adrenomedullin and omapatrilat

Topics: Adrenomedullin; Animals; Antihypertensive Agents; Antioxidants; Clinical Trials as Topic; Drug Delivery Systems; Drug Design; Enzyme Inhibitors; Genetic Therapy; Heart Failure; Humans; Hypertension, Pulmonary; Natriuretic Agents; Neprilysin; Peptides; Pyridines; Thiazepines; Vasodilator Agents

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

Topics: Adrenomedullin; Aged; Angiotensin I; Arteries; Captopril; Female; Humans; Male; Middle Aged; Neprilysin; Protease Inhibitors; Pyridines; Substance P; Thiazepines; Thiorphan; Vasodilation

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

Topics: Adrenomedullin; Angiotensin-Converting Enzyme Inhibitors; Animals; Antimycin A; Cardiotonic Agents; Cell Death; Cell Survival; Cells, Cultured; Chick Embryo; Cytochromes c; Deoxyglucose; Drug Synergism; Electron Transport; Lisinopril; Membrane Potentials; Mitochondria, Heart; Mitochondrial Membranes; Myocytes, Cardiac; Oxidative Phosphorylation; Potassium Cyanide; Pyridines; Thiazepines

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

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 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