atrial-natriuretic-factor and omapatrilat

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

Previous results have shown that inhibition of the renin-angiotensin system (RAS) either with an angiotensin II (Ang II), type 1 receptor blocker (losartan) or with an angiotensin converting enzyme inhibitor (ACEI, enalapril) has a protective effect on cardiovascular, renal, hepatic and cerebral structure and function during aging. The present study has analyzed the effect of chronic administration of a newly developed compound, omapatrilat, on clinical, histological and biochemical changes due to aging. Omapatrilat combines the action of an ACEI and of an inhibitor of a neutral endopeptidase involved in the metabolism of the atrial natriuretic peptide. The final effect is a decrease of a vasoconstrictor and proinflammatory mechanism like the RAS and the potentiation of two vasodilating compounds like bradykinin and the atrial natriuretic peptide. Based on these actions, its protective effect might be greater than formerly used pharmacological agents. Determinations have been performed on young adults (6 months old), adults (12 months old) or senile (18 months old) rats. Omapatrilat (35 mg/kg/day during 6 months and 20 mg/kg/day thereafter) was administered in the drinking water since weaning until sacrifice. Cardiovascular, renal, and cerebral structure as well as cognitive behavior, cardiovascular and renal function has been analyzed. The biochemical analysis has also established whether the beneficial action of Ang II inhibition is related to an increased activity of the nitric oxide synthase as observed in previous studies. Moreover, this study has tried to determine the relationship between the protective effect of these drugs and the levels of antioxidant defenses present in the blood and/or in the tissues. Hence, enzymatic and non-enzymatic antioxidants have been evaluated.

Topics: Aging; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Atrial Natriuretic Factor; Cardiovascular System; Cognition; Inflammation; Kidney; Nitric Oxide Synthase; Protease Inhibitors; Pyridines; Rats; Renin-Angiotensin System; Thiazepines; Vasoconstriction; Vasodilation

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

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

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

Vasopeptidase (VP) inhibitors are novel molecules that co-inhibit neutral endopeptidase 24.11 (NEP), which degrades natriuretic peptides and angiotensin-converting enzyme (ACE). We review the biology of the natriuretic peptide system and a recent study of the role for the natriuretic peptide system in the mechanism of action of omapatrilat (the most clinically advanced VP inhibitor). This study compared the cardiorenal and humoral actions of omapatrilat with those of ACE inhibition. The actions of omapatrilat were further defined in the presence and absence of a natriuretic peptide receptor antagonist. This investigation provided insight into a unique new pharmacologic agent that has beneficial renal actions in experimental mild heart failure that exceed those seen with ACE inhibition alone and that are linked to the natriuretic peptide system.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiovascular Agents; Heart Failure; Humans; Kidney; Neprilysin; Pyridines; Thiazepines

The development of new antihypertensive agents is becoming even more important. We need better blood pressure control and also agents that treat hypertension as a disease of the vascular endothelium. Recently, it has been shown that blocking the renin-angiotensin system with angiotensin converting enzyme (ACE) inhibitors reduces blood pressure and decreases the incidence of vascular disease. Another peptide system, the natriuretic peptide system, has also been shown to be important in blood pressure control and volume homeostasis. Because ACE and neutral endopeptidase, the enzyme responsible for the degradation of the natriuretic peptides, are both zinc metalloproteases, new pharmaceuticals that inhibit both enzymes have been developed. The first of these, omapatrilat, has been shown to be an effective antihypertensive agent and to have great potential for treating congestive heart failure.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Cardiovascular Diseases; Endothelium, Vascular; Humans; Mesylates; Metalloendopeptidases; Natriuretic Peptide, Brain; Protease Inhibitors; Pyridines; Renin-Angiotensin System; Thiazepines; Tyrosine

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

Angiotensin-converting enzyme (ACE) inhibition attenuates ventricular remodeling and improves ventricular function in heart failure patients. Vasopeptidase inhibition has shown similar effects in experimental models.. The OVERTURE echocardiographic study was designed to test the hypothesis that the vasopeptidase inhibitor omapatrilat would attenuate ventricular remodeling and improve ventricular function to a greater extent than an ACE inhibitor.. Three hundred twenty-one patients with heart failure (New York Heart Association class > or = 2) were included in the OVERTURE echocardiographic substudy and were randomized to receive enalapril (10 mg twice a day) or omapatrilat (40 mg every day). Echocardiograms were performed at baseline and at 1 year (n = 214). Left ventricular size was estimated by summation of ventricular areas in apical and short-axis views and by calculation of ventricular volumes. Ejection fraction was calculated from ventricular volumes.. Combined diastolic and systolic areas and volumes decreased significantly (mean diastolic area change -8.36 cm2, 95% CI -9.4 to -7.3 cm2; mean systolic change -8.4 cm2, 95% CI -9.5 to -7.3 cm2), and ejection fractions increased significantly (3.6%, 95% CI 2.6% to 4.6%) in both treatment groups from baseline to 1 year. There were no differences in the magnitude of improvement in ventricular size or function based on treatment assignment. Patients who died or were hospitalized for heart failure subsequent to the final assessment demonstrated the least degree of reverse remodeling.. Ventricular size and function improved similarly after 1 year with ACE or vasopeptidase inhibition in patients with heart failure. Reverse remodeling was associated with improved outcome.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Cohort Studies; Enalapril; Female; Heart Failure; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Neprilysin; Organ Size; Proportional Hazards Models; Protease Inhibitors; Pyridines; Reproducibility of Results; Stroke Volume; Survival Analysis; Thiazepines; Treatment Outcome; Ultrasonography; Ventricular Remodeling

