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)

SCH 34826, i.e., (S)-N-(N-(2,2[(2,2-dimethyl-1,3-dioxolan-4- yl)methoxy]-2-oxo-1-(phenyl-methyl)ethyl)-phenylalanyl)-beta-alanine, is a potent and selective inhibitor of neutral endopeptidase 24.11 (NEP), an enzyme that degrades the atrial natriuretic peptide (ANP). The effects of SCH 34826 on hypertension and left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHRs) were evaluated following 1 month of treatment by measuring the blood pressure, cardiac weight, and left ventricular fibrosis. Adult SHRs were treated with SCH 34826 at 10, 30, or 100 mg/kg given orally twice daily or with vehicle. The systolic blood pressure (SBP) and heart rate (HR) were recorded weekly by the tail-cuff method. Cardiac structural damage was determined by morphometric analysis. Over the dose range examined, the drug produced no significant changes in either blood pressure or heart rate. Despite the lack of antihypertensive activity, SCH 34826 at 100 mg/kg reduced both the cardiac mass (-10%) and the amount of fibrotic tissue present in the left ventricle (-42%). These data indicate that chronic inhibition of NEP by SCH 34826 interacts with mechanisms underlying myocardial hypertrophy and cardiac remodeling.
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PMID:The neutral endopeptidase inhibitor, SCH 34826, reduces left ventricular hypertrophy in spontaneously hypertensive rats. 127 98

A new highly active atrial natriuretic peptide (haANP), synthesized by a solid phase technique, was given by intravenous infusion to 20 patients with severe pregnancy-induced hypertension (PIH) and the curative result of haANP was observed. Compared with basal values, supine systolic and diastolic BP was lowered significantly (P < 0.01), which may be related to the specific receptor of hANP and inhibition of renin-angiotensin-aldosterone system (RAAS). The haANP was found to possess significant effects of antispasm, detumescence and reducing proteinuria, probably by repairing mildly injured glomerulae, strong effects of diuresis and improving heart function with no side effects. Auto-antibody of hANP was found in patients with severe PIH, which affected the function of target cells of highly concentrated endogenous hANP. This auto-antibody might be one of the causes for PIH.
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PMID:Curative effects of highly active atrial natriuretic peptide on severe pregnancy-induced hypertension. 129 57

In 19 patients with unilateral renal artery stenosis and subsequent renovascular hypertension plasma renin activity (PRA), plasma concentrations of atrial natriuretic peptide (ANP), erythropoietin (Epo), H+ and HCO3-, as well as pO2 and pCO2 were assessed in renal venous blood of the 'ischaemic' and normally perfused kidney, both in arterial blood and in the inferior vena cava distally from the orifices of the renal veins. PRA and ANP were significantly elevated in venous blood of the ischaemic kidney as compared with the normally perfused kidney. In contrast to PRA and ANP, plasma concentrations of Epo were similar in blood withdrawn at all vascular sites. pO2 and pCO2, as well as blood H+ and HCO3- concentrations in venous blood of the ischaemic kidney were of the same magnitude as of the normally perfused kidney. From the results presented in this paper it follows that (i) in contrast to plasma renin activity and ANP, unilateral renal 'ischaemia' does not influence plasma concentrations of Epo in renal venous blood, and (ii) chronic haemodynamic alterations do not seem to influence Epo secretion by the kidneys.
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PMID:Plasma erythropoietin concentrations in renal venous blood of patients with unilateral renovascular hypertension. 131 93

In summary, we have seen that endothelins are potent cardiovascular and renal regulatory peptides. Cardiovascular regulation by endothelin requires complex spatial and temporal regulation of endothelin gene expression and the coordinated interplay of numerous signaling pathways. Although the precise physiologic role for endothelin peptides in the cardiovascular and renal systems remains uncertain, two general models can be proposed, as follows. (1) Endothelin appears to act as an autocrine or paracrine hormone involved in long-term (hours to days) regulation of cardiovascular and renal function in normal physiology. Similar regulation occurs in response to other cardiovascular hormones such as angiotensin II, atrial natriuretic peptides, and catecholamines. In this respect it is noteworthy that endothelin also interacts with other hormonal systems that affect cardiovascular status, such as renin-aldosterone and atrial natriuretic peptide (see references 9, 161, 162, and 213-217). (2) Endothelin might also function as a proinflammatory peptide, being locally produced at sites of vascular damage and injury. The fact that endothelin secretion is stimulated by cytokines, growth factors, and transforming growth factor beta is consistent with this role. In addition, the mitogenic actions of endothelin could contribute to vascular remodeling in the inflammatory response. A similar, defensive role has been proposed for other regulatory peptides. Endothelin has also been implicated in the pathogenesis of numerous disorders such as hypertension (see references 28, 56, 168, 184, and 224 through 226), cerebral and myocardial vasospasm (see references 180, 223, and 227 through 233), acute renal failure, and cyclosporine nephrotoxicity. It is clear that the development of specific ECE inhibitors and endothelin receptor antagonists will enable definitive experiments addressing the role of endothelin in normal physiology and the putative role of endothelin in the development of hypertension and other cardiovascular disorders. Further identification and biochemical analysis of signaling networks evoked by endothelin, in conjunction with physiologic studies, should provide a detailed understanding of the complex biologic events regulated by endothelin peptides.
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PMID:The molecular mechanisms of cardiovascular and renal regulation by endothelin peptides. 131 1

