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)

This study was undertaken to determine whether atherosclerosis impairs relaxations mediated by endothelium-derived relaxing factor (EDRF) in human coronary arteries. Epicardial coronary arteries were obtained from the hearts of cardiac transplantation patients with or without histologically documented coronary atherosclerosis (atherosclerotic arteries were from patients aged 42-55 years, nonatherosclerotic arteries were from patients aged 14-24 years). Transverse strip preparations were mounted in organ baths for isometric tension recording. Tension was induced with prostaglandins F2 alpha. Indomethacin (10(-5) M) was present to prevent possible interference from endogenously formed prostaglandins. The EDRF-mediated relaxations in response to substance P (10(-10) to 10(-8) M), bradykinin (10(-9) to 10(-7) M), and Ca2+-ionophore A23187 (10(-9) to 10(-7) M) were significantly attenuated in atherosclerotic arteries. In deendothelialized tissues these compounds had no effect. In contrast, endothelium-independent relaxations induced by isoprenaline (10(-7) to 10(-5) M) were not affected by atherosclerosis. Atherosclerotic arteries showed also normal relaxations with high concentrations of glyceryl trinitrate (10(-8) to 10(-7) M), but reduced relaxations with a lower concentration of the compound (10(-9) M). Acetylcholine (10(-7) to 10(-6) M) only produced endothelium-dependent relaxations in 8 of 60 arterial preparations (with or without atherosclerosis). In most of the arteries, it was a direct vasoconstrictor (which may have masked EDRF release in many cases). Omission of indomethacin from the bath solution increased the incidence of moderate acetylcholine-induced relaxations (9 of 16 preparations). It is concluded that atherosclerosis attenuates EDRF-mediated vasospasm and myocardial ischemia.
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PMID:Selective attenuation of endothelium-mediated vasodilation in atherosclerotic human coronary arteries. 244 55

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

In canine and porcine coronary arteries, experimental atherosclerosis (induced by endothelial denudation followed by a high-cholesterol diet) potentiates the vasoconstrictor effects of histamine, serotonin, and ergonovine. In isolated human atherosclerotic coronary arteries, only hypersensitivity to histamine has been demonstrated. This discrepancy could be due to several factors. First, the atherosclerotic lesions in human vessels are different from those observed in the animal, since experimental atherosclerosis often corresponds only to the early stage of the disease in humans. Second, the human atherosclerotic coronary arteries were isolated mainly from patients with cardiac failure, a condition that alters the responses of coronary smooth muscle to vasoactive amines. With regard to endothelium-dependent vasodilators, marked attenuations of the relaxations to substance P, bradykinin, and the Ca2+ ionophore A23187 have been described in isolated human atherosclerotic arteries. Acetylcholine elicits variable responses in these preparations and even if the arteries are devoid of atherosclerotic lesions, it often fails to relax them. In addition to this endothelial dysfunction, severely atherosclerotic human coronary vessels exhibit a slightly decreased responsiveness to nitroglycerin and SIN-1 but not to forskolin. Another abnormality of the smooth muscle is a marked attenuated beta-adrenergic relaxation. Thus, atherosclerosis of human coronary vessels induces not only marked alterations in endothelium-dependent responses but also modifies the sensitivity to several endothelium-independent vasodilators.
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PMID:Atherosclerosis and responses of human isolated coronary arteries to endothelium-dependent and -independent vasodilators. 248 97

To evaluate the significance of repeated denudation injury in progression of atherosclerosis, we performed a single and then a second balloon denudation on the rabbit carotid arteries. Morphological examinations and organ chamber experiments were performed, and the results were compared. On morphological examinations, reendothelialization was almost completed in 2 wk after redenudation, whereas it required 6 wk after a single denudation. Intimal thickening progressed after redenudation. Organ chamber experiments showed that contractile responses and endothelium-independent relaxation remained unchanged after redenudation. Endothelium-dependent relaxations to acetylcholine, ADP, and substance P decreased progressively by repeating denudation. These relaxation responses were inhibited by NG-nitro-L-arginine, hemoglobin, and methylene blue and were considered to be associated with the production and/or release of endothelium-derived relaxing factor-nitric oxide (EDRF-NO). The diffusion barrier mechanism for the decreased endothelium-dependent relaxations was ruled out using sandwich experiments. In conclusion, repeated endothelial denudation caused progression of intimal thickening and acceleration of endothelial regeneration, and repeated endothelial regeneration resulted in progressively less production and/or release of EDRF-NO.
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PMID:Repeated endothelial removal augments intimal thickening and attenuates EDRF release. 751 59

