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

Depressor and renal activities of atrial natriuretic factor-(99-126) were determined in conscious, unrestrained spontaneously hypertensive rats treated with a neutral endopeptidase inhibitor, SQ 29,072 (7-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]heptanoic acid). SQ 29,072 (100 mumol/kg i.v.) prolonged the transient depressor effects of the peptide for as long as 2 hours. During the first hour after 3, 10, and 30 nmol/kg atrial natriuretic factor, urinary excretion of cyclic 3'5' guanosine monophosphate was significantly increased by 9.2 +/- 3.4, 13.0 +/- 2.2, and 12.7 +/- 4.2 nmol/kg/hr, respectively, in vehicle-treated rats and by 26.9 +/- 7.9, 52.1 +/- 11.1, and 46.4 +/- 12.2 nmol/kg/hr, respectively, in rats given 100 mumol/kg SQ 29,072. During the first hour after 3 and 10 nmol/kg atrial natriuretic factor-(99-126), the sodium loss was 161 +/- 56 and 139 +/- 42 mueq/kg/hr in vehicle-treated rats and was significantly greater (694 +/- 316 and 1,038 +/- 135 mueq/kg/hr) in rats given 100 mumol/kg SQ 29,072. After administration of 3, 10, and 30 mumol/kg SQ 29,072, the area over the curves of the depressor responses to 3 nmol/kg of the peptide increased from 297 +/- 70 to 306 +/- 108, 440 +/- 143, and 669 +/- 186 mm Hg.min, respectively, while the concurrent natriuretic responses rose from 161 +/- 56 to 250 +/- 88, 332 +/- 142, 464 +/- 164, and 694 +/- 316 mueq/kg/hr. In summary, the neutral endopeptidase inhibitor SQ 29,072 increased the magnitudes and especially the durations of the depressor, natriuretic, and cyclic guanosine monophosphate responses to exogenous atrial natriuretic factor-(99-126) in conscious spontaneously hypertensive rats, presumably by inhibition of degradation of atrial natriuretic factor in vivo. In conclusion, neutral endopeptidase inhibition offers an important new technique for enhancement and prolongation of the biological lifetime of atrial natriuretic factor.
Hypertension 1989 Jul
PMID:Potentiation of renal effects of atrial natriuretic factor-(99-126) by SQ 29,072. 254 29

In order to further clarify the role of renal kallikrein-kinin (K-K) system in primary aldosteronism (PA), daily urinary excretions of renal K-K system components including kallikrein (KAL), kinin (KIN), total kininase (K-ase), K-ase I, K-ase II and neutral endopeptidase (NEP) were measured in PA and normotensives (NT). In this study, a new method for the simultaneous determination of human urinary K-ase I, II and NEP was established and employed. The daily excretions of KAL was significantly higher in PA than that in NT, while no difference was found in KIN between PA and NT. On the other hand, total K-ase in PA (897 +/- 258 micrograms/min/day) was significantly higher than that in NT (209 +/- 6). NEP was also significantly higher in PA (262 +/- 22 micrograms/min/day) than that in NT (127 +/- 6), whereas there were no differences in K-ase I and K-ase II between PA and NT. The relative contributions of K-ase I, II and NEP to total K-ase in NT were 14, 27 and 59%, while those in PA were 12, 17 and 36%, respectively. As a result, these three K-ase contributed only 64% to the total K-ase in PA. These findings suggested that 1) NEP may play a major role in the catabolism of renal KIN in human, 2) NEP is accelerated in PA, 3) unknown K-ase, different from K-ase I, II or NEP, may exist in PA, and 4) accelerated renal K-ase activity may play some role on the disorder of renal water-sodium metabolism and high blood pressure in PA.
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PMID:Renal kininases in primary aldosteronism. 255 6

UK 69 578 is a competitive inhibitor of endopeptidase 24.11 (the enzyme that degrades atrial natriuretic factor) in vitro. In vivo, UK 69 578 has renal and cardiovascular effects similar to low-dose atrial natriuretic factor infusion, and may be a useful agent in hypertension and heart failure.
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PMID:Effects of UK 69 578: a novel atriopeptidase inhibitor. 257 Feb 86

To elucidate the role of Met-enkephalin in the hypertension in spontaneously hypertensive rats, the depressor response to Met-enkephalin was compared between normotensive (Wistar) and spontaneously hypertensive rats by administration of bestatin (1.25 mg) as a component of a mixture of enkephalinase inhibitors. All experiments were performed under anesthesia by intraperitoneal injection of pentobarbital (50mg/kg). Catheters were connected to the arterial and venous lines for blood pressure recording and administration of drugs. Hypotensive effects of injected Met-enkephalin were noticeably enhanced by administration of bestatin compared with pre-bestatin responses at each dose of Met-enkephalin(10, 25, 50, and 100n mol). We could not find any statistically significant difference between blood pressure responses to 25n mole Met-enkephalin in Wistar and spontaneously hypertensive rats both before and after administration of bestatin. Our present study dose not suggest the active role of Met-enkephalin in the hypertension of spontaneously hypertensive rats.
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PMID:A comparison of the hypotensive effects of Met-enkephalin in normotensive and spontaneously hypertensive rats. 274 99