To determine the pharmacokinetics, pharmacodynamics and tolerability of omapatrilat, a vasopeptidase inhibitor, in healthy subjects.. The effects of oral omapatrilat were evaluated in healthy men in two double-blind, placebo-controlled, dose-escalation trials. In a single-dose study, subjects received omapatrilat in doses of 2.5, 7.5, 25, 50, 125, 250, or 500 mg. In a multiple-dose study, subjects received doses of 10, 25, 50, 75, or 125 mg daily for 10 days.. In the multiple-dose study, peak plasma concentrations (Cmax = 10-895 ng ml(-1); tmax = 0.5-2 h) of omapatrilat were attained rapidly. Omapatrilat exhibited a long effective half-life (14-19 h), attaining steady state in 3-4 days. In the single-dose study, Cmax (1-1009 ng ml(-1)) and AUC(0,t) (0.4-1891 ng ml(-1) h) were linear but not dose proportional. In the multiple-dose study, based on weighted least-squares linear regression analyses vs dose, Cmax but not AUC(0,t) was linear at the lower doses on day 10. The lowest dose of omapatrilat (2.5 mg) almost completely inhibited (> 97%) serum angiotensin converting enzyme activity at 2 h after dosing. In the multiple dose study, angiotensin converting enzyme activity was inhibited by more than 80% 24 h after all doses of omapatrilat. Inhibition of neutral endopeptidase activity was shown by increases in the daily urinary excretion of atrial natriuretic peptide and cyclic guanosine monophosphate at doses of more than 7.5 and 25 mg, respectively. In the single dose study, omapatrilat increased the daily urinary excretion of atrial natriuretic peptide dose-dependently from 10.8 +/- 4.1 (+/- SD) ng 24 h(-1) in the placebo group to 60.0 +/- 18.2 ng 24 h(-1) in the 500 mg group. Omapatrilat did not affect sodium and potassium excretion or urinary volume. Compared with placebo, omapatrilat produced a decrease in mean arterial pressure at 3 h after all doses in both the single- and multiple-dose studies.. Omapatrilat was generally well tolerated. The pharmacokinetic and pharmacodynamic effects of omapatrilat are consistent with once-daily dosing.

Topics: Administration, Oral; Adult; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dose-Response Relationship, Drug; Double-Blind Method; Half-Life; Humans; Male; Middle Aged; Neprilysin; Pyridines; Renin; Thiazepines

Angiotensin-converting enzyme (ACE) inhibitors exert their effects by modulating the neurohumoral milieu. Vasopeptidase inhibitors (VPI) are ACE and neutral endopeptidase inhibitors and may increase natriuretic peptides, bradykinin, and perhaps endothelin-1 in patients with congestive heart failure. Patients (n = 107) with ischemic or dilated cardiomyopathy, New York Heart Association functional class II to III, with left ventricular ejection fraction <40%, and on ACE inhibitor therapy were randomized to either the VPI omapatrilat 40 mg/day or the ACE inhibitor lisinopril 20 mg/day. Trough levels of neurohormones (24 hours after dosing) were assessed at baseline, and at 12 and 24 weeks of follow-up. C-terminal atrial natriuretic peptide (C-ANP) levels decreased with lisinopril (p = 0.035), but not with omapatrilat. In contrast, N-terminal ANP levels did not change, and brain natriuretic peptide (BNP) levels tended to decrease similarly in both groups. Endothelin-1 levels increased in both groups, the increase reaching statistical significance with omapatrilat (p = 0.008). Levels of the proinflammatory cytokine interleukin-6 tended to decrease, and the anti-inflammatory cytokine interleukin-10 increased in both groups, with statistical significance only for interleukin-10 with omapatrilat therapy. Neither agent changed catecholamines or angiotensin II. Thus, even at trough levels, omapatrilat potentiates C-ANP more than lisinopril. Potentially important effects of omapatrilat on endothelin-1 and anti-inflammatory cytokines were identified, providing potential explanations for differences in clinical outcome.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Chronic Disease; Cytokines; Double-Blind Method; Endothelin-1; Female; Follow-Up Studies; Heart Failure; Humans; Lisinopril; Male; Middle Aged; Natriuretic Peptide, Brain; Neurotransmitter Agents; Predictive Value of Tests; Prospective Studies; Pyridines; Stroke Volume; Thiazepines; Treatment Outcome

