omapatrilat and Hypertension

Adult hypertension can be divided into two relatively distinct forms-systolic/diastolic hypertension in midlife and systolic hypertension of the aged. The two types differ in prevalence, pathophysiology, and therapy. The prevalence of systolic hypertension in the elderly is twice that of midlife hypertension. The systolic pressure is elevated in both forms, but the high diastolic pressure in midlife is due to a raised total peripheral resistance, whereas the normal or low diastolic pressure in the elderly is due to aortic stiffening. Aortic stiffness, as measured by the carotid/femoral pulse wave velocity, has been found to be a cardiovascular risk marker independent of traditional risk factors for atherosclerosis. Instead, it is related to microcirculatory disease of the brain and kidney and to disorders of inflammation. Loss of aortic distensibility is an inevitable consequence of aging, but a review of its causes suggests that it may be amenable to future pharmacologic therapy.

Topics: Aging; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Aorta; Arteriosclerosis; Biphenyl Compounds; Blood Pressure; Diastole; Drug Combinations; Humans; Hypertension; Microcirculation; Prevalence; Pulse Wave Analysis; Pyridines; Risk Factors; Systole; Tetrazoles; Thiazepines; Valsartan; Vascular Resistance; Vascular Stiffness

Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.

Topics: Abnormalities, Drug-Induced; Aminobutyrates; Angioedema; Angiotensin Receptor Antagonists; Biphenyl Compounds; Bradykinin; Contraindications; Drug Combinations; Drug Costs; Drug Synergism; Enalapril; Enzyme Inhibitors; Female; Follow-Up Studies; Heart Failure; Humans; Hyperkalemia; Hypertension; Kidney; Multicenter Studies as Topic; Natriuretic Peptides; Neprilysin; Pregnancy; Prodrugs; Prospective Studies; Pyridines; Randomized Controlled Trials as Topic; Stroke Volume; Tetrazoles; Thiazepines; Valsartan

Despite current practice, patients with chronic kidney disease (CKD) are at increased risk of progression to end-stage renal disease and cardiovascular events. Neprilysin inhibition (NEPi) is a new therapeutic strategy with potential to improve outcomes for patients with CKD. NEPi enhances the activity of natriuretic peptide systems leading to natriuresis, diuresis and inhibition of the renin-angiotensin system (RAS), which could act as a potentially beneficial counter-regulatory system in states of RAS activation such as chronic heart failure (HF) and CKD. Early NEPi drugs were combined with angiotensin-converting enzyme inhibitors but were associated with unacceptable rates of angioedema and, therefore, withdrawn. However, one such agent (omapatrilat) showed promise of NEP/RAS inhibition in treating CKD in animal models, producing greater reductions in proteinuria, glomerulosclerosis and tubulointerstitial fibrosis compared with isolated RAS inhibition. A new class of drug called angiotensin receptor neprilysin inhibitor (ARNi) has been developed. One such drug, LCZ696, has shown substantial benefits in trials in hypertension and HF. In CKD, HF is common due to a range of mechanisms including hypertension and structural heart disease (including left ventricular hypertrophy), suggesting that ARNi could benefit patients with CKD by both retarding the progression of CKD (hence delaying the need for renal replacement therapy) and reducing the risk of cardiovascular disease. LCZ696 is now being studied in a CKD population.

Topics: Aminobutyrates; Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Cardiovascular Diseases; Clinical Trials as Topic; Disease Progression; Drug Combinations; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Natriuresis; Nephrology; Neprilysin; Proteinuria; Pyridines; Renin-Angiotensin System; Tetrazoles; Thiazepines; Treatment Outcome; Valsartan

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.

Topics: Aminobutyrates; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Clinical Trials as Topic; Drug Combinations; Heart Failure; Humans; Hypertension; Indans; Natriuretic Peptide, Brain; Neprilysin; Propionates; Pyridines; Receptors, Angiotensin; Renin-Angiotensin System; Risk Factors; Stroke Volume; Tetrazoles; Thiazepines; Valsartan

The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of hypertension and heart failure. ACE inhibitors, angiotensin receptor II blockers (AT-II blockers) and aldosterone antagonists have been used to tackle the RAAS in the past but combined ACE and neutral endopeptidase (NEP) inhibitors have been shown to be more potent in reducing blood and especially pulse pressure in patients with hypertension.. Different NEP inhibitors have been tested but omapatrilat is the most widely studied in the setting of hypertension, heart failure and chronic angina. We have undertaken a PubMed search on NEP with a special focus on omapatrilat and its efficacy in hypertension and heart failure. The incidence of angioedema is more frequent in patients taking combined ACE and NEP inhibitors and this has prevented these medications from finding a widespread use. Combinations of NEP inhibitors and AT-II blockers are currently being studied and have been shown to reduce the blood pressure significantly. These medications have so far not been associated with angioedema and have a great potential to be safe and effective alternatives in the near future.. NEP inhibitors were effective in the treatment of hypertension and heart failure but the relatively high incidence of angioedema stopped their widespread use. New hope has risen with the introduction of combined NEP inhibitors and AT-II blockers and early studies are encouraging.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Drug Therapy, Combination; Heart Failure; Humans; Hypertension; Models, Biological; Neprilysin; Protease Inhibitors; Pyridines; Renin-Angiotensin System; Thiazepines

Vasopeptidase inhibitors (VPI) are a new promising class of drugs, that simultaneously inhibit Angiotensin - Converting Enzyme (ACE) and an enzyme Neutral Endopeptidase (NEP), that cleaves the natriuretic peptides. These drugs, such as omapatrilat, sampatrilat, fasidotrilat, by combined inhibition of ACE and degradation of natriuretic peptides and in turn by inhibiting the Renin - Angiotensin - Aldosterone system and potentiating the Natriuretic Peptide system and Kinin system should decrease the mortality rate in the group of patients with hypertension being not adequately controlled with ACE inhibitors. Thus, finding the new therapeutic strategy using drugs that act on the hormonal systems other than Renin - Angiotensin - Aldosterone system seems to be crucial. The aim of the study was to compare the molecular aspects of the conventional schemes that are being used in the antihypertension therapy to the new drugs from the vasopeptidase inhibitors group--with focusing on the natriuretic peptide system (NPS)--and, taking these considerations, making clues about therapeutical implications to reveal promising results in antihypertension treatment.

Topics: Alanine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Humans; Hypertension; Mesylates; Protease Inhibitors; Pyridines; Renin-Angiotensin System; Sympathetic Nervous System; Thiazepines; Tyrosine; Vascular Resistance

Omapatrilat is a dual angiotensin converting enzyme and neutral endopeptidase inhibitor. It is another a new class of drugs, which are effective in the treatment of patients with hypertension and heart failure also accompanying diabetes. They are producing difference endocrine changes, vasodilatation, diuresis, natriuresis and they have anti hypertrophic activity on tissues, reduce sympathetic tone. Omapatrilat produces beneficial effects in experimental animals and in clinical studies. The overall safety with omapatrilat appears to be good. Angioedema is a rare but potentially life threatening side-effects of endopeptidase inhibitors. Treatment with omapatrilat has a higher tendency towards preventing death and worsening heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Cardiovascular Agents; Heart Failure; Humans; Hypertension; Pyridines; Thiazepines

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Humans; Hypertension; Natriuresis; Natriuretic Peptides; Neprilysin; Protease Inhibitors; Pyridines; Recombinant Proteins; Thiazepines; Vasodilation

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Biomarkers; Clinical Trials as Topic; Enzyme Inhibitors; Humans; Hypertension; Pyridines; Renin-Angiotensin System; Sodium, Dietary; Stress, Physiological; Thiazepines

Left ventricular hypertrophy (LVH) in patients with hypertension is associated with an increased risk for many cardiovascular events and predicts a higher mortality rate. The pathogenesis of LVH is complicated. In addition to the hemodynamic burden (pressure or volume overload) and demographic factors, several trophic humoral factors, such as angiotensin II, aldosterone, endothelin, leptin, and catecholamines, may also contribute to the development and progression of LVH. Effective antihypertensive therapy can reverse LVH as well as prevent its development. Regression of LVH decreases subsequent cardiovascular morbidity and mortality. The commonly used drugs have various effects on LVH. Angiotensin receptor blockers and angiotensin-converting enzyme inhibitors seem most effective. Several new agents, including direct antifibrotic drugs, aldosterone blockade, vasopeptidase inhibitors, and endothelin receptor antagonists that more specifically target the underlying pathogenesis of LVH may provide us with innovative approaches to treat LVH.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Endothelin Receptor Antagonists; Humans; Hypertension; Hypertrophy, Left Ventricular; Mineralocorticoid Receptor Antagonists; ortho-Aminobenzoates; Protease Inhibitors; Pyridines; Thiazepines

Omapatrilat belongs to the vasopeptidase inhibitors, ie, drugs that possess the ability to inhibit simultaneously the membrane-bound zinc metalloproteases, angiotensin-converting enzyme (ACE), and the neutral endopeptidase EC 3.4.24.11 (NEP). Omapatrilat was targeted to treat patients with hypertension and congestive heart failure. The preclinical and early clinical studies conducted with omapatrilat were very promising. Indeed, omapatrilat appeared to be a very potent antihypertensive agent with very favorable effects on cardiac function in heart failure patients. In contrast to these early studies, the large clinical trials were more disappointing. The results of the OCTAVE trial confirmed the antihypertensive efficacy of omapatrilat, but at the price of an angioedema rate more than threefold higher than that of an ACE inhibitor in the overall population (2.17% vs 0.68%), and close to fourfold higher in the black population. In OVERTURE, a large randomized control trial in heart failure, angioedema was also more common with omapatrilat, but the incidence was much lower (0.8% with omapatrilat vs 0.5% with enalapril). However, omapatrilat was not convincingly superior to the ACE inhibitor. Because angioedema is probably a class side effect of vasopeptidase inhibitors, the higher incidence of this potentially life-threatening complication with omapatrilat has likely stopped the development of this new class of agents. The future of vasopeptidase inhibitors will depend on the ability to improve the risk/benefit ratio either by developing agents that produce less angioedema, or by defining more precisely a high-risk population that could take advantage of dual ACE/NEP inhibition.

