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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vasopeptidase inhibitor omapatrilat inhibits both neutral endopeptidase and angiotensin-converting enzyme (ACE). The in vitro and in vivo inhibitory potency of omapatrilat and the specific ACE inhibitor fosinopril toward the 2 active sites of ACE (called N- and C-domains) was investigated with the use of 3 substrates: angiotensin I, which is equally cleaved by the 2 ACE domains; hippuryl-histidyl-leucine, specific synthetic substrate of the C-domain in high- salt conditions; and a newly synthesized specific substrate of the N-domain designed by acetylating the lysine residue of AcSDKP. In vitro, omapatrilat was 5 times more potent than fosinoprilat in inhibiting angiotensin I hydrolysis. Omapatrilat inhibited similarly both N- and C-domain hydrolysis, whereas fosinoprilat was slightly more specific for the N-domain. The in vivo selective inhibitory potency of single oral doses of 10 mg omapatrilat and 20 mg fosinopril were investigated in a double-blind, placebo-controlled, cross-over study in 9 mildly sodium-depleted normotensive subjects. In accordance with the in vitro results, fosinopril appeared to be more specific for the N-domain than the C-domain in vivo, since plasma and urine AcSDKP concentrations were significantly higher than those observed with omapatrilat. This study shows that it is possible to assess separately in vitro and in vivo the selectivity of ACE or ACE/neutral endopeptidase inhibitors. A differential selectivity may explain some peculiar properties observed with some ACE inhibitors.
Hypertension 2000 Jun
PMID:In vitro and in vivo inhibition of the 2 active sites of ACE by omapatrilat, a vasopeptidase inhibitor. 1085 68

We evaluated whether a novel dual inhibitor of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), SA7060, (S)-2-[3-[(S)-2-(butoxycarbonyl)-2-hydroxyethyl]-3-isobutylureido] -3-(2-naphtyl) propionic acid, prevents deoxycorticosterone acetate (DOCA)-salt-induced hypertension and related organ damage, such as cardiovascular hypertrophy, renal dysfunction and renal tissue injury in rats. The effectiveness was compared with candoxatril and enalapril, which are a selective NEP and ACE inhibitor, respectively. During DOCA-salt treatment for 4 weeks, the rats were given SA7060, candoxatril, enalapril or vehicle, once daily by gavage. The 4-weeks treatment with DOCA and salt produced progressive increases in systolic blood pressure. Daily administration of SA7060, candoxatril or enalapril significantly suppressed the development of hypertension induced by DOCA and salt, although the effect of enalapril was less potent at 4-weeks of the treatment period. In vehicle-treated DOCA-salt rats, decreases in creatinine clearance and increases in urinary excretion of protein and blood urea nitrogen were observed. This functional damage was improved most efficiently by the treatment with SA7060. There were significant increases in urinary excretions of atrial natriuretic peptide and cyclic GMP in SA7060- or candoxatril-treated animals. Histopathological examination of the kidney in DOCA-salt rats revealed tubular, glomerular and vascular lesions, all of which were improved in animals given SA7060 or candoxatril. When the vascular hypertrophy of the aorta was evaluated, there were significant increases in wall thickness, wall area and the wall-to-lumen ratio in vehicle-treated DOCA-salt rats compared with the sham rats. The development of vascular hypertrophy was suppressed by the treatment with SA7060, candoxatril or enalapril. Our findings indicate that SA7060 efficiently prevents DOCA-salt-induced hypertension and related tissue injury, mainly by inhibiting NEP. Thus, SA7060 may be useful for treatment of both renin-dependent and renin-independent hypertensive subjects, although further studies examining efficiency in a renin-dependent hypertensive model are needed.
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PMID:Effects of SA7060, a novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme, on deoxycorticosterone acetate-salt-induced hypertension in rats. 1091 59

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.
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PMID:Vasopeptidase inhibition: a new direction in cardiovascular treatment. 1098 Nov 74