This double-blind placebo-controlled study was designed to investigate the acute and sustained hormonal, renal hemodynamic, and tubular effects of concomitant ACE and neutral endopeptidase (NEP) inhibition by omapatrilat, a vasopeptidase inhibitor, in men. Thirty-two normotensive subjects were randomized to receive a placebo, omapatrilat (40 or 80 mg), or the fosinopril/hydrochlorothiazide (FOS/HCTZ; 20 and 12.5 mg, respectively) fixed combination for 1 week. Blood pressure, renal hemodynamics, urinary electrolytes and atrial natriuretic peptide excretion, and several components of the renin-angiotensin system were measured for 6 hours on days 1 and 7 of drug administration. When compared with the placebo and the FOS/HCTZ combination, omapatrilat induced a significant decrease in plasma angiotensin II levels (P<0.001 versus placebo; P<0.05 versus FOS/HCTZ) and an increase in urinary atrial natriuretic peptide excretion (P<0.01). These hormonal effects were associated with a significant fall in blood pressure (P<0.01) and a marked renal vasodilatation, but with no significant changes in glomerular filtration rate. The FOS/HCTZ markedly increased urinary sodium excretion (P<0.001). The acute natriuretic response to FOS/HCTZ was significantly greater than that observed with omapatrilat (P<0.01). Over 1 week, however, the cumulative sodium excretion induced by both doses of omapatrilat (P<0.01 versus placebo) was at least as great as that induced by the dose of FOS/HCTZ (P=NS versus FOS/HCTZ). In conclusion, the results of the present study in normal subjects demonstrate that omapatrilat has favorable renal hemodynamic effects. Omapatrilat combines potent ACE inhibition with a sustained natriuresis, which explains its well-documented potent antihypertensive efficacy.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Double-Blind Method; Hemodynamics; Humans; Kidney; Kidney Tubules; Kinetics; Male; Natriuresis; Neprilysin; Protease Inhibitors; Pyridines; Renal Plasma Flow; Renin-Angiotensin System; Sodium; Thiazepines

The in vivo inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) were monitored simultaneously by sequentially measuring the urinary excretion of N-Acetyl-Ser-Asp-Lys-Pro and of the atrial natriuretic factor to compare the magnitude and the duration of action of a vasopeptidase inhibitor, omapatrilat, and an ACE inhibitor, fosinopril. Single oral doses of 40 or 80 mg of omapatrilat or 20 mg of fosinopril were administered to 24 normotensive, sodium-depleted or -replete volunteers in a placebo-controlled crossover study. ACE inhibition persisted longer after treatment with omapatrilat than with fosinopril, and there was no major difference between the effects of 40 and 80 mg of omapatrilat. The duration of NEP inhibition by omapatrilat was shorter than that of ACE inhibition. Although omapatrilat effectively inhibited NEP, it had a mild and transient natriuretic effect and did not increase natriuresis more than fosinopril. Omapatrilat induced a decrease in BP and an increase in plasma renin more rapidly and more effectively than fosinopril. The BP and renin effects of omapatrilat persisted despite high sodium intake, which neutralized the effects of fosinopril. The simultaneous inhibition of ACE and NEP may be more effective in reducing BP than the inhibition of ACE alone and less dependent on sodium balance.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Cross-Over Studies; Double-Blind Method; Endothelin-1; Endothelins; Fosinopril; Humans; Male; Neprilysin; Oligopeptides; Peptidyl-Dipeptidase A; Protease Inhibitors; Protein Precursors; Pyridines; Renin; Sodium, Dietary; Thiazepines; Time Factors

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

We investigated the acute and long-term hemodynamic and neurohumoral effects of the vasopeptidase inhibitor omapatrilat in human heart failure.. Angiotensin-converting enzyme (ACE) inhibition constitutes a major advance in the treatment of chronic heart failure (CHF). Simultaneous inhibition of both neutral endopeptidase and ACE with omapatrilat may represent a new treatment strategy in CHF.. Three hundred and sixty-nine patients with symptomatic heart failure were randomized to double-blind treatment with omapatrilat (first 190 patients: 2.5 mg, 5 mg or 10 mg; last 179 patients: 2.5 mg, 20 mg or 40 mg once daily) for 12 weeks.. Acutely, the 10 mg, 20 mg and 40 mg doses of omapatrilat produced greater reductions in pulmonary capillary wedge pressure (PCWP), systolic blood pressure (SBP) and systemic vascular resistance compared with 2.5 mg. Higher doses were associated with greater increases in vasodilator and natriuretic peptides, in addition to ACE inhibition. After 12 weeks, omapatrilat 20 mg and 40 mg showed greater falls from baseline in PCWP (40 mg: 0 h to 12 h average change -7.3 +/- 0.8 mm Hg) and SBP (40 mg: -11.7 +/- 1.7 mm Hg) than 2.5 mg (both p < 0.01 vs. 2.5 mg). The incidence of adverse experiences and patient withdrawal were similar in all groups.. In CHF, the acute hemodynamic benefit seen with higher doses of omapatrilat was associated with increases in plasma vasodilator and natriuretic peptide levels in addition to ACE inhibition. After 12 weeks, the hemodynamic benefit was maintained. Omapatrilat may be a promising new agent in CHF.

Topics: Aged; Atrial Natriuretic Factor; Double-Blind Method; Heart Failure; Hemodynamics; Humans; Middle Aged; Natriuretic Peptide, Brain; Neurotransmitter Agents; Protease Inhibitors; Pulmonary Wedge Pressure; Pyridines; Thiazepines; Time Factors; Vascular Resistance