alpha-Human atrial natriuretic peptide (hANP) is secreted by the heart and acts on the kidney to promote a strong diuresis and natriuresis. In vivo it has been shown to be catabolized partly by the kidney. Crude microvillar membranes of human kidney degrade 125I-ANP at several internal bonds generating metabolites among which the C-terminal fragments were identified. Formation of the C-terminal tripeptide was blocked by phosphoramidon, indicating the involvement of endopeptidase-24.11 in this cleavage. Subsequent cleavages by aminopeptidase(s) yielded the C-terminal dipeptide and free tyrosine. Using purified endopeptidase 24.11, we identified seven sites of hydrolysis in unlabelled alpha-hANP: the bonds Arg-4-Ser-5, Cys-7-Phe-8, Arg-11-Met-12, Arg-14-Ile-15, Gly-16-Ala-17, Gly-20-Leu-21 and Ser-25-Phe-26. However, the bonds Gly-16-Ala-17 and Arg-4-Ser-5 did not fulfil the known specificity requirements of the enzyme. Cleavage at the Gly-16-Ala-17 bond was previously observed by Stephenson & Kenny [(1987) Biochem. J. 243, 183-187], but this is the first report of an Arg-Ser bond cleavage by this enzyme. Initial attack of alpha-hANP by endopeptidase-24.11 took place at a bond within the disulphide-linked loop and produced a peptide having the same amino acid composition as intact ANP. The bond cleaved in this metabolite was determined as the Cys-7-Phe-8 bond. Determination of all the bonds cleaved in alpha-hANP by endopeptidase-24.11 should prove useful for the design of more stable analogues, which could have therapeutic uses in hypertension.
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PMID:Hydrolysis of alpha-human atrial natriuretic peptide in vitro by human kidney membranes and purified endopeptidase-24.11. Evidence for a novel cleavage site. 297 76

MDL 100,240 ([4S-[4 alpha,7 alpha(R*), 12b beta]]-7-[[2- (acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8,12b-octahyd ro-6-oxo- pyrido[2,1-a][2]benzazepine-4-carboxylic acid, I) is the thioacetyl prodrug of the active thiol, MDL 100,173 (II), a dual inhibitor of angiotensin-I converting enzyme (ACE) and neutral endopeptidase (NEP). A drug which simultaneously inhibits both ACE and NEP may provide a unique therapy for hypertension and congestive heart failure. Methods based on high-performance liquid chromatography with UV absorbance detection at 200 nm were developed to support preclinical pharmacokinetic investigations. One method is used to measure unchanged I and free II, while the second method is used to quantify the total level of the thiol II after the plasma is incubated with the disulfide reducing agent, dithiothreitol. By either method, the analytes are quantified over the range of 25-1000 ng/ml with good accuracy and precision. The overall extraction efficiencies of unchanged I and free II in dog plasma were 79% and 86%, respectively, while the extraction efficiency of total II averaged 75%. Described in this report are the results obtained in validating the assay methods for measuring the compounds in plasma. Pharmacokinetic data are presented which were obtained by applying these methods to plasma collected from dogs dosed with I.
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PMID:Quantification of a dual angiotensin I-converting enzyme-neutral endopeptidase inhibitor and the active thiol metabolite in dog plasma by high-performance liquid chromatography with ultraviolet absorbance detection. 749 89

The natriuretic peptide family consists of three members: atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Atrial and brain natriuretic peptides possess similar effects, causing natriuresis, vasodilation, and suppression of the renin-angiotensin-aldosterone system. C-type natriuretic peptide has been suggested to exert its predominant effect on the vasculature, eliciting vasodilation and inhibiting the proliferation of vascular smooth muscle cells. Numerous studies have broadened our current knowledge of the regulation of natriuretic peptide gene expression, biosynthesis, and secretion, as well as structure of specific receptors. This has led to a better understanding of the renal, cardiovascular, and endocrine actions of natriuretic peptides in both normal and pathophysiological states, including hypertensive disease. Development of nonpeptide neutral endopeptidase inhibitors and antagonists for natriuretic peptide receptors may reveal the range of potential therapeutic application of atrial and other natriuretic peptides in hypertension.
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PMID:The natriuretic peptides in hypertension. 749 58

