heart failure is less clear, since numerous small studies have produced conflicting results. Furthermore, preliminary results from the recently completed Omapatrilat Versus Enalapril Randomised Trial of Utility in Reducing Events (OVERTURE) study have failed to establish the VPI, omapatrilat, as a first line therapy in the treatment of chronic heart failure. We review the literature on VPIs in heart failure and discuss possible reasons for the reported lack of benefit over ACE inhibitors. [ABSTRACT FROM PUBLISHER]

The contribution of angiotensin-(1-7) [Ang-(1-7)] to the antihypertensive actions of omapatrilat, a novel vasopeptidase inhibitor, was evaluated in 22 salt-sensitive, low renin, hypertensive subjects as a substudy of a multicenter randomized, double-blind, parallel study of 4 weeks duration. A total of 25 other subjects received lisinopril as the active control. Omapatrilat (40 mg) produced sustained control of blood pressure (BP) (as assessed by 24-h ambulatory BP measurements) that was significantly greater than that produced by 20 mg daily of lisinopril. The antihypertensive response to either drug was accompanied by similar sustained inhibition of angiotensin converting enzyme activity. Plasma levels of angiotensin I (Ang I), angiotensin II (Ang II) and Ang-(1-7) were not altered by treatment with either omapatrilat or lisinopril, even though both regimens produced a modest rise in plasma renin activity. In contrast, urinary excretion rates of Ang I and Ang-(1-7) but not Ang II increased significantly throughout the dosing period of subjects who were given omapatrilat, whereas the smaller antihypertensive response produced by lisinopril had a smaller and transient effect on increasing urinary excretion rates of Ang-(1-7). Omapatrilat, being a single molecule inhibiting neutral endopeptidase and converting enzyme simultaneously, controlled salt-sensitive hypertension by a mechanism that was associated with sustained increases in urinary Ang-(1-7) excretion. We suggest that Ang-(1-7) may be a component of the mechanisms by which omapatrilat induces an antihypertensive response in salt sensitive hypertension. [Copyright &y& Elsevier]

The Omapatrilat in Persons with Enhanced Risk of Atherosclerotic events (OPERA) trial is a large clinical trial of omapatrilat, a vasopeptidase inhibitor, in patients with stage 1 isolated systolic hypertension (ISH). OPERA is the first study to examine whether effective antihypertensive treatment can provide survival and clinical end point benefits in older persons with this common condition. This 5-year multinational, randomized, double-blind, parallel-group, placebo-controlled, forced-titration study will be conducted in approximately 12,600 subjects randomized by approximately 1100 study centers worldwide over a recruitment period of approximately 2 years. The primary objective of OPERA is to determine whether treatment with once-daily omapatrilat (target dose 40 mg) will reduce cardiovascular (CV) morbidity and mortality in older (≥65 years) men and women with enhanced risk for atherosclerotic events due to stage 1 ISH plus other risk factors for which currently there is no evidence-based requirement for treatment. Blood pressure inclusion criteria are systolic blood pressure (SBP) 140 to 159 mm Hg (SBP 125 to 139 mm Hg in diabetic individuals) and diastolic blood pressure (DBP) <90 mm Hg.The primary end point is defined as the composite of fatal/nonfatal stroke, fatal/nonfatal myocardial infarction, fatal/nonfatal heart failure, and other CV mortality. Secondary end points include the individual components of the primary end point, CV mortality, and major cardiovascular end points, as well as effects on cognitive function and initiation of treatment for diabetes. Additional analyses will be conducted in men and women, in diabetic patients, in different risk classes and according to prior evidence of vascular disease. [Copyright &y& Elsevier]