Topics: Angioedema; Antihypertensive Agents; Heart Failure; Humans; Hypertension; Protease Inhibitors; Pyridines; Thiazepines

Vasopeptidase inhibitors are a group of agents capable of inhibiting neutral endopeptidase and angiotensin-converting enzymes, which leads to potentiation of natriuretic peptide actions and suppression of the renin-angiotensin-aldosterone system. With this distinctively characteristic mechanism, these agents have emerged as a new drug class for management of hypertension and heart failure. Several vasopeptidase inhibitors are under clinical investigation. Omapatrilat is the most studied agent in this class. Clinical studies of omapatrilat in hypertension have consistently shown the agent's effectiveness in a variety of patient populations. In patients with heart failure, omapatrilat significantly improved neurohormonal and hemodynamic status. Long-term effects of omapatrilat in patients with heart failure recently were compared with those of conventional therapy in a large phase II trial. Results of the study appear promising. Large clinical trials are ongoing, and additional information regarding safety and efficacy from these studies may help define the place in therapy for this agent.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Dose-Response Relationship, Drug; Heart Failure; Humans; Hypertension; Lisinopril; Mesylates; Natriuretic Peptide, Brain; Neprilysin; Pyridines; Randomized Controlled Trials as Topic; Thiazepines; Tyrosine

Topics: Antihypertensive Agents; Blood Pressure; Cardiovascular Agents; Diabetic Angiopathies; Humans; Hypertension; Pyridines; Renin-Angiotensin System; Thiazepines

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Agents; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Hypertension; Neprilysin; Pyridines; Thiazepines

Initial pharmacologic therapy for hypertension is low-dose thiazide diuretics, beta-blockers, and ACE inhibitors. Increasing data have confirmed that ACE inhibitors have specific benefit in patients with diabetes, atherosclerosis, left ventricular dysfunction, and renal insufficiency. CCBs are alternative agents for ISH in the elderly and appear to decrease stroke with perhaps less protection against progression of renal insufficiency and proteinuria, CAD mortality and new onset heart failure versus other initial agents, especially ACE inhibitors. ARBs are well tolerated and effective blood pressure lowering agents but have not been confirmed as effective as ACE inhibitors for reducing renal progression, clinical events, or mortality from heart failure. Effective pharmacologic antihypertensive therapy may avoid disabling and undetected cerebrovascular disease, cognitive dysfunction, and disturbing symptoms of elevated blood pressure. Vasopeptidase inhibitor, such as omapatrilat, and endothelin-1 antagonist, such as bosentan, may become future agents approved for the reduction of morbidity and mortality with hypertension. The ALLHAT trial continues to examine the potential benefits and harms of amlodipine versus chlorthalidone and lisinopril in a diverse high-risk population. Based on ALLHAT data, however, doxazosin is no longer an acceptable initial pharmacological agent. Intensive pharmacologic treatment with blood pressure lowering to less than 130/85 mm Hg is recommended with diabetes, renal insufficiency, and heart failure with additional goal of less than 125/75 mm Hg with renal failure and proteinuria greater than 1 g/24 h, based on multiple outcome studies.

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arteriosclerosis; Bosentan; Bradykinin; Calcium Channel Blockers; Diabetes Complications; Diuretics; Drug Therapy, Combination; Endothelin-1; Female; Heart Failure; Humans; Hypertension; Male; Middle Aged; Patient Compliance; Pyridines; Quality of Life; Renal Insufficiency; Renin-Angiotensin System; Risk Factors; Sulfonamides; Systole; Thiazepines; Treatment Outcome

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Animals; Heart Failure; Humans; Hypertension; Kidney; Natriuretic Agents; Neprilysin; Protease Inhibitors; Pyridines; Thiazepines

Vasopeptidase inhibitors are a new class of cardiovascular drug that simultaneously inhibit both neutral endopeptidase and angiotensin-converting enzyme (ACE). They increase the availability of peptides that have vasodilatory and other vascular effects; they also inhibit production of angiotensin II. In animal models vasopeptidase inhibitors decrease blood pressure in low, medium, and high renin forms of hypertension, and they also appear to confer benefits in models of heart failure and ischaemic heart disease. Studies in human hypertension show that these agents are effective in decreasing blood pressure regardless of race or age. Experience with omapatrilat, the most clinically advanced of these drugs, has shown it to be more effective than currently available ACE inhibitors or other widely used antihypertensive agents. Studies with omapatrilat in congestive heart failure have shown beneficial effects on haemodynamics and symptoms. The vasopeptidase inhibitors appear to have safety profiles similar to ACE inhibitors, though the frequency of side-effects such as angio-oedema and cough remains to be established. Large trials with clinical endpoints, some already in progress, are needed to establish the place of this class of drug beside that of established therapies in conditions such as hypertension, heart failure, ischaemic heart disease, and nephropathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Clinical Trials as Topic; Enzyme Inhibitors; Heart Failure; Humans; Hypertension; Neprilysin; Pyridines; Thiazepines

Vasopeptidase inhibition is a new concept in blood pressure management. A single molecule simultaneously inhibits two enzymes that regulate cardiovascular function: neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE)[1]. Development of vasopeptidase inhibitors stemmed from the need for new and more efficacious antihypertensive agents that not only reduce blood pressure but also treat hypertension as part of a larger syndrome involving endothelial dysfunction [2]. By inhibiting NEP and ACE, vasopeptidase inhibitors enhance the natriuretic peptide and kallikrein-kinin systems and inhibit the renin-angiotensin-aldosterone system. This article outlines the pharmacodynamic effects of the vasopeptidase inhibitor omapatrilat on biomarkers of NEP and ACE activity in humans.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Neprilysin; Pyridines; Renin-Angiotensin System; Thiazepines; Vasodilator Agents

Bristol-Myers Squibb (BMS) is developing the vasopeptidase inihibitor, omapatrilat, a dual inhibitor of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), for the potential treatment of cardiovascular diseases such as hypertension and heart failure [306287]. An NDA for the use of omapatrilat in hypertension was filed with the FDA and the regulatory authorities in the EU in December 1999 [351207], [353287]. In April 2000, BMS voluntarily withdrew the NDA in response to questions raised by the FDA regarding the comparative incidence and severity of an infrequent side effect (angioedema) reported within the NDA database. Prospective controlled clinical studies in patients with hypertension and heart failure were to continue. In May 2001, BMS reported that its blinded omapatrilat hypertension study was continuing and, pending supportive results from a data analysis anticipated in late summer/early autumn 2001, the company expected to refile an NDA with the FDA [409203]. In July 2000, BMS reported that it planned to conduct a multinational, 25,000 patient study (OCTAVE - Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) to compare the efficacy and safety of omapatrilat against enalapril in the treatment of hypertension [374909]. The OCTAVE trial was expected to generate data by mid-2001, which could allow for a launch by early 2002 [380280]. Phase III trials for hypertension had commenced by January 1998 [273646]. In January 2001, Merrill Lynch expected BMS to refile its NDA with the FDA in the second half of 2001 [395423]. In February 2001, Credit Suisse First Boston made a similar prediction, adding that it believed BMS would launch the drug in late 2002 or early 2003. The analysts also predicted peak sales for the drug of $585 million in 2005 [399484]. In May 2001, Merrill Lynch estimated sales of $1.8 billion in 2005 [411811].

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Heart Failure; Humans; Hypertension; Pyridines; Structure-Activity Relationship; Thiazepines

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Heart Failure; Humans; Hypertension; Protease Inhibitors; Pyridines; Thiazepines

Topics: Animals; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Humans; Hypertension; Metalloendopeptidases; Protease Inhibitors; Pyridines; Thiazepines

Topics: Animals; Antihypertensive Agents; Blood Vessels; Endopeptidases; Hormones; Humans; Hypertension; Protease Inhibitors; Pyridines; Thiazepines

Topics: Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Humans; Hypertension; Protease Inhibitors; Pyridines; Thiazepines

Vasopeptidase inhibition is a new concept in cardiovascular therapy. It involves simultaneous inhibition with a single molecule of two key enzymes involved in the regulation of cardiovascular function, neutral endopeptidase (EC 24.11; NEP) and angiotensin-converting enzyme (ACE). Simultaneous inhibition of NEP and ACE increases natriuretic and vasodilatory peptides (including atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP] of myocardial cell origin, and C-type natriuretic peptide [CNP] of endothelial cell origin) and increases the half-life of other vasodilator peptides including bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide system, vasopeptidase inhibitors (VPIs) reduce vasoconstriction and enhance vasodilation, thereby decreasing vascular tone and lowering blood pressure. Omapatrilat, a heterocyclic dipeptide mimetic, is a novel vasopeptidase inhibitor and a single molecule that simultaneously inhibits NEP and ACE with similar inhibition constants. Unlike ACE inhibitors, omapatrilat demonstrates antihypertensive efficacy in low-, normal-, and high-renin animal models. Unlike NEP inhibitors, omapatrilat provides a potent and sustained antihypertensive effect in spontaneously hypertensive rats (SHR), a model of human essential hypertension. In animal models of heart failure, omapatrilat is more effective than ACE inhibition in improving cardiac performance and ventricular remodeling and prolonging survival. Omapatrilat effectively reduces blood pressure, provides target-organ protection, and reduces morbidity and mortality from cardiovascular events in animal models. Omapatrilat is the first VPI to enter advanced USA clinical trials. Omapatrilat appears to be a safe, well-tolerated and effective antihypertensive in humans. Vasopeptidase inhibition is a novel and efficacious strategy for treating cardiovascular disorders, including hypertension and heart failure, that may offer advantages over currently available therapies.