The mechanisms of action of omapatrilat, an agent that inhibits both neutral endopeptidase 24.11 and angiotensin-converting enzyme, on arterial function in patients with heart failure have not been previously reported. Forty-eight patients in New York Heart Association functional class II to III, left ventricular ejection fraction < or = 40%, and in sinus rhythm were randomized to a dose-ranging (2.5, 5, 10, 20, or 40 mg) study of omapatrilat for 12 weeks. Measurements were obtained at baseline and 12 weeks. Decreases in systolic (25.0 +/- 4.5 vs 2.8 +/- 5.0 mm Hg, p < 0.05) and mean arterial (13.9 +/- 3.0 vs 0.3 +/- 3.3 mm Hg, p < 0.05) pressure were seen after 12 weeks of therapy with higher doses. Ventricular-arterial coupling was improved with a dose-related decrease in augmentation index (-13.8 +/- 1.7% vs +6.1 +/- 2.1%, p < 0.01). There was no change in resting forearm blood flow between groups; however, maximum forearm vasodilator response during reactive hyperemia increased in the high-dose groups compared with the control group (+266 +/- 43% vs - 14 +/- 92%, p < 0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (30 +/- 11 vs -2 +/- 7 pmol/L, p < 0.01) in high-dose groups consistent with endopeptidase 24.11 inhibition. Omapatrilat shows beneficial changes in ventricular-vascular coupling and arterial function in heart failure.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Dose-Response Relationship, Drug; Female; Heart Failure; Humans; Male; Middle Aged; Pyridines; Stroke Volume; Thiazepines; Vasodilation; Ventricular Function, Left

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

We sought to examine the effects of long-term vasopeptidase inhibition in patients with heart failure.. The long-term effects of omapatrilat, an agent that inhibits both neutral endopeptidase and angiotensin-converting enzyme, on clinical status, neurohormonal indexes and left ventricular function in patients with chronic heart failure (CHF) have not been previously documented.. Forty-eight patients in New York Heart Association functional class II or III, with left ventricular ejection fraction (LVEF)< or =40% and in sinus rhythm were randomized to a dose-ranging pilot study of omapatrilat for 12 weeks. Measurements were performed at baseline and 12 weeks.. There was an improvement in functional status, as reported by the patient (p<0.001) and physician (p<0.001) at 12 weeks. Dose-dependent improvements in LVEF (p<0.001) and LV end-systolic wall stress (sigma) (p<0.05) were seen, together with a reduction in systolic blood pressure (p<0.05). There was evidence of a natriuretic effect (p<0.001), and total blood volume decreased (p<0.05). Omapatrilat induced an increase in postdose plasma atrial natriuretic peptide levels (p<0.01) in the high dose groups, with a reduction in predose plasma brain natriuretic peptide (p<0.001) and epinephrine (p<0.01) levels after 12 weeks of therapy. Omapatrilat was well tolerated.. The sustained hemodynamic, neurohumoral and renal effects of omapatrilat, together with improved functional status, suggest that vasopeptidase inhibition has potential as a new therapeutic modality for the treatment of CHF.

Topics: Aged; Aged, 80 and over; Atrial Natriuretic Factor; Blood Volume; Dose-Response Relationship, Drug; Double-Blind Method; Epinephrine; Female; Heart Failure; Hemodynamics; Humans; Kidney; Male; Metalloendopeptidases; Middle Aged; Natriuretic Peptide, Brain; Pyridines; Thiazepines; Ventricular Function, Left

We aimed to assess in patients with congestive heart failure whether dual inhibition of neutral endopeptidase and angiotensin-converting enzyme (ACE) with the vasopeptidase inhibitor omapatrilat is better than ACE inhibition alone with lisinopril on functional capacity and clinical outcome.. We did a prospective, randomised, double-blind, parallel trial of 573 patients with New York Heart Association (NYHA) class II-IV congestive heart failure, left-ventricular ejection fraction of 40% or less, and receiving an ACE inhibitor. Patients were randomly assigned omapatrilat at a daily target dose of 40 mg (n=289) or lisinopril at a daily target dose of 20 mg (n=284) for 24 weeks. The primary endpoint was improvement in maximum exercise treadmill test (ETT) at week 12. Secondary endpoints included death and comorbid events indicative of worsening heart failure.. Week 12 ETT increased similarly in the omapatrilat and lisinopril groups (24 vs 31 s, p=0.45). The two drugs were fairly well tolerated, but there were fewer cardiovascular-system serious adverse events in the omapatrilat group than in the lisinopril group (20 [7%] vs 34 [12%], p=0.04). There was a suggestive trend in favour of omapatrilat on the combined endpoint of death or admission for worsening heart failure (p=0.052; hazard ratio 0.53 [95% CI 0.27-1.02]) and a significant benefit of omapatrilat in the composite of death, admission, or discontinuation of study treatment for worsening heart failure (p=0.035; 0.52 [0.28-0.96]). Omapatrilat improved NYHA class more than lisinopril in patients who had NYHA class III and IV (p=0.035), but not if patients with NYHA class II were included.. Our findings suggest that omapatrilat could have some advantages over lisinopril in the treatment of patients with congestive heart failure. Thus use of vasopeptidase inhibitors could constitute a potentially important treatment for further improving the prognosis and well being of patients with this disorder.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Double-Blind Method; Endothelin-1; Exercise Tolerance; Female; Heart Failure; Humans; Lisinopril; Male; Middle Aged; Neprilysin; Norepinephrine; Prospective Studies; Pyridines; Radionuclide Ventriculography; Severity of Illness Index; Survival Rate; Thiazepines; Treatment Outcome