Objective: To assess the effects of omapatrilat, fosinopril and placebo on blood pressure, plasma insulin, glucose and triglycerides concentrations in Zucker rats, a model for insulin resistance. Design: Double blind, parallel, prospective trial. Methods: Forty-two male obese Zucker ( fa / fa ) rats (aged 13-18 week) initially weighing 400-600 g were used for the experiments. Omapatrilat ( n = 14), placebo ( n = 14) or fosinopril ( n = 14) were administrated once daily at 10 µmol/kg oral for 15 days. At baseline and at the end of the study, a tail-cuff blood pressure measurement was performed; an oral glucose tolerance test was done at the end of the study. Results: Omapatrilat and fosinopril resulted in significant lower systolic blood pressure compared to the placebo group ( p < 0.001). This parameter was significantly lower in the omapatrilat group compared with fosinopril-treated rats (116 ±9 vs 125 ±4 mmHg, p < 0.05). After an overnight fast, there was no difference in the fasting glucose concentrations among treatment groups. The basal and post-glucose challenge insulin concentrations were lower in the omapatrilat group compared to the placebo group. No difference was observed in the fasting triglycerides concentrations between the treatment groups. Conclusions: Compared to placebo and fosinopril treatment, omapatrilat results in lower arterial blood pressure in an animal model of insulin resistance. The results suggest that omapatrilat may have a positive effect on insulin sensitivity. [ABSTRACT FROM AUTHOR]

Objective: The pharmacodynamics and pharmacokinetics of omapatrilat, a member of a new class of cardiovascular compounds, the vasopeptidase inhibitors, were evaluated in subjects with hepatic cirrhosis (n=10) and in healthy subjects (n=10) matched for age, weight, gender and smoking history. Methods: All subjects received omapatrilat 25 mg orally once daily for 14 days. Plasma renin and urinary atrial natriuretic peptide (ANP) levels were measured to assess the effect of omapatrilat on cirrhotic subjects. The effect of omapatrilat on blood pressure as well as changes in ANP and plasma renin levels were not altered by hepatic impairment. Pharmacokinetic parameters were determined from plasma omapatrilat concentrations. Results: There were no significant differences between the two subject groups with regard to log-transformed area under the curve or maximum observed plasma concentration. Systemic accumulation was similar in the two groups. Conclusion: These results suggest, based on findings in otherwise healthy cirrhotic subjects, that no adjustment of standard dosing regimens is indicated for hypertensive patients with mild to moderate cirrhosis. [ABSTRACT FROM AUTHOR]

This is a summary of reports of presentation made at the American College of Cardiology 49th Scientific Sessions, Anaheim, 12–15 March 2000. Studies with a particular interest for heart failure physicians have been reviewed. OPTIME-CHF: Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure. OPTIME-CHF was a randomised-controlled trial comparing a 48-h infusion of Milrinone or standard therapy in 951 patients recruited over a 2-year period. Patients were excluded if the investigator believed their clinical condition mandated inotropic therapy. Patients were randomised within 48 h of admission for an acute exacerbation of chronic heart failure to receive Milrinone or placebo infision for 48 h. Of the patients 43% were diabetics, 70% were receiving an angiotensin converting enzyme inhibitor, 25% were already on a beta-Blocker, and 34% had atrial fibrillation. There was no significant difference between the two groups in length of hospital stay during the index admission, subsequent readmissions and days in hospital over the following 60 days. Subjective clinical assessment scores were also no different. There was an average admission rate over the next year of one per patient in both groups. However, there was a significant increase in the incidence of sustained hypotension in the Milrinone group, which accounted for all of the increased adverse event rates for the active therapy. The 60-day mortality was 10% in both groups. This and previous trials of the oral formulation of Milrinone have now clearly demonstrated a lack of benefit with Milrinone in either during acute exacerbations of or in stable severe chronic heart failure [Packer M, Carver JR, Rodeheffer RJ et al. Effect of oral Milrinone on mortality in severe chronic heart failure. N Engl J Med 1991;325:1468–1475.]. Medium sized studies of Milrinone in patients with milder severities of heart failure also suggested an adverse impact on prognosis in the presence or absence of digoxin [DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC, Wright R. A comparison of oral Milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med 1989;320:677–683.]. Whether Milrinone even has a role for the management of a haemodyamic crisis requiring inotropic therapy must also be questioned. [ABSTRACT FROM PUBLISHER]