We have previously demonstrated that dietary NaCl supplementation is associated with increased circulating atrial natriuretic peptide (ANP) levels in Wistar-Kyoto (WKY) rats but not in spontaneously hypertensive rats (SHR), and that replacement with exogenous ANP prevents NaCl-sensitive hypertension in NaCl-sensitive SHR (SHR-S). The current study tested the hypothesis that chronic administration of the neutral endopeptidase (NEP) inhibitor Sch 34826 prevents NaCl sensitive hypertension in SHR-S by increasing endogenous ANP. Male SHR-S received Sch 34826 (90 mg/kg/day) or vehicle by gavage for 4 weeks beginning immediately before the initiation of 1% or 8% NaCl diets at age 7 weeks. Sch 34826 prevented the increase in arterial pressure in response to 8% NaCl in SHR-S, but had no effect on blood pressure in 1% NaCl fed SHR-S; plasma ANP levels were increased by 63 and 68% in the 1% and 8% NaCl groups, respectively, in response to Sch 34826. To examine the mechanism(s) of the antihypertensive effect of Sch 34826 in NaCl-supplemented SHR-S, a single dose (90 mg/kg) of Sch 34826 or vehicle was administered by gavage to SHR-S that had consumed 1% or 8% NaCl diets for 3 weeks. Sch 34826 abolished the NaCl-induced increase in blood pressure 3 h after treatment in 8% NaCl fed SHR-S, but had no effect in SHR-S fed the 1% NaCl diet. This effect was associated with increased urine volume and urinary sodium, ANP, and cyclic GMP in 8% NaCl fed SHR-S.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of acute and chronic blockade of neutral endopeptidase with Sch 34826 on NaCl-sensitive hypertension in spontaneously hypertensive rats. 131 53

To study the antihypertensive effects of a new synthetic highly active atrial natriuretic peptide (haANP), the effects were observed in patients with moderate and severe pregnancy-induced hypertension (PIH). There were significant decreases in blood pressure (BP) for 10 min after haANP infusion (from 20.46 +/- 1.04/14.15 +/- 1.59 kPa to 18.17 +/- 0.60/11.08 +/- 1.36 kpa; P less than 0.05). 90 min after haANP infusion, BP decrease was the lowest (to 16.00 +/- 1.21/10.5 +/- 0.71 kPa; P less than 0.01), while plasma ANP levels increased 11 folds (from 47.5 +/- 5.5 ng/L to 525.4 +/- 15.6 ng/L). The effects continued for 300 minutes. Antihypertensive effects of magnesium sulphate were relatively relaxed (compared with those of haANP). The results showed strong and rapid antihypertensive effects of haANP. We found that mean RA and ALD levels were significantly decreased after haANP.
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PMID:[Antihypertensive effects of highly active atrial natriuretic peptide (haANP) infusion in patients with pregnancy-induced hypertension]. 132 34

1. Disturbances of sodium and water homoeostasis may contribute to the close association between diabetes, hypertension and proteinuria. We therefore studied the patterns of two natriuretic hormones, plasma atrial natriuretic peptide and urinary dopamine, in 165 Chinese patients with non-insulin-dependent diabetes mellitus controlled by diet or oral hypoglycaemic agents on two occasions over a 6-week period. Patients were divided into three groups based on the mean value of two 24h urinary albumin excretion measurements. In group 1, 88 patients had normoalbuminuria (urinary albumin excretion < or = 30 mg/day), in group 2, 48 patients had microalbuminuria (urinary albumin excretion between 30 and 300 mg/day), and in group 3, 29 patients had macroalbuminuria (urinary albumin excretion > or = 300 mg/day). 2. The supine systolic blood pressure (mean +/- SD) was higher in patients with abnormal albuminuria (group 1: 140.9 +/- 27.4 mmHg; group 2: 158.1 +/- 26.4 mmHg; group 3: 166.7 +/- 23.9 mmHg; F = 13.1, P < 0.001, analysis of variance). Urinary sodium output was similar in these three groups of patients. The geometric means (anti-logarithm of 95% confidence interval logarithm) of plasma atrial natriuretic peptide concentrations increased with increasing proteinuria [group 1: 33.3 (29.9-37.1) pg/ml; group 2: 39.1 (34.2-44.6) pg/ml; group 3: 50 (38.6-54.7) pg/ml; F = 4.24, P < 0.01; analysis of variance], whereas those of urinary dopamine output were related inversely to proteinuria [group 1: 1291.7 (1167.2-1437.0) nmol/day; group 2: 1142.3 (975.9-1337.2) nmol/day; group 3: 982.7 (775.7-1245) nmol/day; F = 3.10, P < 0.05, analysis of variance].(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Atrial natriuretic peptide and urinary dopamine output in non-insulin-dependent diabetes mellitus. 132 42

