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)

The endopeptidase EC 3.4.24.11 (atriopeptidase) degrades atrial natriuretic factor (ANF). Intravenous administration of UK 69,578 (0.025 to 10.0 mg/kg), a new specific atriopeptidase inhibitor, in 16 normal volunteers produced a two- to three-fold rise in endogenous ANF. Peak levels were reached within 2 h declining to control values by 8 h. The rise in ANF was associated with an increase in urine volume and mean urinary sodium excretion rose from 64.9 mmoles/8 h after placebo to 116.1 mmoles/8 h after 10 mg/kg UK 69,578. Despite the natriuresis, plasma active renin concentration was suppressed for up to 8 h. We conclude that inhibition of the endopeptidase EC 3.4.24.11 in humans elevates endogenous ANF and causes a natriuresis and may offer a novel therapeutic approach to the treatment of hypertension and cardiac failure.
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PMID:The atriopeptidase inhibitor UK 69,578 increases atrial natriuretic factor and causes a natriuresis in normal humans. 214 71

Acute coadministrations of an inhibitor of endopeptidase 24.11 (thiorphan) and a ligand (SC-46542) selective for the non-guanylate cyclase-linked atriopeptin binding sites increases urinary sodium excretion to a greater degree in conscious spontaneously hypertensive rats than in normotensive Wistar-Kyoto rats. In the present study, we examined the effects of chronic 10-day intravenous infusions of SC-46542 (des[Phe106,Gly107,Ala115,Gln116] atriopeptin-(103-126] (0.1 mg/kg/hr), thiorphan (1.5 mg/kg/hr), and atriopeptin-(103-126) (100 ng/hr) alone or in combination on direct recording of mean arterial pressure in conscious spontaneously hypertensive rats. During an 11-day time-control infusion of isotonic saline vehicle (100 microliters/hr), mean arterial pressure remained stable. Chronic infusion of atriopeptin-(103-126) decreased mean arterial pressure progressively over the first 3 days; then mean arterial pressure progressively rose to control level over the following 3 days and remained at control level for the remainder of the experiment. Similarly, coinfusions of atriopeptin-(103-126) and SC-46542 or thiorphan, SC-46542 and thiorphan, or the triple infusion of atriopeptin-(103-126), SC-46542, and thiorphan had only transient effects on mean arterial pressure during 10-day infusions. SC-46542 alone had no effect on mean arterial pressure. Similarly, thiorphan alone had no effect on mean arterial pressure except at doses that blocked the acute pressor response to angiotensin I. Chronic infusions of atriopeptin-(103-126), SC-46542, and thiorphan alone or in combination are not effective long-term treatments for hypertension in spontaneously hypertensive rats.
Hypertension 1990 Dec
PMID:Chronic atriopeptin regulation of arterial pressure in conscious hypertensive rats. 214 72

The effects of SCH 34826, an orally active neutral metalloendopeptidase inhibitor, on responses to atrial natriuretic factor-(103-125) or -(99-126) and on blood pressure were evaluated in rats. SCH 34826 (10, 30, and 90 mg/kg s.c. and 90 mg/kg p.o.) potentiated the antihypertensive action of atrial natriuretic factor (30 micrograms/kg i.v.) in conscious spontaneously hypertensive rats. SCH 34826 (90 mg/kg) also potentiated the diuretic and natriuretic responses to atrial natriuretic factor (30 micrograms/kg i.v.) as well as the plasma levels achieved after peptide injection. SCH 34826 significantly reduced blood pressure in the conscious deoxycorticosterone acetate-salt hypertensive rat, at doses of 90 mg/kg s.c. (-35 +/- 12 mm Hg), 10 mg/kg p.o. (-30 +/- 7 mm Hg), and 90 mg/kg p.o. (-45 +/- 6 mm Hg). SCH 34826 was devoid of acute antihypertensive activity in the spontaneously hypertensive rat but reduced blood pressure by day 3 of a 5-day treatment schedule. SCH 34826 (90 mg/kg s.c.) enhanced urine volume output in the deoxycorticosterone acetate-salt rat (2.78 +/- 0.6 vs. 1.27 +/- 0.3 ml/100 g/3 hr in vehicle-control rats, p less than 0.05). SCH 34826 (90 mg/kg s.c.) increased plasma levels of atrial natriuretic factor at 1 hour (753 +/- 89 vs. 451 +/- 79 pg/ml in vehicle-treated rats, p less than 0.05) but not 3 hours after dosing. The renal excretion of atrial natriuretic factor (3,092 +/- 1,089 vs. 21 +/- 6 pg/100 g/3 hr in vehicle-treated rats, p less than 0.05) and cyclic guanosine monophosphate (2,131 +/- 509 vs. 879 +/- 168 pg/100 g/3 hr in vehicle-treated rats, p less than 0.05) was markedly elevated by SCH 34826 in deoxycorticosterone acetate-salt rats. These studies suggest that neutral endopeptidase inhibition may represent a new approach to treatment of some forms of hypertension.
Hypertension 1990 Feb
PMID:Atrial natriuretic factor-potentiating and antihypertensive activity of SCH 34826. An orally active neutral metalloendopeptidase inhibitor. 215 4