Topics: Amino Acid Sequence; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Humans; Hypertension; Molecular Sequence Data; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Neprilysin; Peptidyl-Dipeptidase A; Pyridines; Thiazepines

Hypertension remains uncontrolled worldwide despite the availability of several classes of antihypertensive agents. There is an increased risk of serious cardiovascular, cerebrovascular, and renal events if the disease goes untreated or is poorly treated. Thus, the high incidence of hypertension coupled with its poor control make it imperative that more effective and well-tolerated treatments that exhibit target-organ protection be developed. Vasopeptidase inhibitors are a new class of cardiovascular agents that simultaneously inhibit neutral endopeptidase and angiotensin converting enzyme. They enhance peptides with vasodilatory and possibly organ-protective properties and also inhibit the production of the vasoconstrictor angiotensin II. In preclinical studies, omapatrilat has shown blood pressure-lowering effects independent of renin status and has increased survival in an animal model of congestive heart failure. Human studies with omapatrilat, the most clinically advanced vasopeptidase inhibitor, administered orally once daily have demonstrated powerful dose-dependent reduction of systolic and diastolic blood pressures, regardless of age, race, or gender. Omapatrilat is particularly effective in lowering systolic blood pressure; this article summarizes data from recent clinical trials. This drug is well tolerated, with adverse effects comparable to those of currently available antihypertensive agents. Omapatrilat and other vasopeptidase inhibitors have potential applications in the treatment of hypertension, heart failure, and other cardiac and vascular disorders.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Blood Pressure; Heart Failure; Humans; Hypertension; Pyridines; Renin; Survival Rate; Thiazepines; Treatment Outcome; Vasodilation

Topics: Aminobutyrates; Angiotensin Receptor Antagonists; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Drug Combinations; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Middle Aged; Neprilysin; Pyridines; Renin-Angiotensin System; Tetrazoles; Thiazepines; Valsartan

Augmentation index (AI), a measure of enhanced wave reflection, has been proposed as a bedside measure of aortic stiffness. However, because AI is potentially sensitive to various factors other than vessel wall stiffness, the utility of AI as a stiffness indicator may be limited. To assess relations between AI and vascular properties, we used arterial tonometry and aortic Doppler flow to evaluate trough (24 hours) and peak (4 hours) pulsatile hemodynamics and pulse wave velocity in 159 individuals with systolic hypertension at the completion of a 12-week period of monotherapy with the vasopeptidase inhibitor omapatrilat (80 mg; n=75) or the converting enzyme inhibitor enalapril (40 mg; n=84). Characteristic impedance (Zc) was calculated from the ratio of change in carotid pressure and aortic flow in early systole. Systolic ejection period (SEP), timing of wave reflection, and AI were assessed from the carotid waveform. Comparable acute reductions in mean pressure were associated with greater reductions in peripheral resistance with enalapril, whereas neither drug had an acute effect on Zc. Both drugs reduced AI, but neither drug altered the timing of wave reflection. Both drugs increased heart rate and shortened SEP. Multiple regression analysis demonstrated that the acute reduction in AI was most affected by reductions in SEP and peripheral resistance. Change in AI was inversely related to change in Zc and pulse wave velocity did not enter the model. Our findings indicate that AI is a complex surrogate marker that is inversely related to changes in proximal aortic stiffness in systolic hypertension.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Aorta; Carotid Arteries; Double-Blind Method; Echocardiography; Elasticity; Electrocardiography; Enalapril; Female; Humans; Hypertension; Male; Protease Inhibitors; Pulsatile Flow; Pyridines; Regression Analysis; Single-Blind Method; Systole; Thiazepines

Recent 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.. The 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.. Omapatrilat 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.. Omapatrilat 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.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angioedema; Antihypertensive Agents; Double-Blind Method; Enalapril; Female; Humans; Hypertension; Male; Metalloendopeptidases; Middle Aged; Pyridines; Thiazepines; Treatment Outcome

Using the example of the largest clinical trial so far conducted to obtain marketing approval (OCTAVE--Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril) this paper describes the way the trial was conducted in Germany and the set-up of the trial logistics. OCTAVE was a prospective, randomised, double-blind study in which the efficacy and tolerability of omapatrilat (CAS 167305-00-2) compared to enalapril (CAS 75847-73-3) were studied in 25 302 patients with uncontrolled blood pressure. Patient recruitment was completed on schedule in just under four months in this global study. An appropriate study design, tailor-made logistics, a special monitoring system and effective project and data management allowed the selection and initiation of 430 study centres in Germany. As a result 4868 patients were randomised within about six months of finalising the study protocol.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Data Collection; Double-Blind Method; Enalapril; Humans; Hypertension; Prospective Studies; Pyridines; Research Design; Surveys and Questionnaires; Thiazepines

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 (> or = 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.

Topics: Arteriosclerosis; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Placebos; Protease Inhibitors; Pyridines; Research Design; Risk Factors; Thiazepines

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.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Atrial Natriuretic Factor; Blood Pressure Monitoring, Ambulatory; Double-Blind Method; Female; Humans; Hypertension; Lisinopril; Male; Middle Aged; Pyridines; Renin-Angiotensin System; Sodium, Dietary; Thiazepines; Treatment Outcome

Increased pulse pressure, an indicator of conduit vessel stiffness, is a strong independent predictor of cardiovascular events in hypertensive cohorts, which suggests that reduction of conduit vessel stiffness may be desirable in hypertension.. We assessed changes in pulse pressure and conduit vessel stiffness in a 12-week double-blind, randomized clinical trial that compared monotherapy with the ACE inhibitor enalapril 40 mg daily (n=87) versus the vasopeptidase (dual ACE and neutral endopeptidase) inhibitor omapatrilat 80 mg daily (n=80) in patients with systolic hypertension. Patients were withdrawn from antihypertensive medications 1 to 2 weeks before enrollment, and systolic pressure was confirmed to be > or =160 mm Hg. With the use of calibrated tonometry and pulsed Doppler, pulsatile hemodynamics were assessed before randomization and at 12 weeks. Characteristic impedance (Z(c)), a direct measure of the stiffness of the central aorta, was calculated from the ratio of changes in carotid pressure and aortic flow in early systole. Omapatrilat compared with enalapril produced greater reductions in peripheral (-8.2+/-12.2 versus -4.0+/-12.2 mm Hg, P<0.05) and central (-10.2+/-16.2 versus -3.2+/-16.9 mm Hg, P<0.01) pulse pressures and Z(c) (237+/-83 to 208+/-70 versus 225+/-87 to 231+/-94 dyne x s/cm(5), P<0.001); the latter remained significant (P<0.05) after adjusting for change in mean pressure.. Greater reductions in pulse pressure and Z(c) in hypertensive subjects treated with omapatrilat compared with enalapril suggest that aortic stiffness is maintained by specific, partially reversible mechanisms and underscore a potential role for pharmacological modulation of natriuretic peptides in the treatment of hypertension.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Aorta; Blood Pressure; Double-Blind Method; Enalapril; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged; Protease Inhibitors; Pyridines; Systole; Thiazepines

This multicenter, double-blind study evaluated efficacy and safety of the vasopeptidase inhibitor omapatrilat, which simultaneously inhibits neutral endopeptidase and angiotensin converting enzyme, when given in conjunction with hydrochlorothiazide (HCTZ) to subjects nonresponsive to HCTZ alone. The study enrolled 657 subjects with mild to severe hypertension. After a 2-week placebo lead-in period and a 4-week HCTZ phase, 274 subjects were randomized to receive omapatrilat (10 or 20 mg, electively titrated to 20 or 40 mg, respectively, at week 4 if seated diastolic blood pressure [SeDBP] was > or =90 mm Hg) or matching placebo in addition to 25 mg of HCTZ as continuing therapy. The primary outcome measure was change in SeDBP from baseline to week 8. At week 8, placebo plus HCTZ-adjusted additional reductions in SeDBP in the omapatrilat 10/20 mg and 20/40 mg treatment groups (4 and 5 mm Hg, respectively) were significant (P < .001), as were changes in seated systolic blood pressure in both omapatrilat-treated groups (7 and 10 mm Hg, respectively; P < .001). Seated diastolic blood pressure was normalized (<90 mm Hg) in 38% of subjects in the placebo group compared to 59% and 64% of subjects in the omapatrilat groups (P < or = .008). Adverse events, serious adverse events, and discontinuations attributed to adverse events were infrequent. There were no clinically relevant changes in serum creatinine or potassium. Omapatrilat was effective and well tolerated when added to HCTZ in subjects whose blood pressure was not controlled with HCTZ alone.

Topics: Adult; Aged; Antihypertensive Agents; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hydrochlorothiazide; Hypertension; Male; Middle Aged; Pyridines; Thiazepines; Treatment Outcome

Omapatrilat, a vasopeptidase inhibitor, simultaneously inhibits neutral endopeptidase and ACE. The efficacy and hormonal profile of omapatrilat and lisinopril were compared in salt-sensitive hypertensive patients. On enrollment, antihypertensive medications were withdrawn, and patients received a single-blind placebo. On day 15, salt-sensitivity determinations were made. Salt-sensitive hypertensive patients returned within 5 to 10 days for baseline evaluations of ambulatory diastolic blood pressure, ambulatory systolic blood pressure, and atrial natriuretic peptide. Salt-sensitive hypertensive patients were randomized to receive double-blind omapatrilat (n=28) or lisinopril (n=33) at initial doses of 10 mg for 1 week, increasing to 40 and 20 mg, respectively, for an additional 3 weeks. Ambulatory blood pressure and urinary atrial natriuretic peptide were assessed at study termination. Both omapatrilat and lisinopril significantly reduced mean 24-hour ambulatory diastolic and systolic blood pressures; however, omapatrilat produced significantly greater reductions in mean 24-hour ambulatory diastolic blood pressure (P=0.008), ambulatory systolic blood pressure (P=0.004), and ambulatory mean arterial pressure (P=0.005) compared with values from lisinopril. Both drugs potently inhibited ACE over 24 hours. Omapatrilat significantly (P<0.001) increased urinary excretion of atrial natriuretic peptide over 0- to 24-hour (3.8-fold) and 12- to 24-hour (2-fold) intervals; lisinopril produced no change. Omapatrilat significantly (P<0.001) increased urinary excretion of cGMP over the 0- to 24- and 4- to 8-hour intervals compared with that from lisinopril. Neither drug had a diuretic, natriuretic, or kaliuretic effect. In conclusion, in salt-sensitive hypertensive patients, omapatrilat demonstrated the hormonal profile of a vasopeptidase inhibitor and lowered ambulatory diastolic and systolic blood pressures more than lisinopril.

