Disease relevance of phosphoramidon

• Enzymatic peptide degradation assays revealed the presence of a phosphoramidon-sensitive and thiorphan-insensitive metalloproteolytic activity in the plasma membranes of high-grade glioma cells [1].
• The ET-converting enzyme inhibitor phosphoramidon (50 micromol/liter) completely suppressed arrhythmias and vasoconstriction [2].
• Moreover, the low potencies of captopril and phosphoramidon in counteracting the toxins' effects necessitate the design of improved inhibitors for possible use in the clinical treatment of tetanus or botulism [3].
• Radioimmunoassays give evidence that alpha-MSH was degraded in the presence of the 4 melanoma cell lines and that disappearance of the peptide was significantly reduced by phosphoramidon in 2 lines (GLL-19 and G361) [4].
• Furthermore, phosphoramidon (0.25 mg/kg/min x 30) abolished pressor response to big endothelin-1 (5 micrograms/kg, i.v.) but failed to affect CS-induced hypertension [5].

Psychiatry related information on phosphoramidon

• Intracellular production of beta A4 amyloid of Alzheimer's disease: modulation by phosphoramidon and lack of coupling to the secretion of the amyloid precursor protein [6].
• The administration of deprenyl and/or PEA failed to restore the analgesic effect of phosphoramidon in REM sleep deprived animals [7].
• REM sleep deprivation (REMSD) decreased the basal pain threshold and abolished the analgesic effect of phosphoramidon [7].
• Enkephalinase inhibitors phosphoramidon, thiorphan or phelorphan suppressed naloxone-precipitated withdrawal symptoms in acute and chronic morphine dependent mice and rats [8].

High impact information on phosphoramidon

• The neutral endopeptidase inhibitor phosphoramidon (2.5 mg/kg, i.v.) significantly potentiated the increase of vascular permeability caused by 3.6% NaCl [9].
• The activity was blocked by two selective inhibitors of NEP, thiorphan and phosphoramidon [10].
• Phosphoramidon did not further potentiate the responses to substance P in smoke-exposed guinea pigs, whereas it did so in air-exposed animals [11].
• After exposure to air or to cigarette smoke we measured the change in total pulmonary resistance (RL) induced by increasing concentrations of aerosolized substance P in the absence or presence of the NEP inhibitor phosphoramidon [11].
• The responsiveness of isolated guinea pig lung parenchymal strips to substance P was enhanced by at least 100-fold in the presence of the endopeptidase inhibitors phosphoramidon (1 microM) or thiorphan (1 microM), but not with the converting enzyme inhibitor, captopril, or an inhibitor of serum carboxypeptidase N (both 1 microM) [12].

Chemical compound and disease context of phosphoramidon

• Neither phosphoramidon nor BQ-123 had an effect on severity of ischemia when given alone [13].
• In the present study, we used capsaicin to produce neurogenic inflammation in the nasal mucosa of rats, and we examined the effect of inhibition of NEP-24.11 by phosphoramidon, inhibition of ACE by captopril or inhibition of both enzymes by giving both inhibitors [14].
• 3. Treatment with phosphoramidon did not alter the increase in the lateral pressure at the tracheal tube (Pao) caused by OA inhalation or the increase in bronchial response to methacholine following the allergic reaction [15].
• In the presence of thiorphan or phosphoramidon, the bronchospasm to hyperventilation was significantly reduced (> 70%) with 5 mg/kg, p.o., of Sch 37224 [16].
• After the intracisternal injection of three protease inhibitors which prevent the degradation of methionine enkephalin (amastatin, Des-Pro2-bradykinin, and phosphoramidon) and a mixture of these protease inhibitors, we investigated the effect on convulsive seizures in the seizure-susceptible El mouse [17].

Biological context of phosphoramidon

• Brachial artery infusion of local doses of proendothelin-1, the precursor to endothelin-1, caused a slow-onset dose-dependent forearm vasoconstriction which was abolished by co-infusion of phosphoramidon [18].
• Phosphoramidon caused slow-onset vasodilatation when infused alone, with blood flow increasing by 37% at 90 min (p = 0.03) [18].
• The Km of the enzyme indicated high-affinity binding, and hydrolysis was completely inhibited by phosphoramidon [19].
• The endopeptidase activity was inhibited by divalent cation chelators and by phosphoramidon only at high concentrations (IC50 = 50 microM), whereas it was insensitive to classical inhibitors of chymotrypsin, angiotensin convertase, and serine and cysteine peptidases, as well as carboxypeptidases [20].
• The inhibition of synaptic transmission by phosphoramidon and the synthetic substrates occurred within 2 to 3 min and was completely reversible [21].

