Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Imidapril hydrochloride (imidapril) is a long-acting, non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor, which has been used clinically in the treatment of hypertension, chronic congestive heart failure (CHF), acute myocardial infarction (AMI), and diabetic nephropathy. It has the unique advantage over other ACE inhibitors in causing a lower incidence of dry cough. After oral administration, imidapril is rapidly converted in the liver to its active metabolite imidaprilat. The plasma levels of imidaprilat gradually increase in proportion to the dose, and decline slowly. The time to reach the maximum plasma concentration (T(max)) is 2.0 h for imidapril and 9.3 h for imidaprilat. The elimination half-lives (t(1/2)) of imidapril and imidaprilat is 1.7 and 14.8 h, respectively. Imidapril and its metabolites are excreted chiefly in the urine. As an ACE inhibitor, imidaprilat is as potent as enalaprilat, an active metabolite of enalapril, and about twice as potent as captopril. In patients with hypertension, blood pressure was still decreased at 24 h after imidapril administration. The antihypertensive effect of imidapril was dose-dependent. The maximal reduction of blood pressure and plasma ACE was achieved with imidapril, 10 mg once daily, and the additional effect was not prominent with higher doses. When administered to patients with AMI, imidapril improved left ventricular ejection fraction and reduced plasma brain natriuretic peptide (BNP) levels. In patients with mild-to-moderate CHF [New York Heart Association (NYHA) functional class II-III], imidapril increased exercise time and physical working capacity and decreased plasma atrial natriuretic peptide (ANP) and BNP levels in a dose-related manner. In patients with diabetic nephropathy, imidapril decreased urinary albumin excretion. Interestingly, imidapril improved asymptomatic dysphagia in patients with a history of stroke. In the same patients it increased serum substance P levels, while the angiotensin II receptor antagonist losartan was ineffective. These studies indicate that imidapril is a versatile ACE inhibitor. In addition to its effectiveness in the treatment of hypertension, CHF, and AMI, imidapril has beneficial effects in the treatment of diabetic nephropathy and asymptomatic dysphagia. Good tissue penetration and inhibition of tissue ACE by imidapril contributes to its effectiveness in preventing cardiovascular complications of hypertension. The major advantages of imidapril are its activity in the treatment of various cardiovascular diseases and lower incidence of cough compared with some of the older ACE inhibitors.
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PMID:Protection of the cardiovascular system by imidapril, a versatile angiotensin-converting enzyme inhibitor. 1217 88

The tachykinin neurokinin B (NKB) has been implicated in the hypertension that characterises pre-eclampsia, a condition where tissue oedema is also observed. The ability of NKB, administered intradermally or intravenously, to induce oedema formation (assessed as plasma extravasation) was examined by extravascular accumulation of intravenously injected (125)I-albumin in wild-type and tachykinin NK(1) receptor knockout mice. Intradermal NKB (30-300 pmol) caused dose-dependent plasma extravasation in wild-type (P < 0.05) but not NK(1) knockout mice, indicating an essential role for the NK(1) receptor in mediating NKB-induced skin oedema. Intravenous administration of NKB to wild-type mice produced plasma extravasation in skin, uterus, liver (P < 0.05) and particularly in the lung (P < 0.01). Surprisingly, the same doses of NKB led to plasma extravasation in the lung and liver of NK(1) knockout mice. By comparison, the tachykinin substance P induced only minimal plasma extravasation in the lungs of wild-type mice. The plasma extravasation produced by NKB in the lungs of NK(1) receptor knockout mice was unaffected by treatment with the NK(2) receptor antagonist SR48968 (3 mg kg(-1)), by the NK(3) receptor antagonists SR142801 (3 mg kg(-1)) and SB-222200 (5 mg kg(-1)) or by the cyclo-oxygenase (COX) inhibitor indomethacin (20 mg kg(-1)). L-Nitro-arginine methyl ester (15 mg kg(-1)), an inhibitor of endothelial nitric oxide synthase (eNOS), produced only a partial inhibition. We conclude that NKB is a potent stimulator of plasma extravasation through two distinct pathways: via activation of NK(1) receptors, and via a novel neurokinin receptor-independent pathway specific to NKB that operates in the mouse lung. These findings are in keeping with a role for NKB in mediating plasma extravasation in diseases such as pre-eclampsia.
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PMID:Neurokinin B induces oedema formation in mouse lung via tachykinin receptor-independent mechanisms. 1223 54

