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)

Endothelial cells synthesize and metabolize vasoactive substances which are involved in the regulation of vascular tone. Among these factors, the endothelium-derived nitric oxide (NO) appears to be of major importance. Many studies observed an impairment of the generation, release, or the diffusion of endothelial NO across the vascular intima in laboratory animals with various experimental diseases such as hypercholesterolemia, atherosclerosis and hypertension. In human coronary arteries obtained from explanted hearts impaired endothelium-dependent relaxations were measured in atherosclerotic segments. The hypothesis of a decreased NO mediated vasodilation in patients with coronary artery disease was further underscored by in vivo studies in man using intracoronary infusions of the endothelium-dependent vasodilator acetylcholine and quantitative coronary angiographic measurements of the diameter changes. From these observations it was assumed that endothelial dysfunction, in particular a profound inability of the coronary endothelium to relax via NO dependent mechanisms may play an important role in the pathogenesis of abnormal coronary vasomotion. However, further investigations in man reveal that the ability of the coronary endothelium of patients with coronary artery disease or vasospastic angina to produce endothelial NO is less affected as judged from the effects of acetylcholine. In recent investigations a largely preserved endothelial function could be measured in these patients when the endothelium-dependent vasodilator substance P was used as a tool for the measurement of NO dependent relaxation. Thus, endothelial dysfunction does not appear to serve as a major cause of abnormal vasoconstriction in coronary artery disease or vasospastic angina in man.
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PMID:In vivo measurement of endothelium-dependent vasodilation with substance P in man. 128 20

We evaluated the effect of a low level of hyperlipidemia and the effects of in vitro exposure to atherogenic lipoproteins (LDL, VLDL) on the vascular responsiveness of isolated porcine coronary arteries. Firstly we studied the change in vascular responsiveness induced by feeding a cholesterol-rich diet to pigs for 4 and 9 weeks (C4 and C9 pigs). The serum cholesterol level in pigs fed a cholesterol-rich diet reached 218.5 +/- 32.9 mg/dl compared with 85.5 +/- 8.4 mg/dl in the controls. Segments of the left descending coronary artery were examined. The contraction induced by KCl or prostaglandin F2 alpha was not altered significantly by hypercholesterolemia nor was the relaxation induced by the Ca2+ ionophore, A23187, or by nitroglycerin. Endothelium-dependent relaxation (EDR) evoked by high, but not low, concentrations of bradykinin was reduced in the C4 pigs as compared with those in normal animals. EDRs evoked by bradykinin, substance P, and serotonin were significantly reduced in C9 pigs. Histologically, as observed by light and electron microscopy, fatty changes or intimal thickenings were not seen in the coronary arteries of the C4 pigs. Minimal changes (intimal thickening and fragmentation of internal elastic lamina) were observed only in parts of arteries of the C9 pigs. Secondly, the direct effects of LDL and VLDL on vascular responsiveness were studied. Although preincubation with LDL inhibited the EDR caused by exposure to bradykinin and A23187 in the coronary arteries of normal and cholesterol-fed pigs, preincubation with LDL inhibited the arterial relaxation induced by exposure to substance P or serotonin in both the C4 and the C9 pigs, but not in the control animals. The degree of inhibition was especially marked in the C9 pigs. The inhibitory effect of VLDL on EDR was weaker than that of LDL. Indomethacin (5 microM) did not alter this inhibitory effect of lipoproteins. Neither LDL nor VLDL had any effect on the vascular relaxation induced by nitroglycerin. These results are consistent with the idea that endothelium-dependent arterial relaxation is attenuated even at the very early stage of cholesterol-induced atherosclerosis. Atherogenic lipoproteins may further impair the decreased EDR in the arteries of hyperlipidemic pigs by two factors: one released on stimulation with bradykinin and the calcium ionophore A23187, the other released on stimulation with substance P and serotonin.
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PMID:Low level hyperlipidemia impairs endothelium-dependent relaxation of porcine coronary arteries by two mechanisms. Functional change in endothelium and impairment of endothelium-dependent relaxation by two mediators. 171 35

We examined the effects of a low pathophysiological level of hyperlipidemia and atherogenic lipoprotein (LDL) on the vascular responsiveness of isolated pig coronary arteries. Firstly, we studied the change of vascular responsiveness after feeding a cholesterol-rich diet to pigs for 4 or 9 weeks. Serum cholesterol level in pigs fed with the cholesterol-rich diet reached 218.5 +/- 32.9 mg/dl compared with 85.5 +/- 8.4 mg/dl in controls. Segments of the arteries were mounted in organ chambers for isometric tension recording. Contraction caused by KCl or prostaglandin F2 alpha was not altered significantly by hypercholesterolemia. Relaxation in response to Ca2+ ionophore A23187 or nitroglycerin was not altered significantly by hypercholesterolemia. Relaxation in response to Ca2+ ionophore A23187 or nitroglycerin was not altered. Endothelium-dependent relaxation evoked by high but not low concentrations of bradykinin and substance P were reduced in pigs fed with the cholesterol-rich diet for 4 weeks as compared with those in normal pigs. Those evoked by bradykinin, substance P, and serotonin were significantly reduced in pigs fed with the cholesterol-rich diet for 9 weeks. Histologically, the fatty changes or intimal thickening were not so evident in coronary arteries of pigs fed for 4 weeks with the cholesterol-rich diet, but only minimal changes were observed in those fed with the diet for 9 weeks by light or electron microscopy. Secondly, the direct effects of LDL on the vascular responsiveness were examined.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Hyperlipidemia impairs vascular endothelium-dependent relaxation in pig coronary arteries]. 223 15