To explore the mechanisms of the renal effects of neutral endopeptidase (NEP) inhibition, the effects of an NEP inhibitor, candoxatril (UK 79,300; UK), in Dahl salt-sensitive (SS) and salt-resistant (SR) rats were examined. UK dose-dependently decreased blood pressure (BP) in SS rats (20 mg/kg: 174 +/- 5 vs. 155 +/- 8 mm Hg, p < 0.01) but not in SR rats. Urinary sodium excretion (UNaV) of both rat strains receiving high-salt diets was increased to a greater extent than that of rats receiving low-salt diets. Basal plasma atrial natriuretic peptide (ANP) level in hypertensive SS rats was higher than in SR rats (192 +/- 18 vs. 118 +/- 24 pg/ml, p < 0.05). UK increased ANP levels in the plasma and urine two- and 11-fold, respectively. UK-induced increases in UNaV, urinary cyclic GMP, and plasma ANP concentrations were significantly augmented by coadministration of a clearance receptor agonist, C-ANF(4-23) or brain natriuretic peptide (BNP). Thus, the effects of NEP inhibition appear to be potentiated by the reduced receptor-mediated metabolism of ANP. This may explain the greater response to the NEP inhibitor in Dahl rats with hypertension or high-salt feeding.
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PMID:Mechanisms of the natriuretic effects of neutral endopeptidase inhibition in Dahl salt-sensitive and salt-resistant rats. 751 59

Blockade of atrial natriuretic factor (ANF) degradation by specific neutral endopeptidase (NEP) inhibitors may be useful in treatment of hypertension because of the potential diuretic, natriuretic, and arterial pressure (AP)-lowering effects. To test this possibility, we examined the effects of chronic oral treatment with the NEP inhibitor SCH 42495 on BP, diuresis, natriuresis, plasma ANF, cyclic GMP, and the renin-angiotensin system (RAS) in conscious unrestrained spontaneously hypertensive rats (SHR) and compared them with the effects induced by the angiotensin-converting enzyme (ACE) inhibitor spirapril (SPIR). Four groups of adult SHR were treated orally for 4 weeks with placebo, SCH 42495 3 mg/kg twice daily (b.i.d.), SCH 42495 30 mg/kg b.i.d., and spirapril 1 mg/kg b.i.d. Systolic BP (SBP) was measured weekly, and 24-h urine was collected every week for measurement of urinary volume, sodium, potassium, and cyclic GMP excretion. Plasma ANF, cyclic GMP, renin activity (PRA), and aldosterone (ALDO) were determined from blood collected when the rats were killed. After 4-week treatment with SCH 42495, circulating levels of ANF were similar in both SCH 42495- and placebo-treated SHR; plasma cyclic GMP was higher, however, in the treated rats than in controls and urinary cyclic GMP increased only with the higher dose of SCH 42495. PRA and plasma ALDO tended to be lower in both SCH 42495-treated groups than in controls, yet BP, diuresis, and natriuresis throughout the study were not different from controls. In contrast, spirapril decreased BP; this effect was associated with significant increments in renin and decrements in ALDO and ANF, without changes in plasma and urinary cyclic GMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hemodynamic and humoral effects of chronic treatment with the neutral endopeptidase inhibitor SCH 42495 in spontaneously hypertensive rats. 752 51

We determined the renal and depressor activities of 10, 50, and 100 pmol/kg per minute i.v. of human atrial natriuretic peptide-(99-126) in conscious one-kidney, one clip dogs with chronic hypertension and modest renal dysfunction, as indicated by mild proteinuria. Atrial natriuretic peptide increased fractional sodium excretion by 0.009 +/- 0.002, 0.042 +/- 0.005, and 0.049 +/- 0.007, respectively; urinary excretion of atrial natriuretic peptide by -0.4 +/- 0.8, 3.3 +/- 1.4, and 15.8 +/- 7.4 fmol/min; and cGMP excretion by 0.65 +/- 0.06, 1.65 +/- 0.08, and 4.88 +/- 0.85 nmol/min in one-kidney shams. The changes in fractional sodium excretion were significantly attenuated in the hypertensive dogs (0.005 +/- 0.002, 0.018 +/- 0.003, and 0.022 +/- 0.004, respectively) despite exaggerated increases in atrial natriuretic peptide excretion (3.3 +/- 1.6, 22.0 +/- 5.0, and 46.6 +/- 10.8 fmol/min) and cGMP excretion (0.96 +/- 0.47, 4.51 +/- 1.27, and 7.06 +/- 1.38 nmol/min). The slope of the line relating urinary atrial natriuretic peptide to cGMP was significantly suppressed in the hypertensive dogs, suggesting a downregulation of the guanylate cyclase-linked receptors. The slope of the relationship between cGMP excretion and the natriuretic response was also depressed in the hypertensive dogs, indicating possible impairment of cGMP signal transduction. The differences between sham and hypertensive dogs were diminished when urinary levels of atrial natriuretic peptide were maximized by prior treatment with SQ 28603, an inhibitor of neutral endopeptidase EC 3.4.24.11. Atrial natriuretic peptide caused comparable decreases in mean arterial pressure and increases in glomerular filtration rate in sham and hypertensive dogs, suggesting similar vascular reactivity.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1995 Oct
PMID:Atrial natriuretic peptide in chronically hypertensive dogs. 755 24


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