Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Animal studies have demonstrated that CNP causes endothelium-independent vasodilation, which is limited by neutral endopeptidase (NEP) activity. However, the vasodilating mechanism of CNP in humans is still unknown. Therefore, we investigated the vasodilator actions of CNP in human forearm resistance vessels before and after inhibition of nitric oxide (NO) and then prostacyclin production and after inhibition of Ca(2+)-dependent potassium channel activation and NEP activity. Three separate studies were performed. In each study, forearm blood flow was recorded by venous occlusion plethysmography in 8 healthy nonsmoking subjects. Brachial artery infusion of CNP (70, 140, 280, and 560 ng per 100 mL forearm volume per minute) caused significant forearm vasodilation in all studies (forearm blood flow from 3.94 to 8.50 mL per 100 mL forearm volume per minute). Inhibition of the endogenous generation of NO by L-N(G)-monomethyl arginine (by use of the NO-clamp technique) did not block the maximal vasodilating effects of CNP (forearm blood flow from 3.69 to 6.93). In addition, when the cyclooxygenase system was inhibited by 600 mg of acetylsalicylic acid (aspirin) administered orally 30 minutes before start of measurements, the rise in forearm blood flow remained intact (forearm blood flow from 3.31 to 8.27 mL per 100 mL forearm volume per minute). However, inhibition of Ca(2+)-dependent potassium channels with tetraethylammonium chloride (0.1 mg per 100 mL forearm volume per minute) significantly attenuated vasodilation caused by CNP (forearm blood flow from 2.28 to 3.06 mL per 100 mL forearm volume per minute), which suggests that CNP opens vascular potassium channels. Vasodilation to all doses of CNP was significantly increased when activity of NEP was blocked with thiorphan (30 nmol/min), which suggests that NEP activity limits vasodilation of CNP. CNP is a dilator of human resistance vessels that mediates its effects through hyperpolarization of the vessel wall independent of the NO and prostaglandin system. Inhibition of local NEP activity increases CNP bioavailability. This may be of relevance to cardiovascular disease, given that vascular tone is well balanced between NO and an endothelium-derived hyperpolarizing factor, which suggests that in pathological situations, impaired NO activity can be compensated for by enhanced endothelium-derived hyperpolarizing factor release to maintain vascular homeostasis.
Hypertension 2001 Apr
PMID:C-type natriuretic peptide-induced vasodilation is dependent on hyperpolarization in human forearm resistance vessels. 1130 21

Omapatrilat is the most clinically advanced member of a new class of cardiovascular drugs, vasopeptidase inhibitors. Omapatrilat is a single molecule that simultaneously inhibits neutral endopeptidase and angiotensin-converting enzyme, thus preserving vasodilator peptides and inhibiting production of the vasoconstrictor angiotensin II. In healthy male volunteers, omapatrilat decreased blood pressure while being generally well tolerated, with no serious adverse events. This study was undertaken to determine the effect of age and gender on the pharmacodynamics of omapatrilat. Healthy male or female volunteers between the ages of 18 and 80 were given a single oral dose of omapatrilat 40 mg. Neither age nor gender affected the vasopeptidase inhibition by omapatrilat. There were no differences between subject groups in the effect of omapatrilat on supine systolic, diastolic, or mean arterial blood pressure. Based on this study of healthy subjects, it can be concluded that it is not necessary to adjust the initial dose of omapatrilat for the treatment of hypertension based solely on age or gender.
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PMID:Effects of age and gender on the pharmacodynamics of omapatrilat in healthy volunteers. 1141 36