We recently demonstrated that substance P mediates increased permeability of brain endothelium exposed to HIV-1 gp120. To test whether substance P is involved in immune processes at the blood-brain barrier (BBB), we stimulated rat brain endothelial cultures prepared from cerebral microvessels with Interferon-gamma (IFN-gamma) and Tumor necrosis factor-alpha (TNF-alpha), two proinflammatory cytokines that alter the BBB and measured permeability to albumin and expression of adhesion molecule ICAM-1 and MHC class II antigen in the presence and absence of spantide, a powerful substance P antagonist. In a dose-dependent manner, spantide completely neutralized increased permeability induced by TNF-alpha and IFN-gamma and expression of MHC class II molecule induced by IFN-gamma and prevented associated cell morphological changes as revealed by scanning electron microscope. Spantide also reduced expression of ICAM-1 induced by TNF-alpha and IFN-gamma by 35% and 30%, respectively. Substance P mRNA was found in unstimulated brain endothelial cells and was upregulated after stimulation with TNF-alpha and IFN-gamma. These in vitro findings demonstrate that substance P plays a major pathogenetic role in damaging and activating the BBB vascular component in the presence of proinflammatory cytokines.
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PMID:Substance P antagonist blocks leakage and reduces activation of cytokine-stimulated rat brain endothelium. 1245 35

To characterize the tachykininergic effects in fire smoke (FS)-induced acute respiratory distress syndrome (ARDS), we designed a series of studies in rats. Initially, 20 min of FS inhalation induced a significant increase of substance P (SP) in bronchoalveolar lavage fluid (BALF) at 1 h and persisted for 24 h after insult. Conversely, FS disrupted 51.4, 55.6, 46.3, and 43.0% enzymatic activity of neutral endopeptidase (NEP, a primary hydrolyzing enzyme for SP) 1, 6, 12, and 24 h after insult, respectively. Immunolabeling density of NEP in the airway epithelium largely disappeared 1 h after insult due to acute cell damage and shedding. These changes were also accompanied by extensive influx of albumin and granulocytes/lymphocytes in BALF. Furthermore, levels of BALF SP and tissue NEP activity dose dependently increased and decreased, respectively, following 0, low (10 min), and high (20 min) levels of FS inhalation. However, neither the time-course nor the dose-response study observed a significant change in the highest affinity neurokinin-1 receptor (NK-1R) for SP. Finally, treatment (10 mg/kg im) with SR-140333B, an NK-1R antagonist, significantly prevented 20-min FS-induced hypoxemia and pulmonary edema 24 h after insult. Further examination indicated that SR-140333B (1.0 or 10.0 mg/kg im) fully abolished early (1 h) plasma extravasation following FS. Collectively, these findings suggest that a combination of sustained SP and NEP inactivity induces an exaggerated neurogenic inflammation mediated by NK-1R, which may lead to an uncontrolled influx of protein-rich edema fluid and cells into the alveoli as a consequence of increased vascular permeability.
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PMID:Substance P and neutral endopeptidase in development of acute respiratory distress syndrome following fire smoke inhalation. 1519 66

To evaluate the effect of cetirizine hydrochloride on substance P release in allergic rhinitis, we performed a single-blind placebo-controlled study of 14 patients with perennial allergic rhinitis (7 treated with cetirizine and 7 with placebo). After an initial nasal allergen challenge with lavages, the subjects received treatment with placebo or cetirizine hydrochloride (10 mg by mouth daily) for 1 week, followed by the second nasal allergen challenge with lavages. The levels of albumin, histamine, and substance P in nasal lavages before and after allergen challenge were quantified by enzyme-linked immunosorbent assay. Pretreatment of subjects with cetirizine reduced the level of substance P induced by antigen challenge, but did not significantly reduce levels of histamine. These results suggest that cetirizine may reduce nasal neurogenic inflammation by modulating the release of substance P in allergic rhinitis.
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PMID:Effects of cetirizine on substance P release in patients with perennial allergic rhinitis. 1563 94