Topics: Adult; Aged; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure Monitoring, Ambulatory; Creatinine; Cyclic GMP; Double-Blind Method; Electrolytes; Female; Genetic Predisposition to Disease; Hemodynamics; Humans; Hypertension; Lisinopril; Male; Metalloendopeptidases; Middle Aged; Pyridines; Sodium, Dietary; Thiazepines

[Figure: see text].

Topics: Aminobutyrates; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Body Weight; Hypertension; Lisinopril; Liver; Mice; Mice, Transgenic; Neprilysin; Pyridines; Renin; Thiazepines

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.

Topics: Action Potentials; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta, Thoracic; Blood Pressure; Desoxycorticosterone; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Fibrosis; Heart Ventricles; Hypertension; Hypertrophy; Inflammation; Male; Membrane Potentials; Metalloendopeptidases; Myocardial Contraction; Papillary Muscles; Pyridines; Rats; Rats, Wistar; Sodium Chloride, Dietary; Thiazepines; Ventricular Remodeling

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Cell Adhesion Molecules; Desoxycorticosterone; Drug Therapy, Combination; Fibrosis; Heart Diseases; Hypertension; Inflammation; Kidney Diseases; Metalloendopeptidases; Neprilysin; Organophosphonates; Pyridines; Rats; Thiazepines

The relative roles of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) inhibition on cardiac and renal fibrosis in deoxycorticosterone acetate (DOCA)-salt hypertensive rats were studied.. The ACE/NEP inhibitor omapatrilat (40 mg/kg per day), the ACE inhibitor enalapril (10 mg/kg per day) and the NEP inhibitor CGS 25462(100 mg/kg per day) were administrated for 3 weeks to DOCA rats. Collagen was stained with Sirius red, and mediators of inflammation were identified by immunolabeling (vascular cell adhesion molecule, nuclear factor-kappaB, infiltrating ED-1-positive macrophages and monocyte chemotactic protein-1) or by western blot (platelet-endothelial cell adhesion molecule-1).. Elevated systolic blood pressure of DOCA rats was significantly reduced (P < 0.05) by omapatrilat and CGS 25462. Omapatrilat and CGS 25462 significantly (P < 0.05) decreased interstitial collagen density in the left ventricle of DOCA rats compared with untreated DOCA rats. Enalapril only decreased the subepicardial collagen of DOCA rats. Omapatrilat significantly (P < 0.05) decreased renal mesangial collagen deposition in DOCA rats. Cardiac and renal expression of surface adhesion molecules, nuclear factor-kappaB, monocyte chemotactic protein and ED-1-positive cells were decreased in omapatrilat-treated DOCA rats compared with untreated DOCA rats. Enalapril and CGS 25462 did not alter mesangial collagen of DOCA rats.. Dual ACE/NEP inhibition was more effective than ACE or NEP inhibition in decreasing inflammatory mediators, and improving cardiac and renal fibrosis. This suggests a role for NEP inhibition added to blockade of the renin-angiotensin system that may explain the greater efficacy of omapatrilat.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Cell Adhesion Molecules; Collagen; Desoxycorticosterone; Drug Therapy, Combination; Enalapril; Fibrosis; Heart Diseases; Hypertension; Inflammation; Kidney Diseases; Metalloendopeptidases; Neprilysin; NF-kappa B; Organophosphonates; Pyridines; Rats; Rats, Sprague-Dawley; Thiazepines

Previous studies demonstrated that adrenomedullin (AM) is metabolized by neutral endopeptidases and that the renal effect of AM is augmented by the inhibition of neutral endopeptidases. We have recently shown that the long-term administration of AM has renoprotective effects.. This study assessed the chronic renoprotective effects of AM combined with a vasopeptidase inhibitor in hypertensive rats and attempted to elucidate the mechanism involved.. We studied the following four groups: control Dahl salt-resistant (DR) rats, untreated Dahl salt-sensitive (DS) rats, omapatrilat (35 mg/kg per day)-treated DS rats; and human AM (500 ng/h) plus omapatrilat-treated DS rats. After 7 weeks' treatment, blood pressure, renal function, neurohumoral factors, gene expression levels, and histological findings were examined.. DS rats were characterized by increased blood pressure, decreased renal function, abnormal histological findings, and increased gene expression of collagen I and III, transforming growth factor beta (TGF-beta), and NADPH oxidase subunits (p40phox, p47phox, and gp91phox) in the renal cortex compared with DR rats. Compared with DS rats, omapatrilat significantly decreased systolic blood pressure (-26 mmHg), improved renal function, histological findings, and messenger RNA expression levels of collagen I, collagen III, and TGF-beta. Combined treatment with omapatrilat and AM further improved renal function, histological findings, and mRNA expression levels of collagen I, collagen III, and TGF-beta, without a further reduction in blood pressure. Only combined treatment decreased mRNA levels of p40phox, p47phox, and gp91phox. There were no differences in plasma AM or atrial natriuretic peptide levels among three DS groups.. Our results suggest that combined treatment with omapatrilat and AM provides additional renoprotective effects independent of blood pressure-lowering activity partly via inhibition of gene expressions of oxidative stress and extracellular matrix.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Collagen Type I; Collagen Type III; Drug Therapy, Combination; Gene Expression; Humans; Hypertension; Kidney; Male; Oxidative Stress; Peptides; Protease Inhibitors; Pyridines; Rats; Rats, Inbred Dahl; Recombinant Proteins; RNA, Messenger; Thiazepines; Transforming Growth Factor beta

Vasopeptidase inhibitors are a novel class of antihypertensive agents that concomitantly inhibit angiotensin converting enzyme and neutral endopeptidase. Our purpose was to investigate the effects of omapatrilat, a vasopeptidase inhibitor, on renal function and tubuloglomerular feedback (TGF) response in anesthetized 9-10-week-old spontaneously hypertensive rats (SHR). Intravenous injection of omapatrilat at 10 micromol/kg decreased systemic blood pressure and renal vascular resistance. Renal plasma flow was unchanged, whereas glomerular filtration rate (GFR) and filtration fraction (FF) were reduced. Increased urinary sodium excretion of tubular origin was observed. These parameters remained unaltered with vehicle treatment. Micropuncture study revealed that the maximal reduction of early proximal flow rate (EPFR) induced by orthograde perfusion of Henle's loop with artificial tubular fluid (ATF) was significantly reduced by omapatrilat treatment (28.5+/-3.1% vs. 72.0+/-2.8% of control) and was not significantly changed in the vehicle-treated group (vehicle 70.8+/-1.7% vs. control 71.0+/-2.1%). EPFR at zero perfusion was comparable between omapatrilat and vehicle treatment (29.7+/-2.2 vs. 31.3+/-2.1 nl/min, respectively). Luminal perfusion of 10(-4) mol/l 7-nitroindazole in ATF abrogated the blunting of TGF response by omapatrilat but elicited no change in the vehicle-treated group. The suppression of the TGF mechanism and the reduction in FF suggest that omapatrilat respectively dilates the afferent and efferent arterioles. Under such conditions, reduction of GFR may indicate a fall in intraglomerular pressure. The restoration of nitric oxide signaling in the juxtaglomerular apparatus of SHR seems to participate in the inhibition of TGF by omapatrilat. These findings suggest that omapatrilat may provide a novel approach to the treatment of systemic and glomerular hypertension.

Topics: Animals; Feedback, Physiological; Glomerular Filtration Rate; Hypertension; Kidney Glomerulus; Kidney Tubules; Loop of Henle; Male; Nitric Oxide; Protease Inhibitors; Pyridines; Rats; Rats, Inbred SHR; Thiazepines

The synergistic effects of the combined ACE and NEP inhibition is based both on the blockade of angiotensin II synthesis and degradation of vasoactive peptides and NEP substrates (ANP, arginine, endothelial cells, guanylat cyclase etc.), including bradykinine and the natriuretic peptides, which contribute to vasodilatation, diuresis and improvement of myocardial function.. This study was undertaken to asses the hypotensive effect of a dual ACE/NEP inhibitor (omapatrilat) in comparison to a NEP inhibitor (candoxatril) and ACE inhibitor (enalapril) in SHRS.. The study was performed in 130 male spontaneously hypertensive rats (SHRS) that were divided into 4 groups and treated orally by a gastric tube for 14 days according to the following dosage regimen: omapatrilat (40 mg/kg b.w./24 h); candoxatril (30 mg/kg b.w./24 h); enalapril (20 mg/kg b.w./ 24 h) and control (water). Systolic blood pressure values were determined at the beginning of the study by the tail-cuff pletysmographic method, at the 7th and 14th day of the treatment, as well as 14 days after the end of the drug administration. For evaluation of the effect of omapatrilat, candoxatril and enalapril on the investigated parameters (plasma atrial natriuretic peptide and serum ACE), 10 animals from the control group were sacrificed at the beginning of the study, and afterwards 10 animals from each group were also sacrificed on the 7th and 14th day of the treatment, as well as 14 days after the end of the drug administration (28th day).. The dual ACE/NEP inhibitor, omapatrilat and the ACE inhibitor, enalapril lowered SBP more effectively than the NEP inhibitor, candoxatril at all time points of the experiment (p < 0.01). Omapatrilat was slightly more effective than the enalapril treatment.. Two-week treatment with the dual ACE/NEP inhibitor omapatrilat caused a significant decrease of the SBP, inhibition of the serum ACE activity and increase of the plasma ANP values, and therefore it should be considered as a new potential therapeutic agent in blood pressure management (Tab. 3, Fig. 2, Ref. 20).