The endothelium modulates coronary vascular tone by the release of endothelium-derived relaxing or contracting substances. The endothelium-derived relaxing factor has been identified as nitric oxide synthesized in endothelial cells from L-arginine. The endothelium can release other relaxing substances such as prostacyclin and a hyperpolarizing factor. Endothelin-1 is a potent vasoconstrictor peptide formed by endothelial cells, and is likely to be the physiologic antagonist of endothelium-derived relaxing factor. Other putative contracting factors include superoxide anions and products of arachidonic acid metabolism. Endothelium-derived relaxing factor is released spontaneously and in response to flow, platelet-derived products (that is, serotonin, thrombin and adenosine diphosphate) and certain autacoids (that is, acetylcholine, bradykinin, histamine, substance P, vasopressin, alpha-adrenergic agonists). A considerable heterogeneity of responses exists among vessels of different size from different anatomic origin and different species. Hypercholesterolemia, atherosclerosis, hypertension and myocardial ischemia or reperfusion, or both, impair endothelium-dependent relaxation. Under normal conditions, endothelium-derived relaxing factor appears to dominate the control of vascular tone of large and small coronary vessels, whereas in disease states, endothelium-derived contracting factors are released. Impairments of endothelial function may be important in the development of various forms of cardiovascular disease.
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PMID:Endothelial control of vascular tone in large and small coronary arteries. 240 18

The influence of hypercholesterolemia on the reactivity of coronary arteries was investigated after feeding a high-cholesterol diet to pigs for 9 weeks. After this duration of hypercholesterolemia, the fatty or intimal proliferative changes of atherosclerosis were not yet evident in the coronary arteries by light or electron microscopy. Changes in isometric tension were compared in isolated ring segments of coronary arteries from normal and hypercholesterolemic animals. The endothelium failed to inhibit contractions caused by 5-hydroxytryptamine in coronary arteries from hypercholesterolemic animals, but it did so in normal vessels. In contracted arteries, endothelium-dependent relaxations caused by 5-hydroxytryptamine and substance P were reduced by hypercholesterolemia. In contrast, endothelium-dependent relaxations mediated by norepinephrine acting at alpha 2-adrenoceptors and those caused by the calcium ionophore A23187 were unaffected. Endothelium-independent beta-adrenergic relaxations caused by norepinephrine, as well as those caused by nitroprusside, and papaverine also were unaffected by hypercholesterolemia. The loss of selective endothelial cell receptor-mediated relaxation suggests that it is not the ability of the coronary artery endothelium to elaborate vasodilators, but the initiation of the coronary artery endothelial cell response to 5-hydroxytryptamine and substance P that is affected by hypercholesterolemia. Thus, during hypercholesterolemia, selective endothelial cell dysfunction giving rise to abnormal coronary artery reactivity precedes the onset of coronary artery atherosclerosis.
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PMID:Loss of selective endothelial cell vasoactive functions caused by hypercholesterolemia in pig coronary arteries. 246 Feb 69

Patients with hypercholesterolemia have impaired endothelium-dependent vasodilation. However, previous human studies have invariably used muscarinic agents to assess endothelial function. The purpose of this investigation was to determine whether impaired endothelium-dependent vasodilation of hypercholesterolemic patients is related to a specific and isolated defect of the muscarinic receptor, or to a broader abnormality of the endothelial cells. The forearm vascular responses to the endothelium-dependent agents acetylcholine (7.5, 15, and 30 micrograms/min) and substance P (1, 2, and 4 pmol/min), and to the direct smooth muscle dilator sodium nitroprusside (0.8, 1.6, and 3.2 micrograms/min) were studied in 16 hypercholesterolemic patients (8 men and 8 women; age [mean +/- SD] 50 +/- 7 years; serum cholesterol > 250 mg/dl) and 16 normal volunteers (8 men and 8 women; age 47 +/- 8 years; serum cholesterol < 200 mg/dl). Drugs were infused into the brachial artery and the response of the forearm vasculature was measured by strain-gauge plethysmography. The vasodilator response to acetylcholine was reduced in hypercholesterolemic patients compared with normal controls; at the highest dose (30 micrograms/min) the increase in forearm blood flow was 13.5 +/- 7 ml/min/100 ml in controls and 7.54 +/- 6 in patients (p < 0.05). The response to substance P was also blunted in hypercholesterolemic patients; at the highest dose (4 pmol/min), the increase in forearm blood flow was 12.1 +/- 5 ml/min/100 ml in controls and 7.6 +/- 4 in patients (p < 0.03). A significant correlation was found between the highest blood flow responses with acetylcholine and with substance P (r = 0.58; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Impaired endothelium-dependent vascular relaxation in patients with hypercholesterolemia extends beyond the muscarinic receptor. 752 64