Vasopeptidase inhibitors, a new class of cardiovascular compounds, inhibit both neutral endopeptidase, an enzyme that helps in the breakdown of vasodilator substances, and ACE. Simultaneous inhibition of neutral endopeptidase and ACE enhances peptides with vasodilatory properties, such as atrial natriuretic peptide, brain natriuretic peptide, and C type natriuretic peptide, and inhibits the production of the vasoconstrictor angiotensin II. The properties of these natriuretic peptides and their function in the regulation of the cardiovascular system are reviewed. Clinical results with vasopeptidase inhibitors and other therapeutic modalities based on the natriuretic peptide system in the treatment of hypertension and heart failure are also reviewed. Omapatrilat, an agent that has been recently evaluated, is an effective agent in lowering diastolic and particularly systolic blood pressures in a broad range of populations and may have beneficial effects beyond blood pressure control. The mechanism of action of omapatrilat and clinical results with this compound are discussed. (c)2000 by Le Jacq Communications, Inc.
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PMID:Vasopeptidase Inhibition: A New Approach to the Management of Cardiovascular Disease. 1141 31

There is now substantial evidence supporting a role of the natriuretic peptides as a major defence mechanism against excess salt and water retention and high blood pressure. Because of this there has been considerable interest in the therapeutic potential of the natriuretic peptide system. Several approaches have been explored including the use of native peptides, the development of natriuretic peptides mimetics and targetting of endogenous clearance of natriuretic peptides. While ANP and BNP administration may be valuable in some circumstances, however, the limitations of the use of peptides especially for long-term treatment are well apparent. In view of this, considerable effort has been devoted to the development of orally active agents to enhance endogenous natriuretic peptides through inhibition of breakdown by neutral endopeptidase. This research has now led to the vasopeptidase inhibitors - dual inhibitors of both endopeptidase and angiotensin converting enzyme. These agents clearly provide a novel approach to enhance endogenous natriuretic peptide function on a background of reduced angiotensin II activity and may lead to an important advance in the treatment of hypertension and of conditions associated with overt salt and water overload.
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PMID:Atrial natriuretic peptide mimetics and vasopeptidase inhibitors. 1147 32

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.
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PMID:Efficacy and safety of omapatrilat with hydrochlorothiazide for the treatment of hypertension in subjects nonresponsive to hydrochlorothiazide alone. 1149 95

Omapatrilat, a novel vasopeptidase inhibitor, is a highly potent and selective inhibitor of neutral endopeptidase and angiotensin-converting enzyme; its therapeutic potential is being investigated for treatment of hypertension and heart failure. In the present study, the safety, tolerability, and hemodynamic effects of single oral doses of omapatrilat (1 to 50 mg) are compared with placebo in patients with heart failure. Patients with heart failure (New York Heart Association functional class II to IV) and a resting left ventricular ejection fraction < or = 40% were enrolled in a double-blind, placebo-controlled, sequential-panel study of single doses of omapatrilat of 1, 2.5, 5, 10, 25, or 50 mg, followed by hemodynamic assessment for 24 hours. At 4 to 6 hours after dosing, the 25- and 50-mg doses of omapatrilat, compared with placebo, reduced mean pulmonary capillary wedge pressure by approximately 6 mm Hg from 20 and 23 mm Hg at baseline to 14 and 16 mm Hg. The 50-mg omapatrilat dose maintained this effect compared with placebo with an approximately 2.5-mm Hg reduction in mean pulmonary capillary wedge pressure at 24 hours. Omapatrilat improved additional hemodynamic parameters, including cardiac index, systemic vascular resistance, stroke volume index, and mean arterial pressure. Additionally, by 2 hours after dosing with omapatrilat 25 and 50 mg, a trend in peak increases from baseline in plasma atrial natriuretic peptide (twofold) and cyclic guanosine monophosphate (nearly twofold) was observed. Moreover, omapatrilat was well tolerated. Thus, omapatrilat administered orally to patients with heart failure was safe and well tolerated and resulted in improved hemodynamic performance.
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PMID:Effects of omapatrilat on hemodynamics and safety in patients with heart failure. 1156 90