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Drug Combinations; Enalapril; Hypertension; Indans; Male; Neprilysin; Propionates; Pyridines; Rats; Rats, Inbred SHR; Thiazepines

We have shown previously that the concentration of Vasoactive Intestinal Peptide (VIP) in the heart is inversely correlated with the degree of fibrosis in a number of experimental models of early myocardial fibrosis. Vasopeptidase inhibition and angiotensin converting enzyme inhibition both decrease myocardial fibrosis. In this study, we sought to determine whether this myocardial protective effect might reflect increased VIP concentrations in the heart. We compared the effects of 4 weeks treatment of the vasopeptidase inhibitor omapatrilat and the angiotensin converting enzyme inhibitor enalapril on the degree of fibrosis and the concentration of VIP in the heart in salt sensitive hypertension induced by treatment with L-nitro-omega-methylarginine (L-NAME). Systolic blood pressure decreased in both treatment groups compared with control (omapatrilat P<0.005; enalapril P<0.001). Myocardial fibrosis was less for omapatrilat than control (P<0.0005) and enalapril (P<0.0005) groups. Myocardial VIP was greater in omapatrilat than in controls (P<0.005) and enalapril-treated rats (P<0.05). We conclude that vasopeptidase inhibition exerts a greater myocardial protective effect than angiotensin converting enzyme inhibition. Further, this myocardial protective effect is associated with increased VIP in the heart suggesting a pathogenetic role for VIP depletion in the development of fibrosis in the heart.

Topics: Animals; Enalapril; Fibrosis; Hypertension; Male; Myocardium; Peptide Hydrolases; Protease Inhibitors; Pyridines; Rats; Rats, Inbred WKY; Thiazepines; Vasoactive Intestinal Peptide

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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Genetically Modified; Antihypertensive Agents; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; Body Weight; Cardiomegaly; Disease Models, Animal; Dose-Response Relationship, Drug; Fosinopril; Hypertension; Kidney; Male; Models, Cardiovascular; Neprilysin; Pyridines; Rats; Renin; Statistics as Topic; Survival Analysis; Systole; Thiazepines; Time Factors; Treatment Outcome

The novel antihypertensive agent, omapatrilat, is both an inhibitor of neutral endopeptidase and angiotensin-converting enzyme. This study investigated the effects of omapatrilat in comparison with an angiotensin I-receptor antagonist/diuretic combination on blood pressure, endothelial function and cardiac hypertrophy in stroke-prone spontaneously hypertensive rats (SHRSP).. Male and female SHRSP were treated orally with omapatrilat or irbesartan plus hydrochlorothiazide (I + H) or vehicle for 8 weeks. Systolic blood pressure was measured weekly by tail-cuff. Cardiac hypertrophy was monitored by echocardiography at 8, 12 and 16 weeks of age. Endothelial function [basal nitric oxide (NO) bioavailability and stimulated NO release] was examined in carotid arteries using organ bath pharmacology and in mesenteric resistance arteries using wire myography.. Compared with untreated controls, omapatrilat and I + H significantly attenuated hypertension [male control, 198.3 +/- 6.9 mmHg versus omapatrilat, 149.6 +/- 3.8 mmHg (F = 8.63 P < 0.0001), versus I + H, 145.6 +/- 5.1 mmHg (F = 7.38 P < 0.0001); female control, 170.3 +/-8.3 mmHg versus omapatrilat, 120.0 +/- 4.6 mmHg (F = 8.36, P < 0.0001), versus I + H, 112.2 +/- 2.9 mmHg (F = 9.08, P < 0.0001)] and left ventricular hypertrophy [male + female controls, 3.02 +/- 0.38 mg/g versus omapatrilat, 2.47 +/- 0.26 mg/g (P < 0.0001; 95% confidence interval, 0.27, 0.83), versus I + H, 2.49 +/- 0.21 mg/g (P < 0.0001; 95% confidence interval, 0.25, 0.83)]. Both treatments also significantly increased male carotid artery basal NO bioavailability relative to control [control, 0.62 +/- 0.17 g/g versus omapatrilat, 1.95 +/- 0.17 g/g (P < 0.0001; 95% confidence interval, -1.83, -0.36), versus I + H, 1.57 +/- 0.21 g/g (P < 0.026; 95% confidence interval, -1.31, -0.12)]. However, stimulated NO (EC50) was only improved in omapatrilat-treated males [controls, 0.19 +/- 0.06 micromol/l versus omapatrilat, 0.05 +/- 0.01 micromol/l (P = 0.05; 95% confidence interval, -1.16, -0.03)].. Omapatrilat treatment significantly reduced left ventricular hypertrophy and improved endothelial function in carotid arteries from male SHRSP by NO-dependent mechanisms. Despite equivalent antihypertensive and antihypertrophic actions, a similar improvement in endothelial function, specifically stimulated NO release, was not observed after treatment with I + H.

Topics: Animals; Antihypertensive Agents; Biological Availability; Biphenyl Compounds; Blood Pressure; Carbachol; Cardiomegaly; Carotid Arteries; Drug Synergism; Echocardiography; Endothelium, Vascular; Female; Hormones; Hydrochlorothiazide; Hypertension; Irbesartan; Male; Nitric Oxide; Pyridines; Rats; Rats, Inbred SHR; Sex Characteristics; Stroke; Systole; Tetrazoles; Thiazepines; Vasodilation

While ACE-inhibitors have proven their prognostic benefit in many hypertension studies, a new approach has been proposed by inhibiting neutral endopeptidase, which degrades natriuretic peptides. The combined inhibition of ACE and endopeptidase was named "vasopeptidase-inhibition" and tested in several trial. Though effective in lowering blood pressure, a superiority to ACE-inhibitors alone could not be shown. A potentially serious side effect was the increased incidence of angioneurotic edema, which led to a complete stop in the development of this pharmaceutical strategy.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Combinations; Enalapril; Endopeptidases; Humans; Hypertension; Pyridines; Thiazepines; Treatment Outcome

The aim of our study was to compare the cardioprotective effects of vasopeptidase inhibition with those of angiotensin type 1 (AT1)-receptor blockade, a diuretic and the combination of AT1-receptor blockade and a diuretic in an experimental rat model of essential hypertension on a high salt diet. Spontaneously hypertensive rats (SHR) (n =73) were divided into 6 groups to receive the following diet and drug regimens for 8 weeks: 1) low salt controls (NaCl 0.5%); 2) high salt controls (NaCl 6%); 3) omapatrilat (40 mg/kg/d) on a high salt diet; 4) losartan (30 mg/kg/d) on a high salt diet; 5) hydrochlorothiazide (HCTZ; 10 mg/kg/d) on a high salt diet; and 6) losartan+HCTZ (30+10 mg/kg/d) on a high salt diet. Blood pressure was measured by tail-cuff plethysmography. The histological score of myocardial damage, myocardial collagen volume fraction (CVF), connective tissue growth factor (CTGF) expression and cardiomyocyte apoptosis were determined. As an antihypertensive, omapatrilat showed greater efficacy than monotherapy with losartan or HCTZ, and was equally effective as the combination of losartan+HCTZ. Assessed by myocardial damage score, omapatrilat and losartan protected cardiac morphology better than HCTZ or the drug combination. Omapatrilat decreased CVF to a greater extent than the other therapies, whereas losartan was most effective in decreasing CTGF expression. All drug treatments, except HCTZ, decreased cardiomyocyte apoptosis. Our findings provide evidence that both vasopeptidase inhibition and AT1-receptor blockade exert cardioprotective properties beyond their blood pressure-lowering effects. Cardioprotection was associated with prevention of cardiomyocyte apoptosis and inhibition of extracellular matrix formation.

Topics: Aldosterone; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Apoptosis; Autoradiography; Body Weight; Cardiotonic Agents; Connective Tissue Growth Factor; Fibrosis; Hydrochlorothiazide; Hypertension; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Losartan; Male; Myocardium; Organ Size; Protease Inhibitors; Pyridines; Rats; Rats, Inbred SHR; Renin; Sodium Chloride, Dietary; Thiazepines

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Humans; Hypertension; Pyridines; Sodium Chloride; Thiazepines

To compare the cardiovascular protection provided by omapatrilat and lisinopril in an experimental model of hypertension.. Four-week deoxycorticosterone acetate (DOCA)-salt hypertensive (HT) and age-matched normotensive (NT) rats were treated either with omapatrilat (40 mg/kg per day) or lisinopril (20 mg/kg per day) for 2 weeks before sacrifice, and compared with untreated HT and NT rats sacrificed at ages corresponding to either before or after the drug regimens.. Systolic arterial pressure (SAP) of 2 and 4 week HT rats was increased in comparison to age-matched NT rats (P <0.05). Treatment with omapatrilat or lisinopril reduced SAP in HT (P <0.05) similarly by about 10%. Cardiac interstitial collagen, perivascular collagen and media/lumen ratio of coronary arterioles were increased in HT rats. Both treatments partially prevented the rise in perivascular collagen and completely corrected the increased media/lumen ratio in small arterioles from HT (P <0.05). In contrast to NT rats, only a weak coronary dilatation to bradykinin was observed in Langendorff hearts isolated from untreated-HT. This response was slightly improved by lisinopril and markedly improved by omapatrilat (P <0.05). The coronary dilatation to SNP which was reduced in 4-week HT (P <0.05), was partially improved by omapatrilat treatment but not by lisinopril. The enhanced superoxide anion production in aorta from HT rats was partially corrected with omapatrilat and lisinopril. Finally, omapatrilat, unlike lisinopril, markedly reduced mortality in a more severe form of DOCA-salt hypertension.. Omapatrilat and lisinopril regressed coronary remodelling and cardiac collagen deposition, and reduced vascular oxidative stress in DOCA-salt hypertensive rats. However, despite similar antihypertensive efficacy, omapatrilat was superior to lisinopril in improving the endothelial-dependent coronary dilatation, suggesting a better vascular protection in the DOCA-salt model of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiovascular Diseases; Collagen; Coronary Vessels; Desoxycorticosterone; Heart; Hypertension; In Vitro Techniques; Lisinopril; Male; Myocardium; Pyridines; Rats; Rats, Sprague-Dawley; Sodium Chloride; Superoxides; Thiazepines; Vasomotor System

