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

The vascular endothelium is the site of formation of several powerful mediators. One of these is NO, a chemically unstable radical formed by enzymatic conversion of L-arginine in the presence of molecular oxygen. NO elicits relaxation of VSMC by activating cytosolic guanylate cyclase. NO also counteracts platelet adhesion and aggregation. The biological actions of NO make it a key substance in the endogenous defense against vascular occlusion and thrombosis. The basal formation of NO maintains a moderate but significant vasodilation in the systemic resistance vessels and counteracts platelet activity. When blood flow in conduit arteries is increased there is an augmented endothelial formation of NO, eliciting flow-dependent vasodilation. Beside this, several vasodilators (acetylcholine, bradykinin, histamine, substance P) operate by stimulating endothelial NO formation. On the other hand, drugs like nitroglycerin and papaverine operate independently of the vascular endothelium. Vasodilator mechanisms, physiological as well as pharmacological, may therefore be characterized as endothelium-dependent (i.e. NO-mediated), or endothelium-independent (i.e. not mediated by NO). Physiologically, mixed mechanisms occur. Failure of the vascular endothelium to elicit NO-mediated vasodilatation may be due to decreased formation, increased degradation, decreased sensitivity to the NO formed, or a mixture of these factors. Irrespective of the mechanism behind, this is referred to as endothelial dysfunction. Endothelial dysfunction occurs in several cardiovascular settings, like atherosclerosis, hypercholesterolaemia, diabetes, and essential hypertension. Endothelial dysfunction leads to an impaired tissue perfusion, increased local vascular resistance, decreased defense against thrombus formation, and possibly also decreased defense against hypertrophy of the VSMC in the vessel wall media. In patients with CHD, endothelial dysfunction leads to an impaired coronary flow response to physical and mental stress, and to promotion of platelet adherence and aggregability. Endothelial dysfunction is thereby a probable aggravating factor in the atherosclerotic process, adding a functional component on top of the structural lesions characterizing this disease. A particular form of endothelial dysfunction, limited to the arterial resistance vessels, may explain the symptoms and clinical characteristics of microvascular angina. In patients with essential hypertension, endothelial dysfunction prevails, adding a functional component to the structural factors also in this disease. Hitherto, the only therapeutic tools available to restore endothelial dysfunction appear to be restriction of the dietary intake of lipids, possibly reinforced with intake of antioxidants like fish oil and vitamin E. However, large clinical trials to confirm the efficacy of such therapy in reversing endothelial dysfunction have not been conducted. In the future, more directly acting therapeutic regimens, aimed at supporting or substituting the endogenous formation of NO, are likely to appear as well.
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PMID:Endothelial nitric oxide and cardiovascular disease. 815 Dec 63

Antioxidants and antioxidant enzymes are known to protect against cell death induced by reactive oxygen species. However, apart from directly quenching free radicals, little is known about the effect of antioxidants on hormone-activated second messenger systems. We previously found that antioxidants such as 17-beta estradiol and resveratrol activate membrane-bound guanylate cyclase GC-A, the receptor for atrial natriuretic factor (ANF), in PC12 cells. It is possible that other antioxidants may also activate membrane-bound guanylate cyclase GC-A. The aim of this study was to determine if dithiothreitol (DTT), vitamin C, and vitamin E activate membrane-bound guanylate cyclase GC-A in PC12 cells. The results showed that both DTT and vitamin C increased cGMP levels in PC12 cells, whereas vitamin E had no effect. DTT and vitamin C inhibited membrane-bound guanylate cyclase activity stimulated by ANF in PC12 cells. In contrast, DTT and vitamin C had no effect on soluble guanylate cyclase activity stimulated by substance P. Furthermore, NO synthase inhibitors L-NAME and aminoguanidine did not affect DTT- and vitamin C-stimulated guanylate cyclase activity. The results indicate that DTT and vitamin C, but not vitamin E, activate membrane-bound guanylate cyclase GC-A in PC12 cells.
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PMID:Antioxidants, vitamin C and dithiothreitol, activate membrane-bound guanylate cyclase in PC12 cells. 1127 22

Experimental studies have shown the beneficial effects of antioxidant supplementation on endothelial function in the presence of increased endogenous oxidative stress, whereas limited data are available under normal conditions. The present study tested the hypothesis that in normal pigs long-term antioxidants would have deleterious effects on the cardiovascular system. Normal domestic pigs (V, n=6) were studied 12 weeks after dietary supplementation with vitamin E (100 IU/kg per day) and vitamin C (1 g/day) and compared with normal controls (C, n=7). Myocardial perfusion and permeability index were evaluated by electron beam computed tomography after intravenous adenosine and dobutamine. Coronary endothelial function was evaluated in vitro by organ chamber and coronary tissue studied by immunoblotting and staining. Myocardial perfusion response was lower in V than in C after adenosine (10.1+/-4.5 versus 53.4+/-5.2%; P<0.01) and dobutamine (V, 78.4+/-8.1; C, 193.0+/-39.0%; P<0.05). The permeability index increased in V after adenosine (48.8+/-5.1%) and dobutamine (59.9+/-13.6%) and did not change in C. Coronary vasodilation to bradykinin and substance P was lower in V than in C. Moreover, in V, coronary nitrotyrosine and superoxide content was significantly higher than in C. The groups had similar total monomer expression of endothelial nitric oxide synthase, whereas the dimerized form, reflecting coupled enzyme, was lower in V. These findings suggest that long-term experimental antioxidant vitamin supplementation in normal pigs impairs myocardial perfusion and coronary endothelial function via an increased level of oxidative stress in the arterial wall, which may be partly related to the uncoupling of endothelial nitric oxide synthase and/or the direct prooxidant effect of vitamin radicals.
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PMID:Chronic antioxidant supplementation impairs coronary endothelial function and myocardial perfusion in normal pigs. 1644 99