We exposed 63 adult spontaneously hypertensive rats (SHR) and 10 (mRen-2)27 transgenic hypertensive rats to a 12-day regimen of either a normal diet (0.5%) or a low-salt diet (0.05%) to evaluate the hypothesis that the vasodepressor heptapeptide, angiotensin-(1-7) [Ang-(1-7)], buffers the pressor effects of angiotensin II during endogenous stimulation of the renin-angiotensin system. Catheters were inserted into a carotid artery and jugular vein under light anesthesia the day before the experiment. Separate groups of conscious instrumented SHR were given short-term infusions of an affinity-purified monoclonal Ang-(1-7) antibody or the neprilysin inhibitor SCH 39370. In addition, SHR and (mRen-2)27 rats were given the Ang-(1-7) receptor antagonist [D-Ala(7)]Ang-(1-7). Exposure to the low-salt diet increased plasma renin activity and elevated plasma levels of angiotensin I and angiotensin II in SHR by 81% and 68%, respectively, above values determined in SHR fed a normal salt diet. Concentrations of angiotensin I and angiotensin II were also higher in the kidney of salt-depleted SHR, whereas plasma and renal tissue levels of Ang-(1-7) were unchanged. Infusion of the Ang-(1-7) antibody produced dose-dependent pressor and tachycardic responses in salt-depleted SHR but no effect in SHR maintained on a normal-salt diet. A comparable cardiovascular response was produced in salt-depleted SHR given either SCH 39370 or [D-Ala(7)]Ang-(1-7). These agents had negligible effects on SHR fed a normal-salt diet. Blockade of Ang-(1-7) receptors produced a similar cardiovascular response in (mRen-2)27 transgenic hypertensive rats fed a low-salt diet. Injections of the heat-inactivated antibody or the subsequent infusion of the antibody to rats given [D-Ala(7)]Ang-(1-7) produced no additional effects. The data support the hypothesis that the hemodynamic effects of neurohormonal activation after salt restriction stimulate a tonic depressor action of Ang-(1-7).
Hypertension 2000 Sep
PMID:Contribution of angiotensin-(1-7) to blood pressure regulation in salt-depleted hypertensive rats. 1098 75

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.
Hypertension 2000 Oct
PMID:Beneficial renal and hemodynamic effects of omapatrilat in mild and severe heart failure. 1104 Feb 30

1. Cardiac remodelling is a fundamental response to hypertension, myocardial infarction and chronic heart failure, and involves cardiac fibroblast proliferation and production of extracellular matrix components such as collagen. The present study was performed to examine the role of endogenous atrial natriuretic peptide (ANP) as a possible paracrine factor for cardiac fibroblasts, and to examine the effects of three neutral endopeptidase (NEP) inhibitors, thiorphan, phosphoramidon and ONO-BB-039-02 (ONO-BB) on endogenous ANP-induced changes in collagen synthesis by cultured neonatal rat cardiac fibroblasts. 2. Each NEP inhibitor singly had no significant effect on collagen synthesis by cardiac fibroblasts, except for maximum concentration (10(-3) M) of thiorphan. 3. Exogenous ANP inhibited collagen synthesis in a concentration-dependent manner (10(-8) - 10(-6) M). Thiorphan (10(-4) and 10(-3) M) and phosphoramidon (10(-5) and 10(-4) M) enhanced the ANP (10(-7) M)-induced decrease in collagen synthesis. ONO-BB (10(-5) and 10(-4) M) slightly enhanced the ANP-induced decrease in collagen synthesis. 4. Myocyte-conditioned medium (MC-CM), as well as exogenous ANP, inhibited collagen synthesis dose-dependently. The decrease in collagen synthesis at 100% MC-CM was augmented by thiorphan (10(-3) M), phosphoramidon (10(-4) M) and ONO-BB (10(-4) M). 5. HS-142-1, a natriuretic peptide receptor antagonist, significantly reduced the MC-CM plus thiorphan- and MC-CM plus ONO-BB-induced decrease in collagen synthesis, by 92 and 62%, respectively and showed a tendency to attenuate the MC-CM plus phosphoramidon-induced decrease in collagen synthesis by 40%. 6. Our observations suggested that endogenous ANP released from cardiomyocytes inhibited collagen synthesis as a paracrine factor and that NEP inhibitors enhanced the activity of this peptide in cardiac fibroblasts.
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PMID:Effect of neutral endopeptidase inhibitor on endogenous atrial natriuretic peptide as a paracrine factor in cultured cardiac fibroblasts. 1108 29