Microvascular remodeling contributes to increased cardiovascular risk in hypertension. The dual angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitor omapatrilat improves small artery remodeling in hypertension. The aim of the present study was to compare effects of omapatrilat to the ACE inhibitor fosinopril and the AT(1) antagonist irbesartan on the coronary microvasculature in spontaneously hypertensive rats (SHR). Ten-week-old SHR were treated for 10 weeks with omapatrilat (20 or 40 mg/kg/d), irbesartan (50 mg/kg/d), or fosinopril (20 mg/kg/d). Arterioles and capillaries were identified in the myocardium by immunolabeling. After 10 weeks, systolic blood pressure (BP) was significantly reduced in treated versus untreated SHR (P <.01). Myocardial arteriolar density/mm(2) was higher (P <.05) in untreated SHR versus Wistar-Kyoto (WKY), and was reduced by omapatrilat (at both high and low doses) and by fosinopril (P <.01). Irbesartan decreased only subepicardial arteriolar density (P <.05). Myocardial capillary density/mm(2) was decreased in untreated SHR versus WKY (P <.01), associated with increase in cardiomyocyte cross-sectional area and cardiomyocyte-to-capillary ratio, and a decrease in myocyte density. Omapatrilat (at both high and low doses) resulted in increased capillary density, decreased myocyte hypertrophy and cardiomyocyte to capillary ratio, and increased myocyte density (P <.01). Fosinopril and irbesartan reduced myocyte hypertrophy of SHR, but had no effect on capillary density. Dual ACE/NEP inhibition was more effective than ACE inhibition or AT(1) antagonism in improving microvascular and cardiomyocyte remodeling in the hypertensive heart. This suggests a role for NEP inhibition added to blockade of the renin-angiotensin system that may explain the greater efficacy of omapatrilat.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Arterioles; Biphenyl Compounds; Blood Pressure; Capillaries; Coronary Circulation; Drug Therapy, Combination; Fosinopril; Hypertension; Irbesartan; Male; Myocytes, Cardiac; Neprilysin; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Tetrazoles; Thiazepines

Vasopeptidase inhibitors are a new class of antihypertensive drugs that are single molecules having dual inhibitory action on angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The best known drug in this class is omapatrilat, which has been proposed to be more efficacious than ACE inhibitors because of its ability to inhibit NEP and prevent the breakdown of atrial peptides and bradykinin. However, survival of endothelin (ET) may also be enhanced and therefore, NEP inhibitors may have limited efficacy under conditions of low renin and high ET production. The purpose of the current study was to contrast the effects of the ACE inhibitor, enalapril, with omapatrilat in a model of established hypertension where ACE inhibitors are ineffective, the deoxycorticosterone acetate (DOCA)-salt-treated rat. Two weeks after starting DOCA-salt treatment, rats were given either enalapril (10 mg/kg/day) or omapatrilat (30 mg/kg/day) for 5 days. Mean arterial pressure (MAP) measured by radiotelemetry in untreated DOCA-salt rats increased from 102 +/- 2 to 181 +/- 12 mm Hg (P<.05) as a result of DOCA-salt treatment for 3 weeks. MAP was unaffected by either enalapril (189 +/- 3 mm Hg) or omapatrilat (184 +/- 8 mm Hg). DOCA-salt treatment significantly increased urinary ET excretion compared to baseline (1.6 +/- 0.2 vs. 0.5 +/- 0.1 pmol/day). Administration of omapatrilat significantly increased urinary ET excretion in DOCA-salt rats (2.9 +/- 0.4 pmol/day) compared to enalapril-treated (1.6 +/- 0.2 pmol/day) or untreated (1.5 +/- 0.1 pmol/day) rats. These results indicate that combined ACE/NEP inhibition does not lower blood pressure in a model of established hypertension with high ET activity. These results also support the hypothesis that combined ACE/NEP inhibition can increase renal ET production.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Desoxycorticosterone; Drinking; Eating; Enalaprilat; Endothelin Receptor Antagonists; Endothelins; Hypertension; Kidney; Male; Protease Inhibitors; Pyridines; Rats; Rats, Sprague-Dawley; Sodium; Thiazepines

Topics: Advisory Committees; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Humans; Hypertension; Neprilysin; Protease Inhibitors; Pyridines; Thiazepines

Vasopeptidase inhibitors are potent new antihypertensive agents. The dual inhibition of ACE and neutral endopeptidase may result in synergistic humoral effects with unique hemodynamic actions. We investigated the hemodynamic and neurohumoral effects of vasopeptidase inhibition in conscious dogs made hypertensive by bilateral renal wrapping and subsequently instrumented for long-term assessment of left ventricular pressure and volume (n=8). Intravenous vasopeptidase inhibition (omapatrilat, 30 micromol/kg over 10 minutes) reduced peak left ventricular pressure (171+/-6 versus 130+/-6 mm Hg immediately after infusion, P<0.01) through arterial vasodilation (arterial elastance, 9.8+/-0.8 to 5.8+/-1.6 mm Hg/mL, P<0.01) and preload reduction (left ventricular end-diastolic volume, 51.1+/-6.8 to 46.0+/-6.9 mL, P<0.01). At 60 minutes, preload decreased further (40.5+/-5.9 mL, P<0.01 versus baseline). Vasopeptidase inhibition increased plasma levels of adrenomedullin (41.2+/-9.6 versus 72.3+/-15 pg/mL, P<0.01), whereas levels of the natriuretic peptides and cGMP were unchanged. Similar hemodynamic and humoral effects were observed with long-term therapy. Neither an equimolar dose of an ACE inhibitor (fosinopril) nor exogenous adrenomedullin had as potent of a hypotensive effect, and neither reduced preload. In summary, the potent short-term and long-term hypotensive effects of vasopeptidase inhibition were prominently mediated by preload reduction, an effect not reproduced by ACE inhibition nor adrenomedullin augmentation and not associated with enhanced natriuretic peptide levels. Combined arterial vasodilation and preload reduction may confer additional potency as well as unique cardioprotective effects. Synergistic effects on humoral and probably endothelial vasodilatory factors appear to be important in mediating the unique hemodynamic profile of vasopeptidase inhibition in this form of experimental hypertension.

Topics: Adrenomedullin; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Dogs; Fosinopril; Hemodynamics; Hypertension; Kinetics; Male; Neprilysin; Peptides; Protease Inhibitors; Pyridines; Thiazepines; Vasoconstrictor Agents

Omapatrilat, an inhibitor of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), is an effective antihypertensive agent. Here, we studied the relative roles of NEP and ACE inhibition and their effect on resistance artery structure and function of deoxycorticosterone acetate (DOCA)-salt hypertensive rats.. Omapatrilat (40 mg/kg per day), the NEP inhibitor CGS 25462 (CGS, 100 mg/kg per day) and the ACE inhibitor enalapril (10 mg/kg per day), were given for 3 weeks to DOCA-salt hypertensive rats. Effects on small mesenteric resistance arteries were studied on a pressurized myograph. Collagen deposition was evaluated by confocal microscopy.. Systolic blood pressure of DOCA-salt rats was significantly reduced (P < 0.05) by omapatrilat and CGS. Omapatrilat and CGS treatment increased lumen diameter and decreased media width and media/lumen ratio of small arteries of DOCA-salt rats (P < 0.05). Small artery relaxation responses to acetylcholine improved under omapatrilat or CGS treatment. The stress-strain curve shifted leftward in mesenteric arteries from DOCA-salt rats compared to control rats. Omapatrilat or CGS treatment resulted in a rightward shift, which was significantly different from that induced by enalapril. Omapatrilat and CGS decreased collagen deposition in the vessel wall of DOCA-salt rats. Enalapril had no effect on blood pressure, vascular structure, endothelial function or collagen deposition in the vessel wall of DOCA-salt rats.. Dual inhibition of ACE/NEP in DOCA-salt hypertensive rats resulted in potent anti-hypertensive effects, prevented vascular remodelling and improved endothelial function of resistance arteries. NEP inhibition is involved to a large extent in the effect of omapatrilat in DOCA-salt rats. These actions of omapatrilat may confer protection against end-organ damage characteristic of severe hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biphenyl Compounds; Blood Pressure; Collagen; Desoxycorticosterone; Drug Therapy, Combination; Endothelium, Vascular; Enzyme Inhibitors; Hypertension; Male; Mesenteric Arteries; Myocardium; Neprilysin; Organ Size; Organophosphonates; Pyridines; Rats; Rats, Sprague-Dawley; Sodium Chloride; Systole; Thiazepines; Vascular Resistance

Omapatrilat represents a new class of drugs capable of inhibiting both ACE and neutral endopeptidase 24.11, the so-called vasopeptidase inhibitors. It therefore contributes to neurohumoral modulation, which might improve endothelial function in cardiovascular diseases. This study investigated the effect of omapatrilat in comparison to the ACE inhibitor captopril on systolic blood pressure and endothelial function in salt-induced hypertension. Dahl salt-sensitive rats (n=6/group) on standard or salt-enriched (4% NaCl) chow were treated for 8 weeks with either omapatrilat (36+/-4 mg/kg per day), captopril (94+/-2 mg/kg per day), or placebo. Aortic rings were then isolated and suspended in organ chambers for isometric tension recording. Systolic blood pressure of salt-fed, placebo-treated animals increased to 196+/-6 mm Hg, which was prevented by omapatrilat (162+/-5 mm Hg, P<0.05) and captopril (164+/-7 mm Hg, P<0.05) to a comparable degree. In control rats, acetylcholine (10(-10) to 10(-5) mol/L) induced endothelium-dependent relaxation (97+/-4%), which was reduced by high-salt diet to 30+/-5% (P<0.005; n=6). Omapatrilat improved relaxation to a greater extent (86+/-5%) than did captopril (57+/-6%; P<0.05). eNOS protein expression and aortic nitrite/nitrate content were reduced in hypertensive rats and improved by both omapatrilat and captopril. Aortic endothelin-1 levels were increased in salt-fed animals and unaffected by omapatrilat or captopril. These data suggest that despite comparable blood pressure, omapatrilat is superior to captopril in improving endothelium-dependent relaxation in salt-sensitive hypertension.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Captopril; Endothelin-1; Endothelium, Vascular; Enzyme Inhibitors; Hypertension; Male; Neprilysin; Nitrates; Nitric Oxide Synthase; Nitrites; Pyridines; Regression Analysis; Renal Artery; Sodium, Dietary; Statistics, Nonparametric; Thiazepines; Vasoconstriction; Vasodilation