The tachykinin family of receptors has been of strong interest recently due to the potential of the tachykinin NK(3) receptor antagonism in treatment of schizophrenia. However, critical differences in the tachykinin NK(3) receptor between rats, mice and humans make rats and mice less acceptable species for testing tachykinin NK(3) receptor antagonism. This has led to testing of tachykinin NK(3) receptor activity in gerbils and guinea pigs. As these species are much less common laboratory animals than rats and mice, there is a relative paucity of in vivo testing models for tachykinin NK(3) receptor activation. In the present study, locomotor activity induced by the tachykinin NK(3) receptor agonist senktide was characterized. Injection of senktide i.c.v. was found to dose-dependently induce hyperlocomotion from a dose of 0.06 nmol to the maximal dose tested, 0.6 nmol. Locomotion induced by 0.1 nmol of senktide could be blocked by injection of the tachykinin NK(3) receptor antagonists SB222200 (10 and 30 mg/kg i.p.) and talnetant (SB223412; 10 and 30 mg/kg i.p.), as well as by osanetant (SR142801; 10 and 30 mg/kg i.p.) when administered in a vehicle containing vitamin E and glycofurol. Senktide-induced activity was also reversed by the antipsychotics haloperidol (0.3 and 1 mg/kg p.o.) and risperidone (1 mg/kg p.o.), but not by the serotonin 5HT(2a/c) receptor antagonist MDL100907 (tested at 0.1, 0.3 and 1 mg/kg p.o.). Hyperlocomotion induced by 0.03 nmol of senktide was potentiated by antagonism of the tachykinin NK(1) receptor with aprepitant (1, 3 and 10 mg/kg, p.o.). Thus, hyperlocomotion induced by senktide in gerbils is a tachykinin NK(3) receptor-mediated behavior that is appropriate for use in testing tachykinin NK(3) receptor activity of novel compounds.
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PMID:The tachykinin NK3 receptor agonist senktide induces locomotor activity in male Mongolian gerbils. 1893 Jul 26

Substance P (SP), a sensory nerve derived neuropeptide, has been implicated in wound repair. Our hypothesis was that oxidative effects of elevated glucose and fatty acid levels as seen with diabetes mellitus inhibit SP-mediated endothelial cell directional migration and proliferation. Using a 2% agarose gel, immortalized human microvascular endothelial cells (HMEC-1) were plated into a 1.5-mm well, and agonist (SP; 10(-4) mol/L) was loaded into a 3-mm well; controls included NaCl, albumin (bovine serum albumin), and vascular endothelial cell growth factor. The SP receptor antagonist spantide 1 was used to confirm SP specificity. Elevated glucose (40 mmol/L) and fatty acids (40 micromol/L) were added to the medium with and without vitamin E and vitamin C treatment to determine whether endothelial cell responses to SP were altered by metabolic perturbations and whether they could be recovered with antioxidant treatment. Using computer-assisted image analysis, migration distance was measured. Cells were counted using a hemocytometer. Human microvascular endothelial cell 1 migration toward the SP exceeded NaCl or bovine serum albumin; vascular endothelial cell growth factor had similar effects. The SP receptor antagonist, spantide, inhibited SP-induced HMEC-1 migration. Substance P treatment was associated with increased cell number. Ki-67 staining was increased in SP-treated cells compared with controls. Elevated glucose and fatty acid levels diminished cell migration toward SP. The antioxidants vitamins C and E significantly improved proliferation but only marginally improved migration. Our data suggest that glucose and fatty acids perturb SP-induced HMEC-1 migration and proliferation in an agarose gel migration model.
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PMID:Elevated glucose and fatty acid levels impair substance P-induced dermal microvascular endothelial cell migration and proliferation in an agarose gel model system. 1929 89

Hypomagnesemia continues to be a significant clinical disorder that is present in patients with diabetes mellitus, alcoholism, and treatment with magnesuric drugs (diuretics, cancer chemotherapy agents, etc.). To determine the role of magnesium in cardiovascular pathophysiology, we have used dietary restriction of this cation in animal models. This review highlights some key observations that helped formulate the hypothesis that release of substance P (SP) during experimental dietary Mg deficiency (MgD) may initiate a cascade of deleterious inflammatory, oxidative, and nitrosative events, which ultimately promote cardiomyopathy, in situ cardiac dysfunction, and myocardial intolerance to secondary stresses. SP acts primarily through neurokinin-1 receptors of inflammatory and endothelial cells, and may induce production of reactive oxygen and nitrogen species (superoxide anion, NO*, peroxynitrite, hydroxyl radical), leading to enhanced consumption of tissue antioxidants; stimulate release of inflammatory mediators; promote tissue adhesion molecule expression; and enhance inflammatory cell tissue infiltration and cardiovascular lesion formation. These SP-mediated events may predispose the heart to injury if faced with subsequent oxidative stressors (ischemia/reperfusion, certain drugs) or facilitate development of in situ cardiac dysfunction, especially with prolonged dietary Mg restriction. Significant protection against most of these MgD-mediated events has been observed with interventions that modulate neuronal SP release or its bioactivity, and with several antioxidants (vitamin E, probucol, epicaptopril, d-propranolol). In view of the clinical prevalence of hypomagnesemia, new treatments, beyond magnesium repletion, may be needed to diminish deleterious neurogenic and prooxidative components described in this article.
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PMID:Neurogenic inflammation and cardiac dysfunction due to hypomagnesemia. 1959 99