S21402 is a vasopeptidase inhibitor that simultaneously inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). This study determined whether chronic treatment with S21402 produced different effects on sodium and water excretion, hormonal parameters, and cardiovascular structure compared with selective inhibition of ACE and NEP in a rat model of myocardial infarction-induced congestive heart failure (CHF). CHF rats received the vasopeptidase inhibitor (S21402, 100 mg. kg(-1). d(-1)), an ACE inhibitor (captopril, 50 mg. kg(-1). d(-1)), a NEP inhibitor (SCH42495, 60 mg. kg(-1). d(-1)), or vehicle for 4 weeks. S21402 alone caused a diuresis and natriuresis (P<0.01) in CHF. After 4 weeks, blood pressure was lowered by captopril but not other treatments (P<0.01). Both S21402 and captopril increased plasma renin activity (P<0.01), all treatment lowered plasma aldosterone (P<0.05) and plasma natriuretic peptide levels were unchanged. In the kidney, S21402 inhibited NEP and ACE (P<0.01), SCH42495 inhibited NEP (P<0.01), and captopril inhibited ACE (P<0.01). Heart mass was reduced by all active treatments; captopril reduced left ventricular mass (P<0.01), SCH42495 reduced right ventricular mass (P<0.01), and S21402 decreased left (P<0.05) and right ventricular mass (P<0.01), atrial mass (P<0.05), and lung mass (P<0.01). In CHF, vasopeptidase inhibition with S21402 produces effects that differ from those of selective NEP or ACE inhibition. S21402 improved sodium and water excretion, reduced pulmonary congestion, and attenuated both right and left ventricular remodeling. These effects, which occurred in the absence of any hypotensive action, suggest that S21402 may offer several advantages over ACE inhibition alone in the treatment of heart failure.
Hypertension 2000 Dec
PMID:Beneficial renal and cardiac effects of vasopeptidase inhibition with S21402 in heart failure. 1111 33

-To determine whether natriuretic peptides in addition to the renin-angiotensin system are involved in functional and structural vascular changes in salt-sensitive hypertension, we compared equipotent hypotensive treatment with the dual neutral endopeptidase/ACE inhibitor omapatrilat (35 mg. kg(-1). d(-1)) or the ACE inhibitor captopril (100 mg. kg(-1). d(-1)). The reactivity and geometry of mesenteric resistance arteries from Dahl salt-sensitive rats were studied in vitro under perfused and pressurized conditions. Chronic salt administration increased systolic blood pressure by 57+/-4 mm Hg, whereas concentrations of atrial natriuretic peptide were reduced in heart and in plasma (P:<0.05). In addition, the medial cross-sectional area of small mesenteric arteries was increased and endothelium-dependent relaxation in response to acetylcholine and contraction in response to endothelin-1 were impaired in the mesenteric arteries of salt-sensitive rats on a high-salt diet (P:<0.05). Concomitant treatment with either omapatrilat or captopril reduced the increase in systolic blood pressure and hypertrophic remodeling to a similar degree (P:<0.05) but affected plasma and cardiac atrial natriuretic peptide levels differently (P:<0.05). In addition, omapatrilat normalized endothelium-dependent relaxations to a greater extent than captopril (P:<0.05). Furthermore, vasopeptidase inhibition increased cGMP levels compared with captopril (P:<0.05). Contractions to endothelin-1 were normalized by either antihypertensive drug. These results suggest that in the Dahl rat, with similar reductions in systolic blood pressure, omapatrilat is superior to captopril in preventing impaired endothelial function in small resistance arteries. Thus, vasopeptidase inhibition may have therapeutic advantages of the prevention of changes in vascular function and structure in salt-sensitive forms of hypertension.
Hypertension 2001 Jan
PMID:Vasopeptidase Inhibition Prevents Endothelial Dysfunction of Resistance Arteries in Salt-Sensitive Hypertension in Comparison With Single ACE Inhibition. 1120 52