There is currently no clear evidence that dual neutral endopeptidase-angiotensin-converting enzyme inhibitors have effects on angiotensin-converting enzyme, renin, or blood pressure that are different from specific angiotensin-converting enzyme inhibitors in humans.. In a double-blind, placebo-controlled crossover study, single oral doses of the dual neutral endopeptidase-angiotensin-converting enzyme inhibitor, 10 mg BMS-186716 and the angiotensin-converting enzyme inhibitor fosinopril (20 mg) were administered to 9 normotensive subjects with induced mild sodium depletion. Values for area under the time curve from 0 to 24 hours [AUC(0-24)] for the plasma angiotensin II/angiotensin I ratio and for angiotensin II were similar for 10 mg BMS-186716 and 20 mg fosinopril. Plasma atrial natriuretic peptide decreased significantly after 20 mg fosinopril (9+/-3 pg/mL; P < .05 versus 10 mg BMS-186716 and placebo) compared with 10 mg BMS-186716 (16+/-5 pg/mL) and placebo (16+/-5 pg/mL). BMS-186716, 10 mg, significantly increased urinary atrial natriuretic peptide from baseline by 2+/-1.3-fold (P < .05 versus placebo and 20 mg fosinopril). AUC(0-24) of plasma active renin did not differ significantly between 10 mg BMS-186716 (3898+/-333 pg x h x mL(-1)) and 20 mg fosinopril (4383+/-302 pg x h x mL(-1); difference not significant). Both drugs decreased blood pressure, but the AUC(0-24) of the changes in mean blood pressure differed significantly from placebo (79+/-84 mm Hg x h) only for 20 mg fosinopril (181+/-6 mm Hg x h; P < .05) but not for 10 mg BMS-186716 (118+/-7 mmHg x h).. In this model, single oral doses of 10 mg BMS-186716 and 20 mg fosinopril induced similar 24-hour in vivo angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, increased urinary atrial natriuretic peptide and blunted the expected decrease in plasma atrial natriuretic peptide caused by angiotensin-converting enzyme inhibition. BMS-186716, 10 mg, did not inhibit plasma active renin rise compared with 20 mg fosinopril. A single oral dose of 10 mg BMS-186716 had a shorter blood pressure-lowering effect than 20 mg fosinopril.

Topics: Administration, Oral; Adult; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Natriuretic Factor; Cross-Over Studies; Double-Blind Method; Enzyme Inhibitors; Fosinopril; Humans; Male; Neprilysin; Pyridines; Reference Values; Renin; Thiazepines; Time Factors

Increased arterial endothelial cell permeability (ECP) is considered an initial step in atherosclerosis. Atrial natriuretic peptide (ANP) which is rapidly degraded by neprilysin (NEP) may reduce injury-induced endothelial cell leakiness. Omapatrilat represents a first in class of pharmacological agents which inhibits both NEP and angiotensin converting enzyme (ACE). We hypothesized that ANP prevents thrombin-induced increases of ECP in human aortic ECs (HAECs) and that omapatrilat would reduce aortic leakiness and atherogenesis and enhance ANP mediated vasorelaxation of isolated aortas. Thrombin induced ECP determined by I(125) albumin flux was assessed in HAECs with and without ANP pretreatment. Next we examined the effects of chronic oral administration of omapatrilat (12 mg/kg/day, n=13) or placebo (n=13) for 8 weeks on aortic leakiness, atherogenesis and ANP-mediated vasorelaxation in isolated aortas in a rabbit model of atherosclerosis produced by high cholesterol diet. In HAECs, thrombin-induced increases in ECP were prevented by ANP. Omapatrilat reduced the area of increased aortic leakiness determined by Evans-blue dye and area of atheroma formation assessed by Oil-Red staining compared to placebo. In isolated arterial rings, omapatrilat enhanced vasorelaxation to ANP compared to placebo with and without the endothelium. ANP prevents thrombin-induced increases in ECP in HAECs. Chronic oral administration of omapatrilat reduces aortic leakiness and atheroma formation with enhanced endothelial independent vasorelaxation to ANP. These studies support the therapeutic potential of dual inhibition of NEP and ACE in the prevention of increased arterial ECP and atherogenesis which may be linked to the ANP/cGMP system.

Topics: Angiotensins; Animals; Aorta; Atherosclerosis; Atrial Natriuretic Factor; Diet, High-Fat; Endothelial Cells; Humans; Neprilysin; Organ Culture Techniques; Permeability; Pyridines; Rabbits; Thiazepines; Vasodilation

We and other investigators have reported that short- and long-term treatment with adrenomedullin has beneficial effects in heart failure. This study examined the effects of long-term treatment with a vasopeptidase inhibitor plus adrenomedullin in a model of heart failure in rats and assessed potential mechanisms of action.. Dahl salt-sensitive rats aged 11 weeks were randomly divided into three groups: an omapatrilat group, an omapatrilat plus adrenomedullin group, and an untreated group. The effects of these treatments were evaluated after 7 weeks of treatment.. Omapatrilat monotherapy significantly improved left ventricular weight (LVW), blood pressure (BP), and central hemodynamics as compared with the untreated group. Omapatrilat decreased the gene expression levels of adrenomedullin and atrial natriuretic peptide (ANP) in the left ventricle. In addition, omapatrilat decreased mRNA levels of transforming growth factor-beta (TGF-beta), collagen I, collagen III, plasminogen activator inhibitor-1 (PAI-1), and intercellular adhesion molecule-1 (ICAM-1) in the left ventricle, and omapatrilat decreased perifibrosis score and myocyte area histologically. Omapatrilat plus adrenomedullin further improved LVW, central hemodynamics, and mRNA expression of TGF-beta, collagen I, collagen III, PAI-1, and ICAM-1 without changing BP. Omapatrilat plus adrenomedullin further reduced mRNA levels of ANP and adrenomedullin without altering levels of ANP or adrenomedullin in plasma. Interestingly, omapatrilat slightly decreased mRNA levels of subunits of NADPH oxidase, whereas omapatrilat plus adrenomedullin further decreased these variables.. Our results suggest that combined treatment with adrenomedullin and omapatrilat may be a new strategy for the management of heart failure, acting partly by inhibition of the extracellular matrix gene, adhesion molecule, antifibrinolysis, and oxidative stress production.