Anatomical context of phosphoramidon

• Specific binding of substance P to its receptor on bronchial membranes was increased by three- to fourfold in the presence of phosphoramidon [12].
• CALLA antigen purified from the NALM-6 leukemic cell line by affinity to 44C10-IgG Sepharose retained a peptidase activity that was completely blocked by thiorphan and phosphoramidon [10].
• The membrane-bound endothelin-converting enzyme from human umbilical vein endothelial cells and bovine aortic endothelial cells showed marked similarities, including IC50 values for phosphoramidon of 2.7 and 1.8 microM and Km values for big-ET-1 of 45.4 and 20.9 microM, respectively [22].
• Synaptic membranes generated peptides with the same HPLC retention times and hydrolysis of substance P by either preparation was inhibited completely by 10 microM phosphoramidon [23].
• A washed membrane fraction from human neutrophils rapidly cleaved 0.5 mM Glut-Ala-Ala-Phe-MNA (96 nmol X min-1 X mg-1) and the hydrolysis was inhibited by phosphoramidon and by specific antiserum to human renal NEP [24].

Associations of phosphoramidon with other chemical compounds

• Leucine-thiorphan (10(-5) M) and phosphoramidon (10(-5) M) potentiated substance P-induced cough; NEP inhibitors also potentiated capsaicin-induced cough significantly [25].
• The activity found at neutral pH values in the cytosolic fraction was only partially inhibited by EDTA and 1,10-phenanthroline but was not inhibited by phosphoramidon [22].
• This value is in line with the concentrations obtained with [Met]enkephalin, tested in the presence of the specific neutral endopeptidase 24.11 inhibitor phosphoramidon, and this opioid's synthetic analog [D-Ala2, Met5]enkephalin which, like [D-Ala2]deltorphin I, is resistant to proteolytic degradation [26].
• Therefore, we examined the effect of an NEP inhibitor, phosphoramidon, on myocardial perfusion in rats after (1) stimulating sensory nerves with capsaicin and (2) inducing myocardial hypoperfusion with isoproterenol, with or without pretreatment with selective antagonists of the substance P (NK1) and bradykinin (B2) receptors [27].
• Relative to baseline values in rats with remnant kidneys, phosphoramidon led to elevations of plasma ANP levels and concomitant increases in urinary sodium excretion, fractional excretion of sodium, glomerular filtration rate, filtration fraction, and urinary cyclic GMP excretion [28].

Gene context of phosphoramidon

• Phosphoramidon did not affect responses to endothelin-1 [18].
• The size of the neointima was effectively reduced by phosphoramidon, an inhibitor of neutral metalloproteases, including ECE-1 [29].
• Both ET(A) receptor antagonist [(hexahydro-1H-azepinyl)carbonyl-Leu-D-Trp-D-OH (BQ485)] and endothelin-converting enzyme inhibitor (phosphoramidon) inhibited the increased DNA synthesis caused by ET-1 [30].
• Both agents markedly inhibited the degradation of GRP, indicating that this process involves a lysosomal pathway and a phosphoramidon-sensitive pathway, possibly involving the EC 3.4.24.11 enzyme [31].
• 7. To conclude we have demonstrated the presence of a phosphoramidon-sensitive ECE on the smooth muscle layer of the human umbilical vein which can convert big ET-1, big ET-2(1-37), big ET-2(1-38) and big ET-3 to their mature biologically active forms [32].

Analytical, diagnostic and therapeutic context of phosphoramidon

• However, both BQ788 and RES-701-1 enhanced by 40% to 50% the 3 nmol/L ET-1-induced constriction elicited in spastic vessels previously relaxed with 0.1 mmol/L phosphoramidon, an ET-converting enzyme inhibitor [33].
• Reverse phase high performance liquid chromatography analysis indicated that the effect of phosphoramidon was not due to inhibition of 125I-ET-1 degradation [34].
• Inhibition of ET-1 secretion by PA improved allograft survival to 28.8+/-3.3 days (P<0.01, n=8) [35].
• When MDCK or Chinese hamster ovary transfected cells were pre-treated with the ECE inhibitor phosphoramidon, a 3-fold increase in the level of ECE-1b was observed both by Western blotting and by enzymic activity [36].
• The change in bronchial reactivity to bradykinin was therefore investigated after treatment with inhaled phosphoramidon, a potent neutral endopeptidase (NEP) inhibitor, in a double blind, placebo controlled, randomised study of 10 asthmatic subjects [37].

References