Endothelial dysfunction is associated with hypertension, hypercholesterolemia, and heart failure. We tested the hypothesis that spontaneously diabetic Goto-Kakizaki (GK) rats, a model for type 2 diabetes, exhibit endothelial dysfunction. Rats also received a high-sodium diet (6% NaCl [wt/wt]) and chronic angiotensin type 1 (AT(1)) receptor blockade (10 mg/kg PO valsartan for 8 weeks). Compared with age-matched nondiabetic Wistar control rats, GK rats had higher blood glucose levels (9.3+/-0.5 versus 6.9+/-0.2 mmol/L for control rats), 2.7-fold higher serum insulin levels, and impaired glucose tolerance (all P<0.05). Telemetry-measured mean blood pressure was 15 mm Hg higher in GK rats (P<0.01) compared with control rats, whereas heart rates were not different. Heart weight- and kidney weight-to-body weight ratios were higher in GK rats (P<0.05), and 24-hour albuminuria was increased 50%. Endothelium-mediated relaxation of noradrenaline-precontracted mesenteric arterial rings by acetylcholine was impaired compared with the control condition (P<0.05), whereas the sodium nitroprusside-induced relaxation was similar. Preincubation of the arterial rings with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester and the cyclooxygenase inhibitor diclofenac inhibited relaxations to acetylcholine almost completely in GK rats but not in Wistar rats, suggesting that endothelial dysfunction can be in part attributed to reduced relaxation via arterial K(+) channels. Perivascular monocyte/macrophage infiltration and intercellular adhesion molecule-1 overexpression were observed in GK rat kidneys. A high-sodium diet increased blood pressure by 24 mm Hg and 24-hour albuminuria by 350%, induced cardiac hypertrophy, impaired endothelium-dependent relaxation further, and aggravated inflammation (all P<0.05). The serum level of 8-isoprostaglandin F(2alpha), a vasoconstrictor and antinatriuretic arachidonic acid metabolite produced by oxidative stress, was increased 400% in GK rats on a high-sodium diet. Valsartan decreased blood pressure in rats fed a low-sodium diet and prevented the inflammatory response. In rats fed a high-sodium diet, valsartan did not decrease blood pressure or improve endothelial dysfunction but protected against albuminuria, inflammation, and oxidative stress. As measured by quantitative autoradiography, AT(1) receptor expression in the medulla was decreased in GK compared with Wistar rats, whereas cortical AT(1) receptor expression, medullary and cortical angiotensin type 2 (AT(2)) receptor expressions, and adrenal ACE and neutral endopeptidase expressions were unchanged. A high-sodium diet did not influence renal AT(1), AT(2), ACE, or neutral endopeptidase expressions. In valsartan-treated GK rats, the cortical and medullary AT(1) receptor expressions were decreased in the presence and absence of a high-sodium diet. A high-sodium diet increased plasma brain natriuretic peptide concentrations in presence and absence of valsartan treatment. We conclude that hypertension in GK rats is salt sensitive and associated with endothelial dysfunction and perivascular inflammation. AT(1) receptor blockade ameliorates inflammation during a low-sodium diet and partially protects against salt-induced vascular damage by blood pressure-independent mechanisms.
Hypertension 2001 Feb
PMID:Endothelial dysfunction and salt-sensitive hypertension in spontaneously diabetic Goto-Kakizaki rats. 1123 Mar 14

The development of pharmacological agents that block the renin-angiotensin system (RAS) specifically have helped to define all the components of the system and their contribution to blood-pressure control and to the pathogenesis of hypertension, congestive heart failure and chronic renal failure. The angiotensin converting-enzyme inhibitors (ACEi) are among all available drugs that interfere with the RAS, the most efficient, so far, in the treatment of several cardiovascular diseases, with comfortable posologic schemes and an acceptable safety profile. The most important difference between them are more related to pharmacokinetic profile rather than to pharmacodynamic characteristics. With the use of ACEi the interference with other neurohumoral systems is unavoidable and the controversy has been pharmacologically and clinically installed. With the advent of oral selective AT1 angiotensin II receptor blockers (ARB) the pharmacological interference became eventually much more selective. Their antihypertensive efficacy is identical and their tolerability is better than that showed by ACEi. The ARBs differ mainly in their pharmacokinetics and in their binding capacity to the AT1 angiotensin receptor. The results of several ongoing clinical trials will show if the ARBs as ACEi will be capable to protect target-organs and to promote a significant reduction in cardiovascular morbility and mortality. In parallel there is an intense experimental and clinical research with other groups of drugs which also markedly interfere with RAS: renin inhibitors, chymase inhibitors and simultaneous inhibitors of vasopeptidases (ACE, endothelin converting-enzyme, neutral endopeptidase). From the pharmacological point of view, it is now possible to block effectively RAS with some relevant clinical results that will be certainly widen in the near future.
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PMID:[Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor antagonists. Pharmacologic features]. 1130 8


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