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output, Low; Collagen; Disease Progression; Drug Therapy, Combination; Gene Expression Regulation; Heart Ventricles; Intercellular Adhesion Molecule-1; Male; NADPH Oxidases; Plasminogen Activator Inhibitor 1; Pyridines; Rats; Rats, Inbred Dahl; RNA, Messenger; Thiazepines; Transforming Growth Factor beta

The vasopeptidase inhibitor omapatrilat improves insulin sensitivity and survival following myocardial infarction (MI). It also improves left ventricular (LV) remodelling following MI and reduces MI size.. To determine whether improvement in LV remodelling and function is accompanied by a reduction in fetal gene expression of the contractile apparatus, and whether reduction in MI size is accompanied by an increase in the expression of the glucose transporter GLUT-4.. Eighty-nine rats were pretreated for seven days with omapatrilat 20 mg/kg/day and 91 rats were left untreated. MI was induced in 180 Zucker lean male rats by ligating the left anterior descending coronary artery, and omapatrilat was given for another 38 days in the survivors. After 30 days, echocardiography was performed. At 38 days, hemodynamic measurements were performed, the rats were sacrificed and morphological measurements were done. Using quantitative reverse transcriptase-polymerase chain reaction, gene expression was measured in the LV using transcript levels.. Treatment with omapatrilat resulted in improved early (24 h) and late (38 days) survival following MI (50% to 67%, P=0.023, and 44% to 59%, P=0.045, respectively). Omapatrilat treatment reduced MI size and resulted in beneficial ventricular remodelling as reflected by a reduction in cardiac dimensions by echocardiography, and LV and right ventricular hypertrophy, which resulted in borderline hemodynamic improvement. A large MI resulted in an increased expression of beta-myosin heavy chain, alpha-skeletal actin and atrial natriuretic peptide, and a decreased expression of GLUT-4. Omapatrilat treatment did not modify the expression of these genes.. The results suggest that the vasopeptidase inhibitor omapatrilat does not modify fetal gene expression of the contractile apparatus or the expression of GLUT-4 despite reducing cardiac hypertrophy and MI size.

Topics: Animals; Atrial Natriuretic Factor; Disease Models, Animal; Drug Evaluation, Preclinical; Echocardiography; Gene Expression Regulation; Glucose Transporter Type 4; Heart Ventricles; Hypertrophy, Left Ventricular; Hypertrophy, Right Ventricular; Ligation; Male; Monosaccharide Transport Proteins; Muscle Proteins; Myocardial Infarction; Protease Inhibitors; Pyridines; Random Allocation; Rats; Rats, Zucker; Reverse Transcriptase Polymerase Chain Reaction; Survival Rate; Thiazepines; Ventricular Function, Left; Ventricular Myosins; Ventricular Remodeling

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

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

Congestive heart failure (CHF) results in decreased cardiac sympathetic innervation.. The purpose of this study was to test the hypothesis that therapy with the vasopeptidase inhibitor omapatrilat (OMA) attenuates cardiac neuronal remodeling in CHF.. We induced CHF in dogs with rapid ventricular pacing for 5 weeks with (CHF+OMA group, n = 8) or without (CHF group, n = 10) concomitant OMA treatment (10 mg/kg twice daily). Cardiac catheterization and echocardiography were performed to determine cardiac structure and hemodynamic parameters. Myocardial nerve density was determined by immunocytochemical staining with anti-growth associated protein 43 (GAP43) and anti-tyrosine hydroxylase (TH) antibodies. Seven normal dogs were used as histologic controls.. In the CHF group, ascites developed in 3 dogs and 4 dogs died, compared with no ascites or death in the CHF+OMA group (P = .07). In the 6 CHF dogs that survived, all had atrial fibrosis, severely depressed left ventricular systolic function, and increased atrial and ventricular chamber size. OMA treatment decreased the atrial and ventricular chamber sizes and the degree of atrial fibrosis. Most CHF dogs showed severe myocardial denervation, although some showed normal or abnormally high nerve counts. OMA treatment prevented heterogeneous reduction of nerve density. The left ventricular TH-positive nerve densities were 128 +/- 170 microm(2)/mm(2), 261 +/- 185 microm(2)/mm(2), and 503 +/- 328 microm(2)/mm(2) (P < .05), and the atrial GAP43-positive nerve densities were 1,683 +/- 1,365 microm(2)/mm(2), 305 +/- 368 microm(2)/mm(2), and 1,278 +/- 1,479 microm(2)/mm(2) (P < .05) for the control, CHF, and CHF+OMA groups, respectively.. CHF results in heterogeneous cardiac denervation. Long-term OMA treatment prevented the reduction of nerve density and promoted beneficial cardiac structural remodeling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiovascular Agents; Disease Models, Animal; Dogs; Heart Atria; Heart Failure; Heart Ventricles; Hypertrophy, Left Ventricular; Male; Myocardium; Natriuretic Peptide, Brain; Nerve Tissue; Pyridines; Renin; Stroke Volume; Thiazepines; Ventricular Dysfunction, Left; Ventricular Pressure; Ventricular Remodeling