The mechanisms by which topical mustard oil causes vasodilatation in the mouse were investigated using the tachykinin NK1 receptor antagonist SR140333 and the calcitonin gene-related peptide (CGRP) antagonist BIBN4096BS, alongside alphaCGRP or NK1 receptor knockout mice. Blood flow was assessed by laser Doppler flowmetry and plasma extravasation by 125I-albumin accumulation. Mustard oil produced significant plasma extravasation and vasodilatation in wild type mice, although the plasma extravasation was less than that seen with capsaicin whilst the vasodilatation was greater. The plasma extravasation was abolished in tachykinin NK1 knockout mice, whilst the vasodilatation was enhanced. BIBN4096BS was unable to inhibit the vasodilatation in wild type mice but abolished it in the NK1 knockout mice. In alphaCGRP knockout mice, mustard oil also caused plasma extravasation and vasodilatation, which were both inhibited by treatment with SR140333. These data suggest that both a tachykinin NK1 receptor agonist and a CGRP agonist are active as vasodilators, producing redundancy, requiring blockade of both mediators to prevent vasodilatation.
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PMID:An examination of neurogenic mechanisms involved in mustard oil-induced inflammation in the mouse. 1565 18

Every year in the United States, respiratory syncytial virus (RSV) infections in infants and young children cause more than 120,000 hospitalizations, often complicated by the need for mechanical ventilation; yet no effective therapy is currently available for this disease. We showed previously that RSV infection is associated with neurogenic inflammation in the lower respiratory tract. In the present study, we sought to determine whether aerosolized beta(2)-receptor agonists inhibit neurogenic-mediated albumin extravasation in the airways of RSV-infected, mechanically ventilated rats, and to compare the anti-inflammatory effects of racemic albuterol ((RS)-albuterol) to its individual enantiomeric components (R)-albuterol and (S)-albuterol. Albumin extravasation evoked by sensorineural stimulation with capsaicin was inhibited only partially by 0.63 mg (RS)-albuterol, and higher doses had minimal incremental effects. In contrast, the anti-inflammatory effect of (R)-albuterol was already larger at the lowest dose of 0.31 mg, and complete inhibition of neurogenic exudation was observed at higher doses. (S)-albuterol had no significant inhibitory effect up to 1.25 mg, and had only partial inhibitory effect at higher doses. The anti-inflammatory effect of (R)-albuterol was independent from the expression of substance P neurokinin 1 receptors, suggesting a direct vascular effect. Our data show that (R)-albuterol has a much stronger inhibitory effect on neurogenic inflammation in RSV-infected airways when aerosolized in enantiomerically pure form, rather than in a racemic mixture with (S)-albuterol. Based on these data, we speculate that (R)-albuterol may be more effective than other adrenergic agents in the management of bronchiolitis.
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PMID:Anti-inflammatory effect of albuterol enantiomers during respiratory syncytial virus infection in rats. 1595 75

Atherosclerotic vascular disease is associated with abnormal vasomotor function and oxidized low density lipoproteins (OxLDL) are believed to play a keyrole therein. Several compounds emerging from LDL lipid peroxidation have been shown to be able to alter vasomotion but the role of oxidized apoB in this process is not fully understood. Myeloperoxidase has been identified in atherosclerotic lesions and hypochlorite produced by this enzyme represents a strong oxidant. LDL oxidation by hypochlorite differs from most other forms of LDL oxidation in that hypochlorite-mediated oxidation shows a predilection for the protein moiety of LDL and does not result in lipid peroxidation. In this work, we use porcine coronary artery segments and show that hypochlorite-oxidized LDL (hyp-OxLDL) are able to impair dilatation induced by substance P in a dose- and modification-dependent way. Treatment of hyp-OxLDL with methionine resulted in quantitative elimination of reactive chloramines in LDL and complete recovery of relaxation. As application of the scavenger receptor antagonist maleylated albumin strongly interferes with the effects of hyp-OxLDL on vasomotion, we conclude that specific binding of hypochlorite-modified apoB is likely to be involved in mediating the observed effects.
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PMID:Redox-sensitive impairment of porcine coronary artery vasodilation by hypochlorite-modified LDL. 1673 Jul 31