Adrenomedullin and endothelin are novel peptides that are produced in the blood vessel wall and have contrasting biologic actions. Both may play a pathophysiological role in atherosclerosis and chronic heart failure. It has also been suggested that both peptides may be metabolized by neutral endopeptidase and that pharmacological manipulation of this enzyme may be of therapeutic interest. We investigated the effect of thiorphan, a neutral endopeptidase inhibitor, on the vasodilator response to adrenomedullin and the vasoconstrictor response to endothelin in small resistance arteries taken from patients with heart failure caused by coronary heart disease. Small resistance arteries were dissected from gluteal biopsy samples and studied with wire myography. Thiorphan did not affect the vasodilator response to adrenomedullin in arteries preconstricted with norepinephrine. Maximal responses were 66% (SD 11%) and 72% (8%) in the absence and presence of thiorphan, respectively (n=8). The vasoconstrictor response to endothelin was also unaffected. The maximum vasoconstrictor responses in the absence and presence of thiorphan were 152% (11%) and 132% (12%), respectively (n=8). The values of corresponding -log concentrations of agonist required to effect a 50% response (pD(2)) were 8.52 (0.11) and 8.64 (0.15), respectively. We showed that the inhibition of neutral endopeptidase does not augment the vasodilator and vasoconstrictor activities of adrenomedullin and endothelin, respectively, in small resistance arteries from patients with chronic heart failure. This suggests that neutral endopeptidase inhibition, as a therapeutic strategy, will enhance neither the potentially desirable vascular actions of adrenomedullin nor the potentially unfavorable vascular effects of endothelin-1 in human cardiovascular disease states.
Hypertension 2001 Sep
PMID:Effect of neutral endopeptidase inhibition on the actions of adrenomedullin and endothelin-1 in resistance arteries from patients with chronic heart failure. 1156 14

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.
Hypertension 2001 Sep
PMID:Omapatrilat in subtotal nephrectomy-salt hypertension: role of calcitonin gene-related peptide. 1156 59

The preferred initial agents for the treatment of high blood pressure are low-dose thiazide diuretics, beta blockers, calcium antagonists, and angiotensin-converting enzyme (ACE) inhibitors. In high-risk patients, including those with diabetes, renal insufficiency, left ventricular dysfunction, and atherosclerosis, ACE inhibitors may have specific benefit in reducing cardiovascular morbidity and mortality. Omapatrilat, the prototypical vasopeptidase inhibitor, inhibits not only ACE but also neutral endopeptidase. Like conventional ACE inhibitors, omapatrilat causes extracellular volume reduction and vasodilatation; moreover, it increases levels of atrial and brain natriuretic peptides and bradykinin. Effective blood pressure control, especially in the high-risk patient, usually necessitates combination therapy. A recent study randomized 274 subjects with mild to severe hypertension (stages 1-3 diastolic blood pressure elevation) and confirmed the benefits of omapatrilat combined with hydrochlorothiazide in patients not controlled on hydrochlorothiazide alone. The frequencies of adverse events, serious adverse events, and discontinuation attributed to adverse events were similar for omapatrilat and placebo. Furthermore, there were no clinically significant changes in serum creatinine, potassium, or other laboratory parameters. Adding omapatrilat to the background of hydrochlorothiazide treatment produced statistically significant additional reductions in trough diastolic and systolic blood pressures at weeks 4 and 8.
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PMID:Advances in antihypertensive combination therapy: benefits of low-dose thiazide diuretics in conjunction with omapatrilat, a vasopeptidase inhibitor. 1158 9

The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure. The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) of myocardial cell origin, and C-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sodium/water balance, and, in turn, decrease peripheral vascular resistance and blood pressure and improve local blood flow. Within the blood vessel wall, this leads to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and increased local levels of bradykinin (and, in turn, nitric oxide) and natriuretic peptides. Preliminary clinical experiences with vasopeptidase inhibitors are encouraging. Thus, the combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure.
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PMID:Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease? 1159 26


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