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

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

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 (OMA), a vasopeptidase inhibitor, simultaneously inhibits angiotensin-converting enzyme (ACE) and neutral endopeptidase, which degrades vasodilatory factors (eg, ADM) and natriuretic peptides. Based on the beneficial cardiorenal and humoral properties of the natriuretic peptides, we hypothesized that an acute vasopeptidase inhibitor with or without diuretic would result in more favorable cardiorenal and hormonal actions than ACE inhibition plus diuretic (ACEI+D) in congestive heart failure.. We compared the actions of OMA alone and with diuretic (OMA+D) to ACEI+D in a model of pacing-induced congestive heart failure. OMA+D decreased pulmonary arterial and pulmonary capillary wedge pressures to a greater level than OMA alone or ACEI+D. Glomerular filtration rate was lower with ACEI+D than with either OMA group. Plasma renin activity and aldosterone immediately increased with ACEI+D, whereas OMA+D resulted in higher plasma renin activity and a delayed increase in aldosterone. OMA alone did not increase plasma renin activity and aldosterone, but resulted in a sustained increase in plasma adrenomedullin, with higher urinary atrial natriuretic peptide, adrenomedullin, and cGMP excretions than with ACEI+D.. Acute administration of OMA with or without diuretic results in more favorable cardiorenal and humoral responses in experimental congestive heart failure than does ACEI+D. There is no acute activation of renin and aldosterone with OMA alone such as occurs with ACEI+D and OMA+D. Thus, OMA with or without a diuretic possesses beneficial cardiorenal and humoral actions comparable to those observed with ACEI+D that can be explained by potentiation of natriuretic peptides.

Topics: Adrenomedullin; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cyclic GMP; Disease Models, Animal; Diuretics; Dogs; Drug Therapy, Combination; Glomerular Filtration Rate; Heart Failure; Heart Function Tests; Hemodynamics; Kidney Function Tests; Male; Neprilysin; Peptides; Peptidyl-Dipeptidase A; Protease Inhibitors; Pulmonary Wedge Pressure; Pyridines; Renin; Thiazepines; Treatment Outcome

A hallmark of congestive heart failure (CHF) is the elevation of the cardiac natriuretic peptides (NPs), which have natriuretic, renin-inhibiting, vasodilating, and lusitropic properties. We have reported that chronic subcutaneous (SQ) administration of brain natriuretic peptide (BNP) in experimental CHF improves cardiorenal function. Vasopeptidase inhibitors (VPIs) are single molecules that simultaneously inhibit both neutral endopeptidase 24.1 (NEP) and ACE. We hypothesized that acute VPI administration would potentiate the cardiorenal actions of SQ BNP in experimental CHF.. We determined the cardiorenal and humoral responses to acute VPI alone with omapatrilat (OMA) (1 micromol/kg IV bolus) (n=6), acute low-dose SQ BNP (5 microg/kg) alone (n=5), acute VPI plus low-dose SQ BNP (n=5), and acute high-dose SQ BNP (25 microg/kg) alone in 4 groups of anesthetized dogs with experimental CHF produced by ventricular pacing for 10 days. Plasma BNP was greater with VPI+low-dose SQ BNP compared with VPI alone or low-dose SQ BNP alone and was similar to high-dose SQ BNP alone. Urinary BNP excretion was greatest with VPI+SQ BNP. Urinary sodium excretion was also highest with VPI+SQ BNP, with the greatest increase in glomerular filtration rate. VPI+SQ BNP resulted in a greater increase in cardiac output and reduction in cardiac filling pressures as compared with low-dose SQ BNP, high-dose SQ BNP, or VPI alone.. This study reports that acute VPI potentiates the cardiorenal actions of SQ BNP in experimental CHF. This study advances the concept that protein therapy with BNP together with vasopeptide inhibition represents a novel therapeutic strategy in CHF to maximize the beneficial properties of the natriuretic peptide system.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Cyclic GMP; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Injections, Subcutaneous; Kidney; Male; Natriuretic Peptide, Brain; Neprilysin; Peptidyl-Dipeptidase A; Pyridines; Sodium; Thiazepines

Angiotensin-converting enzyme (ACE) is mainly responsible for converting angiotensin I (AI) to angiotensin II (AII), and ACE inhibitors prevent atherosclerosis in animal models. Neutral endopeptidase 24.11 (NEP) degrades substance P, kinins and atrial natriuretic peptide (ANP), and aortic wall NEP activity was found to be increased in atherosclerosis. In the present study, we have evaluated the effect of candoxatril, a NEP inhibitor, and of omapatrilat, a dual ACE and NEP inhibitor, on the development of fatty streak in apolipoprotein E (apoE)-deficient mice. Groups of ten male apoE-deficient mice were given either placebo, candoxatril 50 mg/kg per day, or omapatrilat 10, or 100 mg/kg per day for 4 months. None of the treatments influenced body weight, serum total or HDL-cholesterol. Compared with the placebo, candoxatril did not protect the mice from fatty streak deposit. In contrast, omapatrilat dose dependently inhibited the constitution of fatty streak in apoE-deficient mice. The precise advantages of the dual ACE and NEP inhibition versus the inhibition of only ACE should now be considered in the prevention of atherosclerosis as well as in the occurrence of its complications.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apolipoproteins E; Arteriosclerosis; Atrial Natriuretic Factor; Body Weight; Bradykinin; Cholesterol; Cholesterol, HDL; Drug Evaluation, Preclinical; Indans; Male; Mice; Mice, Knockout; Neprilysin; Propionates; Protease Inhibitors; Pyridines; Substance P; Thiazepines; Triglycerides