Pain and itch sensations are induced by depolarization of C-fibre nerves and possibly other types of fibres. We have evidence from several species, including mice, that skin plasma extravasation induced by the Phoneutria nigriventer spider venom (PNV) is dependent on tachykinin NK(1) receptors. We have now investigated the itching measured as bouts of scratching in response to intradermal (i.d.) PNV in wildtype (NK(1)(+/+)) and NK(1) receptor knockout (NK(1)(-/-)) mice. Mice, either NK(1)(+/+) or NK(1)(-/-), were given a single i.d. injection (0.05 ml) of test agent or vehicle into the shaved dorsal skin, in the intercostal region, in a randomized way. The bouts of scratching were recorded in a blinded manner for 60 min. Oedema formation was concomitantly assessed by the extravascular accumulation of i.v. injected (125)I-albumin. The i.d. injection of either substance P (at a high dose of 100 nmol/site), or PNV (0.3-10 microg/site) induced oedema formation in NK(1)(+/+) but substantially less was observed in NK(1)(-/-) mice, as previously reported. PNV also induced scratching, but significantly less scratching was observed in NK(1)(-/-) compared with NK(1)(+/+) mice. In contrast, SP did not induce significant scratching at amounts up to 100 nmol in NK(1)(+/+) mice. Experiments with an NK(1) receptor antagonist SR140333 (at doses that blocked PNV-induced oedema) revealed that whilst a local co-injection i.d. (1 nmol) in NK(1)(+/+) mice had no effect on PNV (3 microg/site)-induced scratching (18.5+/-3.7 vs. 14.4+/-3.5 bouts, mean+/-S.E.M., n=5-7), systemic treatment with SR140333 (120 nmol/kg, i.v.) significantly inhibited scratching (14+/-3.5 vs. 3.1+/-1.2 bouts, n=4-6; P<0.05). These results indicate that NK(1) receptors are involved in mediating PNV-induced scratching and that the location of the receptors is unlikely to be skin. Thus, a distinct separation between endogenous microvascular and PNV nociceptive NK(1)-dependent effects is suggested.
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PMID:How important are NK1 receptors for influencing microvascular inflammation and itch in the skin? Studies using Phoneutria nigriventer venom. 1691 87

Proteomics samples often contain both abundant proteins and low-level proteins and peptides. Highly abundant proteins can mask and/or bind those of lower abundance and thereby hinder their analysis. In particular, we were concerned with samples containing large amounts of albumin (up to 4.0 microM). In this study, a novel set-up for multidimensional nano-liquid chromatography-mass spectrometry (nanoLC-MS) with three columns coupled on-line was developed and characterised. A 1-mm-I.D. restricted-access-material (RAM) cartridge and a 100-microm-I.D. reversed-phase trap column are coupled in forward-flush mode to remove albumin before on-line separation on a 50 microm I.D. reversed-phase capillary analytical column. Volumes up to 100 microL of a complex matrix (containing 0.4 or 4.0 microM albumin) could be injected onto this system, enabling a 5000-fold volume reduction. Up to 99.7% of the albumin present in samples could be efficiently removed over the RAM cartridge. The total analysis time was about 40 min. Using Substance P as a model peptide, separations were efficient, with a peak width of 10s at half height. Moreover, separations were highly reproducible (relative standard deviation (RSD) on retention time approximately 3% over 1 week). The set-up proved to be robust and was used for about 750 analyses without exchanging one of the columns. Flexibility with respect to the stationary phase material in the sample preparation cartridge allows for other separation modes to be applied as well.
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PMID:Restricted-access material-based high-molecular-weight protein depletion coupled on-line with nano-liquid chromatography-mass spectrometry for proteomics applications. 1741 20


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