We examined the effect of hypercholesterolemia on vasodilatory responses to clonidine in isolated and perfused rabbit common carotid arteries that had been preconstricted by phenylephrine. The responses decreased in rabbits fed an atherogenic diet for 4 or 8 weeks, whereas the responses to acetylcholine, nitroglycerin and substance P were not changed after the cholesterol feeding. Attenuated responses to clonidine were maintained for 24 weeks after cessation of the atherogenic diet, suggesting that this response might be an early marker of atherosclerosis.
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PMID:Attenuation of clonidine-induced vascular alpha 1-antagonistic action in hypercholesterolemic rabbit common carotid arteries. 786 61

1. Langendorff hearts, perfused at constant volume, were prepared from rabbits fed a cholesterol-enriched diet for 4 months. Coronary perfusion pressure and nitric oxide (NO) release (oxyhaemoglobin technique) into the coronary effluent were measured continuously. Prostacyclin (PGI2) in the effluents was determined by radioimmunoassay (6-oxo-PGF1 alpha). 2. Basal NO release was not different between control and hypercholesterolaemic rabbits. However, the coronary vasculature of hypercholesterolaemic rabbits showed a considerably (> 50%) reduced endothelium-dependent relaxation in response to short-term (3 min) infusion of bradykinin (50 nM) and substance P (50 nM) (P < 0.05, n = 8-9). Under these conditions, NO release into the vessel lumen was increased, by 26%, in hypercholesterolaemic hearts (P < 0.05, n = 8-9). NG-nitro-L-arginine (L-NOARG, 30 microM) significantly attenuated both bradykinin-induced NO formation and vessel relaxation in control hearts but only NO release in hypercholesterolaemia. L-Arginine (200 microM) restored the response to that before L-NOARG but did not improve the reduced endothelium-dependent relaxation in cholesterol-fed rabbits. 3. Superoxide dismutase (10 u ml-1) significantly improved vessel relaxation without changing the hypercholesterolaemia-related coronary dysfunction. Vasodilatation in response to exogenous NO donors (linsidomine) was diminished in hypercholesterolaemia as compared to controls. 4. Basal PGI2 release was unchanged in hypercholesterolaemic hearts. There was a tendency in these hearts for greater PGI2 formation after stimulation by substance P and bradykinin (P > or = 0.05). The coronary relaxation to iloprost was unchanged. 5. The data demonstrate impaired endothelium-dependent relaxation of coronary arterial resistance vessels in hypercholesterolaemia. This diminished vascular response was not due to reduced NO generation but probably a reduced action of released NO, either by accelerated degradation and/or disturbed signal transduction pathways to vascular smooth muscle cells. There was no significant change in PGI2 related pathways of vasomotor control in hypercholesterolaemia.
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PMID:Reduced endothelium-dependent relaxation at enhanced NO release in hearts of hypercholesterolaemic rabbits. 803 87

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

The endothelium modulates vascular tone by producing vasodilator vasoconstrictor substances. Of these, the most well characterized and potentially important are .NO and .02-. These small molecules exhibit opposing effects on vascular tone, and chemically react with each other in a fashion which negates their individual effects and leads to the production of potentially toxic substances. These dynamic interactions may likely have important implications, altering not only tissue perfusion but also contributing to the process of atherosclerosis. .NO is produced in endothelial cells by an enzyme termed nitric oxide synthase. The endothelial .NO-synthase is activated when the intracellular level of calcium is increased. This occurs in response to neurohormonal stimuli and in response to shear stress. Acetylcholine and substance P are examples of neurohumoral substances that are able to stimulate the release of nitric oxide and to assess endothelial regulation of vasomotor tone. Importantly, the vasodilator potency of nitric oxide released by the endothelium is abnormal in a variety of diseased states such as hypercholesterolemia, atherosclerosis and diabetes mellitus. This may be secondary to decreased synthesis of nitric oxide or increased degradation of nitric oxide due to superoxide anions. More recent experimental observations demonstrate increased production of superoxide in atherosclerosis, diabetes mellitus and high renin hypertension suggesting that endothelial dysfunction in these states is rather secondary to increased .NO metabolism rather than due to decreased synthesis of .NO. Superoxide rapidly reacts with nitric oxide to form the highly reactive intermediate peroxynitrite (ONOO-). Peroxynitrite can be protonated to form peroxynitrous acid which in turn can yield the hydroxyl radical (OH.). These reactive species can oxidize lipids, damage cell membranes, and oxidize thiol groups. .NO given locally, exerts potent antiatherosclerotic effects such as inhibition of platelet aggregation, inhibition of adhesion of leukocytes and the expression of leukocyte adhesion molecules. It is important to note, however, that in-vivo treatment with .NO (via organic nitrates) increases rather than decreases oxidant load within endothelial cells. It remains therefore questionable whether systemic treatment with .NO may have antiatherosclerotic properties or whether .NO may initiate or even accelerate the atherosclerotic process.
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PMID:The physiology and pathophysiology of the nitric oxide/superoxide system. 923 65


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