Modification of dietary fatty acid (FA) has been shown to affect the incidence of hypertension and coronary artery disease. We studied whether these effects involve changes in the receptor characteristics of vasoactive substance. Characteristics of atrial natriuretic peptide (ANP) receptors were examined in glomeruli isolated from rats fed a diet containing 5% in weight omega 6, 5% omega 3, 20% omega 6, 20% omega 3 polyunsaturated FA or 20% saturated FA (SFA) for greater than 4 weeks. The FA composition of phospholipids in isolated glomeruli showed an elevation in 20:4 omega 6 (arachidonic acid, AA) in 5% omega 6, 20% omega 6 and 20% SFA, and elevations in 20:5 omega 3 (eicosapentaenoic acid, EPA) in 5% omega 3 and 20% omega 3 groups. The radioligand binding study revealed: (1) in 20% FA group, receptor density (Ro, fmol/mg prot) of ANP was significantly decreased compared to 5% group (262 +/- 13, n = 8 to 120 +/- 13, n = 12) without changes in equilibrium dissociation constant (KD), (2) among high FA (20%) groups, type of FA was essential for determining Ro; higher omega 6 was associated with a lower ANP Ro (177 +/- 11 vs. 103 +/- 3 fmol/mg prot, P less than 0.05) and KD (0.43 +/- .04 vs. 0.27 +/- .02 nM, P less than 0.05). To examine whether the alteration in receptor characteristics is mediated by FA, effects of FA were examined in vitro. In cultured mesangial cells, AA, but not EPA, decreased Ro of ANP receptors (48.7 +/- 4.8% of control, P less than 0.05) without affecting KD.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dietary fatty acid modulates glomerular atrial natriuretic peptide receptor. 132 48

Two metallopeptidases, angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) are involved respectively in the release of angiotensin II which is a vasoconstrictor, and in the metabolism of atrial natriuretic peptide which is diuretic and bradykinin which is a vasodilatator. The dual inhibition of these two peptidases represents a new way to regulate the blood pressure in various cardiovascular diseases. Taking into account the mechanism of action of metallopeptidases and the substrate specificity of ACE and NEP, dual inhibitors corresponding to the general formula HS-CH2-CH(R1)CONH-CH(R2)COOH and HS-CH(R1)CONH-CH(R2)CONH-CH(R3)COOH and having inhibitory potencies on each enzyme in the nanomolar range were designed. The most efficient inhibitors have been transformed into lipophilic prodrugs which were found to be active after oral administration. These compounds have been tested on an experimental model of hypertension in rats and, as expected, have been shown to be both diuretic (NEP inhibition) and hypotensive (ACE inhibition).
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PMID:[Dual inhibition of converting enzyme and neutral endopeptidase: a research new way in the field of hypertension]. 133 91

Diabetes mellitus (DM) is frequently associated with hypertension for which an independent pathomechanism has been suggested. We studied 26 patients with insulin-dependent (IDDM) and 18 patients with non-insulin-dependent (NIDDM) uncomplicated DM; all patients were in metabolic balance and none of them had hypertension. Exchangeable body sodium (NaE was estimated by isotope dilution, using appr. 1.1 Mbq 24NA. In a subset of 8 IDDM and 8 NIDDM patients atrial natriuretic peptide (ANP) plasma concentration was determined prior to and after the infusion of 2000 ml physiological saline over 2 hr. NaE was significantly increased both in IDDM and NIDDM patients (104.4 +/- 11.4% and 109.9 +/- 8.0% of the normal value for healthy subjects of identical body surface area; p < 0.05 and < 0.001 resp.). Mean blood pressure (MBP) correlated significantly with NaE in both groups (r = 0.364 and r = 0.520; p < 0.05 and < 0.025, resp.) but not in healthy control subjects (r = 0.112; N.S.). Resting ANP levels were not significantly different in IDDM (34.9 +/- 11.3 pg/ml), NIDDM (42.6 +/- 11.7 pg/ml) or control subjects (40.9 +/- 17.2 pg/ml) however the infusion of saline resulted in a significantly greater increase of plasma ANP in the NIDDM patients (to 82.9 +/- 43.2 pg/ml; P < 0.01) than in the controls (55.6 +/- 23.7 pg/ml; P < 0.01) which was associated with a significantly less increase in sodium excretion (UNAV) in the NIDDM patients (+86% vs. 3170%; P < 0.02) indicating down-regulation of ANP receptors in the kidney of NIDDM patients.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Body sodium, atrial natriuretic peptide and blood pressure in diabetes mellitus. 134 Jun 60


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