Vasopeptidase inhibition (VPI) represents a new therapeutic principle including both inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). The present study investigated the effect of the vasopeptidase inhibitor omapatrilat on endothelin-1 (ET-1)-mediated vascular function in salt-induced hypertension.. Dahl salt-sensitive rats (n=6/group) on standard or salt-enriched (4% NaCl) chow were treated for 8 weeks with either omapatrilat (36+/-4 mg/kg/day), captopril (94+/-2 mg/kg/day) or placebo. Aortic and renal artery segments were isolated and suspended in organ chambers for isometric tension recording. Functional endothelin-converting enzyme (ECE) activity was assessed in native segments and after preincubation with omapatrilat. Furthermore, vascular ECE protein levels as well as plasma and tissue ET-1 levels were determined.. The increase in systolic blood pressure of salt-fed rats was prevented by omapatrilat and captopril to a comparable degree. In salt-induced hypertension, functional ECE activity (calculated as the ratio of the contraction to big ET-1 divided by the contraction to ET-1) in renal arteries (0.46+/-0.05) and in aorta (0.68+/-0.05) was reduced as compared with control animals (0.9+/-0.05 and 0.99+/-0.04, respectively; P<0.05). While omapatrilat in vitro blunted the response to big endothelin-1 (big ET-1) and diminished ECE activity further (P<0.01 vs native segments), chronic treatment with omapatrilat in vivo restored contractions to ET-1 (120+/-6%) and big ET-1 (98+/-9%) in renal arteries, and therefore normalized renovascular ECE activity. In addition, omapatrilat normalized plasma ET-1 concentrations (12.9+/-1.2 vs 16.6+/-1.4 pg/ml on high salt diet; P<0.05) and renovascular ECE protein levels.. In salt-induced hypertension, vasopeptidase inhibition restores alterations in the endothelin system, such as renovascular ECE activity and responsiveness to ET-1 and big ET-1 with chronic but not acute in vitro application. Thus, the beneficial effects of vasopeptidase inhibition may reflect a resetting of cardiovascular control systems and therefore may be particularly suited to treat hypertension and heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Captopril; Endothelin-1; Endothelins; Enzyme Inhibitors; Hypertension; Male; Metalloendopeptidases; Neprilysin; Protein Precursors; Pyridines; Rats; Rats, Inbred Dahl; Renal Artery; Sodium, Dietary; Thiazepines

Calcitonin gene-related peptide (CGRP), a potent vasodilator neuropeptide, plays a counterregulatory role in subtotal nephrectomy-salt (SN-salt)-induced hypertension, reflecting a stimulation of the efferent vasodilator function of perivascular sensory nerves. To determine the effect of omapatrilat, a dual ACE and neutral endopeptidase inhibitor, on blood pressure and the potential antihypertensive role for CGRP, 24 male Sprague-Dawley rats were separated into 4 groups: (1) SN-salt, (2) SN-salt plus omapatrilat (80 mg. kg(-1). d(-1) in the drinking water), (3) sham-operated plus salt, (4) sham-operated plus salt and omapatrilat. After 11 days the mean arterial pressure was higher in the SN-salt group (174+/-10 mm Hg) versus the sham-operated-salt (109+/-4 mm Hg) and sham-operated-salt plus omapatrilat (105+/-3 mm Hg) groups. Omapatrilat treatment of the SN-salt rats significantly decreased the mean arterial pressure to 123+/-7 mm Hg and significantly reduced the heart-to-body weight ratio. Intravenous administration of a specific CGRP receptor antagonist produced a significant 10+/-2 mm Hg mean arterial pressure increase in the untreated SN-salt hypertensive rats but was without effect in the other groups. This indicates that CGRP does not contribute to the antihypertensive actions of omapatrilat. In addition, CGRP mRNA and protein content in dorsal root ganglia were decreased approximately 25% in the SN-salt plus omapatrilat rats. Thus, omapatrilat not only markedly reduces the blood pressure in this model of renal failure-induced hypertension but may also prevent the abnormal compensatory stimulation of the vasodilator activity of the peripheral sensory nervous system.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Blotting, Northern; Calcitonin Gene-Related Peptide; Cardiomegaly; Hypertension; Male; Nephrectomy; Peptide Fragments; Pyridines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium Chloride, Dietary; Thiazepines

The present study was designed to analyze the chronic renal response to omapatrilat, a new vasopeptidase inhibitor, in spontaneously hypertensive rats (SHR). To that end, the renal and blood pressure response to a 4-day salt loading protocol was analyzed and the respective chronic renal curves constructed.. In non treated animals, and under normal sodium intake (around 2 mEq/day), mean arterial pressure (MAP), was significantly higher in the SHR as compared with the controls (WKY). After increasing salt intake (8 times normal), MAP did not change significantly in any group and the animals reached a normal sodium balance in four days. In a second group of animals, omapatrilat was given orally for 15 days at the dose of 40 mg/kg/day in the drinking water. In these omapatrilat-treated animals, and under normal sodium intake, MAP was significantly lower in both groups, although the antihypertensive effect was much greater in the SHR, so that the MAP of the SHR group was completely normalized and similar to the WKY-treated group. The subsequent elevation of sodium intake did not significantly elevate MAP in any group and the animals could manage the sodium excess as well as the non treated groups.. These results indicate that chronic treatment with omapatrilat normalizes blood pressure in SHR without affecting adversely the renal ability to eliminate a sodium load. Chronic treatment with omapatrilat resets the chronic pressure natriuresis relationship of the SHR to a normal level, thus without altering the normal salt-independence of this arterial hypertension model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Hypertension; Kidney; Male; Pyridines; Rats; Rats, Inbred SHR; Thiazepines

Renovascular hemodynamics plays a pivotal role in the regulation of BP. The effect of the vasopeptidase inhibitor omapatrilat (O) and the ACE-inhibitor captopril (C) on endothelial function in the renal circulation in salt-induced hypertension were investigated. Dahl salt-sensitive rats (n = 6 per group) on standard or salt-enriched chow were treated for 8 wk with O (36 +/- 4 mg/kg per d), C (94 +/- 2 mg/kg per d), or placebo. Renal arteries were suspended in organ chambers for isometric tension recording. Vascular hypertrophy was assessed by determination of standardized heart weight and aortic weight, and morphologic analysis of glomerular injury was performed. Systolic BP of salt-fed, placebo-treated animals increased to 196 +/- 6 mmHg, which was reduced by O (162 +/- 5 mmHg; P < 0.05) and C (164 +/- 7 mmHg; P < 0.05) to a comparable degree. In salt-induced hypertension, endothelium-dependent relaxations in renal arteries (56 +/- 6 versus 100 +/- 6%; P < 0.05) as well as contractions to endothelin-1 (ET-1) (98 +/- 5% versus 128 +/- 5%; P < 0.05) and big ET-1 (47 +/- 6% versus 116 +/- 7%; P < 0.05) were markedly reduced as compared with control animals, whereas standardized aortic weight and heart weight (4.9 +/- 0.4 versus 3.2 +/- 0.3 g/kg; P < 0.05) increased. Treatment with O restored endothelium-dependent relaxations (88 +/- 6%; P < 0.05 versus C) and contractions to ET-1 (120 +/- 6%) and big ET-1 (98 +/- 9%). O prevented vascular hypertrophy (0.23 +/- 0.019 mg/mm(2) versus 0.31 +/- 0.018 mg/mm(2) in high-salt diet; P < 0.05), but, in contrast to C, it only had a modest effect on glomerular injury. In conclusion, O restored renovascular endothelial function and prevented vascular hypertrophy in salt-induced hypertension and therefore may advance as a beneficial approach in the therapy of various forms of hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Vessels; Captopril; Cardiomegaly; Endothelium, Vascular; Hypertension; Hypertrophy; Kidney Glomerulus; Male; Myocardium; Neprilysin; Protease Inhibitors; Pyridines; Rats; Rats, Inbred Dahl; Renal Circulation; Sodium Chloride; Thiazepines; Vasoconstriction; Vasodilation

Left ventricular remodeling in hypertension is associated with cardiac interstitial and perivascular collagen deposition. The dual angiotensin I converting enzyme/neutral endopeptidase inhibitor omapatrilat (also called vasopeptidase inhibitor) improves left ventricular remodeling in experimental heart failure. We hypothesized that omapatrilat would induce regression of cardiac and vascular fibrosis in hypertension. We, therefore, investigated the effect of omapatrilat on collagen deposition in heart and aorta of stroke-prone spontaneously hypertensive rats (SHRSP). Twenty-week-old normotensive Wistar-Kyoto (WKY) rats, untreated SHRSP, and SHRSP treated with omapatrilat (40 mg/kg per day, orally) for 10 weeks were investigated. Collagen in the heart and the descending thoracic aorta was stained with Sirius red. After 10 weeks, systolic blood pressure (BP) was significantly (P < .01) reduced in omapatrilat-treated versus untreated SHRSP. Interstitial collagen density was significantly decreased in the subendocardial myocardium (to 2.71 +/- 0.24% v 4.12 +/- 0.30%, respectively, P < .05) and in the midmyocardium of omapatrilat-treated versus untreated SHRSP (to 3.01 +/- 0.25 v 4.19 +/- 0.17% respectively, P < .05). Perivascular collagen was significantly (P < .05) decreased in the subepicardial, mid-myocardial and, subendocardial regions of the myocardium of omapatrilat-treated versus untreated SHRSP. Aortic collagen content decreased in omapatrilat-treated versus untreated SHRSP (to 36.1 +/- 2.8 v 58.8 +/- 6.1 x 10(3) microm2/mm section, respectively, P < .05). In conclusion, in addition to being a potent antihypertensive agent, omapatrilat significantly improves cardiac and vascular fibrosis in SHRSP.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Aorta; Collagen; Disease Models, Animal; Fibrosis; Hypertension; Myocardium; Neprilysin; Pyridines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Thiazepines; Ventricular Remodeling