Endothelins 1-3 are a family of 21-amino acid peptides whose structure consists of two rings formed by intra-chain disulfide bonds and a linear "COOH-terminal tail." These peptides were originally described on the basis of their potent vasoconstrictor activity. The hydrolytic inactivation of endothelin action has recently been implicated to be attributed, at least in part, to the enzyme neutral endopeptidase 24.11 (Scicli, A. G., Vijayaraghavan, J., Hersh, L., and Carretero, O. (1989) Hypertension 14, 353). The kinetic properties and mode of hydrolysis of the endothelins by this enzyme are reported in this study. The Km for endothelins 1 and 3 hydrolysis is approximately 2 microM while endothelin2 exhibits a 5-fold higher Km. Endothelins 1 and 2 exhibit similar Vmax values while endothelin3 is hydrolyzed considerably more slowly. The initial cleavage site in endothelin1 is at the Ser5-Leu6 bond located within one of the cyclic structures. Thermolysin, a bacterial neutral endopeptidase with a similar substrate specificity to neutral endopeptidase 24.11 initially cleaves endothelin1 between His16-Leu17 which lies within the COOH-terminal linear "tail" portion of the molecule. The cleavage of endothelins 2 and 3 by neutral endopeptidase 24.11 differs from that observed with endothelin1 in that cleavage of these endothelins occurs at Asp18-Ile19 within the linear COOH-terminal tail structure. These results demonstrate that the endothelins are good substrates for neutral endopeptidase 24.11 and suggest that their mode of cleavage is dependent upon both amino acid sequence as well as peptide conformation.
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PMID:The hydrolysis of endothelins by neutral endopeptidase 24.11 (enkephalinase). 220 81

The biological actions of Atrial Natriuretic Peptide (ANP) make it potentially useful in the treatment of hypertension and heart failure. We review here the physiology of ANP, the effects of infusion in heart failure and hypertension and preliminary data suggesting that inhibition of endopeptidase 24.11, the enzyme degrading ANP, is an effective mechanism of raising circulating levels of endogenous ANP. Due to the rate of progress in this field we have restricted ourselves to recent work much of which is still available only in abstract form. For more complete accounts the reader is referred to recent reviews [9, 11, 14].
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PMID:Harnessing the therapeutic potential of atrial natriuretic peptide. 253 Mar 92

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

Arterial plasma kinins and mean arterial pressure were measured in intact and bilaterally nephrectomized rats infused with vehicle or bradykinin to study the role of 1) angiotensin converting enzyme (ACE) and other peptidases and 2) the kidney (a kininase-rich organ) in the metabolism of kinins in vivo. Before the infusion, rats were pretreated with vehicle, enalaprilat (an ACE inhibitor), or a cocktail of kininase inhibitors containing 1) enalaprilat, 2) DL-2-mercaptomethyl-3-guanidinoethyl-thiopropanoic acid (MGTA), a carboxypeptidase N inhibitor, 3) phosphoramidon, a neutral endopeptidase 24.11 inhibitor, and 4) bestatin, an aminopeptidase B inhibitor. In the rats with vehicle (n = 8), the cocktail did not significantly increase endogenous kinins (from 31 +/- 6 to 41 +/- 9 pg/ml, p = 0.94). In the rats infused with bradykinin (peptidase substrate), plasma kinins increased threefold in the group pretreated with the vehicle, 21-fold in the enalaprilat group, and 22-fold in the cocktail group. These increases were doubled by nephrectomy but were not affected by ureteral ligation. In the groups pretreated with the cocktail or enalaprilat, the hypotensive effect of bradykinin was correlated with plasma kinin concentration (r = 0.75, p less than 0.001). After bradykinin infusion was stopped, plasma kinins decreased by half in 10-12 seconds in the rats pretreated with vehicle, enalaprilat, or cocktail. We concluded that ACE and the kidney are important to the metabolism of circulating kinins while carboxypeptidase N, neutral endopeptidase 24.11 and aminopeptidase B are not. We also concluded that other tissue peptidases, not affected by either the above inhibitors or nephrectomy, play an important role in kinin metabolism.
Hypertension 1989 Sep
PMID:Role of angiotensin converting enzyme and other peptidases in in vivo metabolism of kinins. 254 61

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

The natriuretic effects of atrial peptide hormones have been attributed, at least in part, to their stimulation of guanylate cyclase activity in renal cell membranes. The effects of atrial natriuretic factor (ANF) on stimulation of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) accumulation were investigated in cloned human kidney tumor (hKT) cells and parent cells from a human renal tumor epithelial cell line (SK-NEP-1). Human ANF-(99-126) (10(-6)M) stimulated (p less than 0.001) cellular cGMP accumulation in a dose-dependent manner from a basal level of 0.26 +/- 0.04 to 3.73 +/- 0.81 pmol/mg protein/5 mi (mean +/- SEM, n = 13). ANF stimulation of cGMP accumulation was specific, in that high concentrations (10(-6)M) of atriopeptin I [rat ANF-(103-123)], angiotensin II, arginine vasopressin, and amiloride (10(-4)M) did not increase basal cGMP. Amiloride (10(-4)M) enhanced (p less than 0.01, n = 6) the ANF stimulation of cGMP accumulation (1.24 +/- 0.39 pmol/mg protein/5 min), particularly at low doses of ANF (10(-10)M) where stimulation by ANF without amiloride (0.34 +/- 0.08 pmol/mg protein/5 min) was barely distinguishable from a basal level (0.19 +/- 0.02 pmol/mg protein/5 min) of cGMP accumulation. The stimulatory effect of ANF (1.59 +/- 0.07 pmol/mg protein/5 min) was attenuated (0.75 +/- 0.06 pmol/mg protein/5 min, p less than 0.01, n = 6) by preincubation of the cells with pertussis toxin but not by cholera toxin. ANF (4.56 +/- 0.93 pmol/mg protein/5 min, n = 8) did not affect cAMP accumulation (4.32 +/- 0.98 pmol/mg protein/5 min) in hKT cells. This is the first report of an ANF responsive human renal cell line, and its use should facilitate investigation of ANF-receptor interactions.
Hypertension 1989 Jun
PMID:Atrial natriuretic factor effects on cyclic nucleotides in a human renal cell line. 256 5

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


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