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

Topics: Administration, Oral; Area Under Curve; Atrial Natriuretic Factor; Blood Pressure; Cardiovascular Agents; Case-Control Studies; Female; Humans; Liver Cirrhosis; Male; Metabolic Clearance Rate; Middle Aged; Pyridines; Renin; Thiazepines

Mild heart failure is characterized by increases in atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in the absence of activation of the renin-angiotensin-aldosterone system (RAAS). Vasopeptidase (VP) inhibitors are novel molecules that coinhibit neutral endopeptidase 24.11, which degrades the natriuretic peptides (NPs) and ACE. In a well-characterized canine model of mild heart failure produced by ventricular pacing at 180 bpm for 10 days, we defined the renal and humoral actions of acute VP inhibition with omapatrilat (OMA, n=6) and acute ACE inhibition (n=5) alone with fosinoprilat. We also sought to determine whether the NPs participate in the renal actions of acute VP inhibition by the administration of OMA together with an intrarenal administration of the NP receptor antagonist HS-142-1 (n=5). OMA resulted in a greater natriuretic response than did ACE inhibition in association with increases in plasma cGMP, ANP, BNP, urinary cGMP, urinary ANP excretion, and glomerular filtration rate (P<0.05 for OMA versus ACE inhibition). Plasma renin activity was increased only in the group subjected to ACE inhibition. Administration of intrarenal HS-142-1 attenuated the renal properties of OMA in association with a decrease in urinary cGMP excretion despite similar increases in plasma ANP and BNP. This study provides new insight into a unique new pharmacological agent that has beneficial renal actions in experimental mild heart failure beyond the actions that are observed with ACE inhibition alone and that are linked to the NP system.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Dogs; Fosinopril; Glomerular Filtration Rate; Heart Failure; Male; Neprilysin; Polysaccharides; Protease Inhibitors; Pyridines; Receptors, Atrial Natriuretic Factor; Sodium; Thiazepines

The pharmacological profile of a vasopeptidase inhibitor is dependent on the ratio of neutral endopeptidase (NEP)vs angiotensin converting enzyme (ACE) inhibition of the particular drug. We used in vitro autoradiography to determine the local renal and cardiac NEP and ACE inhibition after oral treatment with the dual NEP/ACE inhibitor omapatrilat in rat. Maximal inhibition of both renal NEP and ACE was achieved at the omapatrilat dose of 40 mg kg(-1)day(-1). Effective local ACE inhibition was detected also in the myocardium. The haemodynamic effects were similar to captopril, but omapatrilat treatment produced more favorable effect on natriuretic peptide levels. In conclusion, good tissue penetration of omapatrilat and balanced NEP/ACE inhibition may prove to be useful in the treatment of hypertension and heart failure.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Captopril; Dose-Response Relationship, Drug; Heart; Kidney; Male; Myocardium; Natriuretic Agents; Natriuretic Peptide, Brain; Neprilysin; Organ Size; Peptidyl-Dipeptidase A; Pyridines; Rats; Rats, Wistar; Thiazepines

Omapatrilat is a member of the new drug class of vasopeptidase inhibitors that may offer benefit in the treatment of heart failure (HF) through simultaneous inhibition of angiotensin-converting enzyme and neutral endopeptidase. We examined the effects of omapatrilat in a placebo-controlled crossover study using a pacing model of HF. Seven sheep were paced sequentially at 180 bpm (mild HF) and then 225 bpm (severe HF) for 7 days each. Omapatrilat (0.005 mg/kg) or vehicle was administered by intravenous bolus on days 4 to 7 of each paced period. Omapatrilat lowered mean arterial and left atrial pressure and increased cardiac output acutely and chronically in both mild and severe HF (P<0.01 for all). Plasma atrial and brain natriuretic peptide and cGMP levels were stable acutely (P=NS), while brain natriuretic peptide increased after repeated dosing in severe HF (P<0.05). Plasma renin activity rose, whereas angiotensin II and aldosterone levels fell after acute and repeated dosing in both states (P<0.01 for all). Omapatrilat increased urinary sodium excretion by day 7 in both mild and severe HF (P<0.05). Effective renal plasma flow and glomerular filtration rate increased or were stable after omapatrilat in mild and severe HF after both acute and repeated dosing. Omapatrilat exhibited pronounced acute and sustained beneficial hemodynamic and renal effects in both mild and severe heart failure.

Topics: Aldosterone; Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Cardiac Output; Cardiovascular Agents; Cross-Over Studies; Cyclic GMP; Disease Models, Animal; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Injections, Intravenous; Kidney; Natriuretic Peptide, Brain; Pyridines; Renin; Sheep; Sodium; 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