Omapatrilat is a newly developed vasopeptidase inhibitor that inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase and has potent antihypertensive efficacy. However, the specific effect of omapatrilat on cardiac function and left ventricular hypertrophy with hypertension remains controversial. Therefore, we investigated the effect of omapatrilat on blood pressure, cardiac hypertrophy, and cardiac function in spontaneously hypertensive rats (SHR). Studies were performed in SHR that received vehicle (n = 9), omapatrilat (n = 10), or fosinopril (ACE inhibitor, n = 7) by daily gavage for 56 days. Systolic blood pressure (SBP) and mean blood pressure (MBP) were measured by tail plethysmography. Left ventricular fractional shortening and left ventricular mass were measured by echocardiography at day 56. Omapatrilat and fosinopril significantly decreased SBP and MBP from day 1 through day 56, and omapatrilat markedly reduced SBP and MBP compared with fosinopril from day 21 to day 56. Although both omapatrilat and fosinopril decreased left ventricular mass and left ventricular mass-to-body weight ratio with increased LV fractional shortening, omapatrilat had a more potent effect on the reduction of left ventricular mass and improvement of cardiac function. This study shows that in SHR, omapatrilat mediated a potent and stable antihypertensive effect and a reduction in left ventricular mass with improvement of cardiac function, compared with ACE inhibition alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiovascular Agents; Endocardium; Fosinopril; Hemodynamics; Hypertension; Hypertrophy, Left Ventricular; Male; Pyridines; Rats; Rats, Inbred SHR; Thiazepines; Ventricular Function, Left

The novel principle of vaso-peptidase inhibition is based on the simultaneous inhibition of two enzymes, the angiotensin converting enzyme (ACE) and the neutral endopeptidase (NEP) by a single drug. NEP participates in metabolism of various natriuretic and vasodilatating peptides produced by atria and ventricles of the heart and endothelium (arterial natriuretic peptide, brain natriuretic peptide and C-Type natriuretic peptide). The orally effective vaso-peptidase inhibitor omapatrilate has recently become available. This substance reduced blood pressure in hypertensive patients in a dose-dependent fashion. It is tolerated as well as ACE inhibitors and seems to ameliorate mainly systolic pressure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Humans; Hypertension; Metalloendopeptidases; Neprilysin; Protease Inhibitors; Pyridines; Thiazepines; Vasodilation

The antihypertensive agent omapatrilat represents a novel approach to antihypertensive therapy, namely vasopeptidase inhibition. Omapatrilat (BMS-186716) concomitantly inhibits neutral endopeptidase and angiotensin-converting enzyme, leading to protection from degradation of natriuretic and other hypotensive peptides in addition to interruption of the renin-angiotensin system. Although the potency of omapatrilat on reduction of blood pressure has been reported, its effects on resistance artery structure and function were unknown. We tested omapatrilat in stroke-prone spontaneously hypertensive rats (SHRSP), a malignant model of hypertension, with the hypothesis that it would improve the structure and endothelial function of mesenteric resistance arteries. Ten-week-old SHRSP were treated orally for 10 weeks with omapatrilat (40 mg/kg per day). Mesenteric arteries (lumen <300 microm) were studied on a pressurized myograph. After 10 weeks, untreated SHRSP had a systolic blood pressure of 230+/-2 mm Hg that was significantly reduced (P<0.05) by omapatrilat (145+/-3 mm Hg). Omapatrilat treatment improved endothelium-dependent relaxation of resistance arteries as elicited by acetylcholine (10(-5) mol/L) but had no significant effect on endothelium-independent relaxation produced by a nitric oxide donor (sodium nitroprusside). This suggested that there existed endothelial dysfunction in SHRSP that was corrected by vasopeptidase inhibition, probably in part caused by the potent blood pressure-lowering effect of omapatrilat. Media width and media/lumen ratio were significantly decreased (P<0.05) by omapatrilat, and a trend (P=0.07) to increase lumen diameter was observed. Vascular stiffness (slope of the elastic modulus versus stress curve) was unaltered by omapatrilat. In conclusion, omapatrilat, acting as a potent antihypertensive agent, may improve structure and endothelial function of resistance arteries in SHRSP, a severe form of genetic hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Enzyme Inhibitors; Genetic Predisposition to Disease; Hypertension; Male; Mesenteric Arteries; Neprilysin; Pyridines; Rats; Rats, Inbred SHR; Stroke; Thiazepines; Vascular Resistance; Vasodilation

Vasopeptidase inhibitors, such as omapatrilat are single molecules that simultaneously inhibit neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE). In normotensive rats, a single dose of oral omapatrilat (10 mg/kg) and 1 mg/kg inhibited plasma ACE (P < .01) for 24 h and increased plasma renin activity for 8 h (P < .01). In vitro autoradiography using the specific NEP inhibitor radioligand 125I-RB104 and the specific ACE inhibitor radioligand 125I-MK351A showed omapatrilat (10 mg/kg) caused rapid and potent inhibition of renal NEP and ACE, respectively, for 24 h (P < .01). In spontaneously hypertensive rats, 10 days of oral omapatrilat (40 mg/kg/day) reduced blood pressure (vehicle 237 +/- 4 mm Hg; omapatrilat, 10 mg/kg, 212 +/- 4 mm Hg; omapatrilat 40 mg/kg, 197 +/- 4 mm Hg, P < .01) in a dose-dependent manner (10 v 40 mg/kg, P < .01). Left ventricular hypertrophy was significantly reduced by high-dose omapatrilat (vehicle 2.76 +/- 0.03 mg/g body weight; omapatrilat, 10 mg/kg, 2.71 +/- 0.02 mg/g; omapatrilat 40 mg/kg, 2.55 +/- 0.02 mg/g, P < .01) and omapatrilat also increased kidney weight compared to vehicle (both doses, P < .01). Omapatrilat caused significant inhibition of plasma ACE and increased plasma renin activity (both doses, P < .01), and in vitro autoradiographic studies indicated sustained inhibition of renal ACE and NEP (both doses, P < .01). Omapatrilat is a potent vasopeptidase inhibitor, and its antihypertensive effects are associated with inhibition of NEP and ACE at the tissue level and beneficial effects on cardiovascular structure. Relating the degree of tissue inhibition to physiologic responses may allow further definition of the role of local renin angiotensin and natriuretic peptide systems in the beneficial effects of vasopeptidase inhibitors.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cardiomegaly; Dose-Response Relationship, Drug; Hypertension; Kidney; Male; Myocardium; Neprilysin; Organ Size; Peptidyl-Dipeptidase A; Protease Inhibitors; Pyridines; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Renin; Thiazepines; Time Factors

Topics: Animals; Cricetinae; Drug Interactions; Drugs, Investigational; Heart Failure; Humans; Hypertension; Metalloendopeptidases; Protease Inhibitors; Pyridines; Thiazepines

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Humans; Hypertension; Pyridines; Thiazepines

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Humans; Hypertension; Neprilysin; Pyridines; Systole; Thiazepines; Treatment Outcome

Combined inhibition of neutral endopeptidase (NEP) and angiotensin converting enzyme (ACE) produces cardiovascular effects greater than those elicited by selective inhibition of either enzyme alone. Dual metalloprotease inhibitors are single molecules that inhibit both NEP and ACE and produce cardiovascular effects in animal models similar to those elicited by the combination of NEP and ACE inhibitors. The purpose of this study was to determined the duration of antihypertensive activity of the dual metalloprotease inhibitor omapatrilat in rodent models of hypertension. Omapatrilat inhibited NEP (Ki = 9 nmol/L) and ACE (Ki = 6 nmol/L) activities in vitro and inhibited the pressor response to angiotensin I in rats after intravenous administration with a potency and duration of action similar to those of the long acting ACE inhibitor fosinoprilat. After single dose administration, omapatrilat lowered mean arterial blood pressure (aortic catheter) in sodium depleted spontaneously hypertensive rats (high renin model) from 148+/-5 to 106+/-3 mm Hg (baseline to 24 h), in deoxycorticosterone acetate-salt hypertensive rats (low renin) from 167+/-4 to 141+/-5 mm Hg and in spontaneously hypertensive rats (normal renin) from 162+/-4 to 138+/-3 mm Hg (P < .05 at 24 h v vehicle in all models). After oral administration, omapatrilat (100 micromol/kg/day) persistently lowered systolic blood pressure (tail cuff) in spontaneously hypertensive rats during 11 days of treatment; at 24 h after dosing on day 12, mean arterial pressure (aortic catheter) was lower (P < .05) in the group receiving omapatrilat (133+/-5 mm Hg) than in the group receiving vehicle (149+/-2 mm Hg). The results indicate that omapatrilat is a potent dual metalloprotease inhibitor of NEP and ACE with long lasting, oral antihypertensive effects in low, normal, and high renin models of hypertension. Omapatrilat has the potential to be an effective, broad spectrum antihypertensive agent.

Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Drug Administration Schedule; Hypertension; Metalloendopeptidases; Neprilysin; Pyridines; Rats; Rats, Inbred SHR; Renin; Thiazepines

A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Cardiovascular Agents; Cyclic GMP; Enzyme Inhibitors; Heart Failure; Hypertension; Macaca fascicularis; Neprilysin; Pyridines; Rats; Renin; Sodium; Thiazepines