Mast cells and their chemical mediators play a role in cardiac and systemic anaphilaxis. Perivascular and cardiac mast cells have been implicated in the pathogenesis of coronary artery spasm, atherosclerosis, myocardial ischemia, and cardiomyopathy. Despite this, nothing is known about the immunological and biochemical characteristics of the human heart mast cell (HHMC). We have isolated and partially purified HHMC and compared them with mast cells isolated from lung (HLMC) and skin (HSMC) tissues. Cross-linking of the high-affinity receptor for IgE (Fc epsilon RI) by a polyclonal anti-Fc epsilon antibody caused the release of preformed (histamine and tryptase) and de novo synthesized mediators [peptide leukotriene C4 (LTC4) and prostaglandin D2 (PGD2)]. The tryptase content of HHMC (19.4 +/- 1.5 micrograms/10(6) cells) was lower than HSMC (33.4 +/- 2.5 micrograms/10(6) cells) and higher than HLMC (10.6 +/- 1.9 micrograms/10(6) cells). Maximal stimulation of HHMC with anti-IgE led to the release of LTC4 (17.5 +/- 5.1 ng/10(6) mast cells) and PGD2 (17.8 +/- 5.0 ng/10(6) mast cells, whereas HSMC synthesized more PGD2 (65.0 +/- 6.8 ng/10(6) mast cells) and much less LTC4 (< 5 ng/10(6) cells). Recombinant human C5a anaphylatoxin and protamine induced histamine release from HHMC and HSMC, but not from HLMC. Substance P and morphine selectively induced the release of histamine from HSMC, but not from HHMC and HLMC. Compound 48/80 caused histamine release from HSMC and HHMC, but not from HLMC. The pattern of mediators synthesized and the responsiveness of HHMC to different secretagogues appear unique providing strong evidence of human mast cell heterogeneity.
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PMID:Human heart mast cells: a definitive case of mast cell heterogeneity. 753 2

Nitric oxide (NO), a potent vasodilator produced by endothelial cells, is thought to be the endothelium-dependent relaxing factor (EDRF) which mediates vascular relaxation in response to acetylcholine, bradykinin and substance P in many vascular beds. NO has been implicated in the regulation of blood pressure and regional blood flow, and also affects vascular smooth-muscle proliferation and inhibits platelet aggregation and leukocyte adhesion. Abnormalities in endothelial production of NO occur in atherosclerosis, diabetes and hypertension. Pharmacological blockade of NO production with arginine analogues such as L-nitroarginine (L-NA) or L-N-arginine methyl ester affects multiple isoforms of nitric oxide synthase (NOS), and so cannot distinguish their physiological roles. To study the role of endothelial NOS (eNOS) in vascular function, we disrupted the gene encoding eNOS in mice. Endothelium-derived relaxing factor activity, as assayed by acetylcholine-induced relaxation, is absent, and the eNOS mutant mice are hypertensive. Thus eNOS mediates basal vasodilation. Responses to NOS blockade in the mutant mice suggest that non-endothelial isoforms of NOS may be involved in maintaining blood pressure.
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PMID:Hypertension in mice lacking the gene for endothelial nitric oxide synthase. 754 86

Endothelial-dependent relaxation of vascular smooth muscle cells evoked by a number of agonists, including cholinomimetics and substance P, is often accompanied by an increase (repolarization and/or hyperpolarization) in the membrane potential. This change in membrane potential appears predominantly to reflect the action of an endothelial-derived hyperpolarizing factor (EDHF), which is distinct from NO (or endothelial-derived relaxing factor), and is discussed in this article by Chris Garland and colleagues. In large conducting arteries, EDHF may provide a secondary system to NO, which assumes primary importance in some disease states such as pulmonary hypertension and atherosclerosis. However, in small resistance arteries (100-300 microns), EDHF appears to be a major determinant of vascular calibre under normal conditions, and may therefore be of primary importance in the regulation of vascular resistance.
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PMID:Endothelium-dependent hyperpolarization: a role in the control of vascular tone. 773

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

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

Studies on such injury processes as atherosclerosis, angioplasty, and restenosis, have shown an impairment of relaxations mediated by endothelium-derived relaxing factor (EDRF). Increasingly, the rabbit carotid artery is being used as the vessel of choice in such studies, but a definite protocol for the assessment of endothelial dysfunction or denudation has not been developed. Using isolated carotid artery rings, we have obtained reproducible dose-response curves in endothelially intact and denuded vessels from normally fed rabbits to a variety of vasoconstrictors and endothelium-dependent and -independent vasodilators. Endothelium-dependent vasodilators (acetylcholine (1 x 10(-8)-1 x 10(-6) M), carbachol (1 x 10(-8)-5 x 10(-6) M), substance P (0.01-100 nM), and A23187 (1 x 10(-8)-1 x 10(-7) M) relaxed the arteries in a concentration-dependent manner but produced no relaxation in denuded vessels. Endothelium-independent nitric oxide (NO) donors [Sin-1 (1 x 10(-8)-1 x 10(-6) M)] and sodium nitroprusside (1 x 10(-8)-1 x 10(-6) M)) relaxed both intact and denuded vessels to a similar degree (slight augmentation of the relaxation induced in denuded vessels was not significant), demonstrating that denuded vessels did not have an impaired reactivity to NO. Concentration response curves to the vasoconstrictors [5-HT (1 x 10(-7)-1 x 10(-4) M) and KCl (15-60 mM)] were produced in intact vessels and it was shown that similar contraction was produced by 1 x 10(-6) M 5-HT in intact and denuded vessels. This indicated that the vessels retained contractile ability following denudation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the responses of isolated rings of rabbit left carotid artery. A potential protocol for the assessment of pathologically induced functional changes. 840 Apr 14


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