UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cells can produce at least 3 substances which cause relaxation of vascular smooth muscle: (1) endothelium-derived nitric oxide (NO, which is secreted not only toward the underlying vascular smooth muscle but also into the blood vessel lumen). NO also has a physiological role at the interface between the endothelial cells and the blood content; in particular, NO inhibits the adhesion of platelets and leukocytes to the endothelium. (2) Endothelium-derived hyperpolarizing factor, presumably a labile metabolite of arachidonic acid formed through the P-450 pathway, which appears to act on smooth muscle by being one of the few physiologic openers of the potassium channels. (3) Prostacyclin, which can be considered as an endothelium-derived relaxing substance, given its vasodilator activity and its primarily endothelial origin. One of the main factors modulating the release of these EDRFs is the shear stress of blood on the arterial wall, which explains why flow-induced vasodilation is endothelium-dependent in the intact organism. The peptide bradykinin is a potent stimulus for EDRF release. The normal lifespan of an adult human endothelial cell is some 30 years, after which aging takes its toll and the cells must be replaced. The regenerated cells lose some of their ability to release EDRF, in particular in response to platelet aggregation and thrombin. Finally, in hypertension and atherosclerosis, a decrease in endothelium-dependent relaxation is obvious in response to a variety of stimuli. All converting enzyme inhibitors tested so far share a potentiating effect on endothelium-dependent relaxation to bradykinin, and augmented local production of bradykinin may help to explain the acute vasodilator properties of these compounds.
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PMID:Endothelium-derived relaxing factors and converting enzyme inhibition. 748 85

From pharmacologic investigations and clinical studies it is known that angiotensin-converting enzyme (ACE) inhibitors exhibit additional local actions, which are not related to hemodynamic changes and which cannot be explained simply by interference with the renin-angiotensin system with subsequent inhibition of angiotensin II formation. Because ACE is identical to kininase II, which inactivates the nonapeptide bradykinin (BK), potentiation of BK might be responsible for these additional effects of ACE inhibitors. To prove the specificity of BK-mediated effects by ACE inhibition, we used the specific B2 kinin receptor antagonist HOE 140 in different models: endothelial cell cultures; atherosclerosis in high-cholesterol-fed rabbits; neointima formation with smooth cell proliferation and migration after endothelial denudation in rats; myocardial ischemia in rats, rabbits, and dogs; and left ventricular hypertrophy in rats. The beneficial effects of ramipril or BK given in non-blood pressure-lowering doses in these models were abolished by HOE 140 (icatibant). Ramipril exerts cardioprotective effects in different experimental models. The formation of the endothelial autacoids nitric oxide and prostacyclin, enhanced when BK degradation is inhibited by ACE inhibition, may contribute to the observed beneficial effects.
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PMID:Contribution of bradykinin to the cardiovascular effects of ramipril. 751 34

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

The effects of 3 days' exposure to native and oxidatively modified human low density lipoprotein (LDL and Ox-LDL) on cultured bovine aortic endothelial cell cholesterol content, membrane microviscosity and intracellular free calcium concentration ([Ca2+]i) were studied. Free cholesterol content increased by 35% and 100% in LDL and Ox-LDL treated cells, respectively, these effects being reversed by vitamin E; esterified cholesterol, which rose by 110% in the Ox-LDL group only, was not affected by vitamin E. Membrane microviscosity, measured as the fluorescence polarization of the trimethylammonium derivative of diphenyl-hexatriene, increased by 9% in Ox-LDL treated cells only. This effect was also reversed by vitamin E. Using the calcium sensitive fluorescent dye fura 2-AM, increases in basal [Ca2+]i of 36% in LDL and 81% in Ox-LDL treated cells were observed. The bradykinin mediated increase in [Ca2+]i was enhanced in both the LDL and, to a greater extent, the Ox-LDL group. Vitamin E reversed the effects of LDL on [Ca2+]i but had no influence in the Ox-LDL group. The lipoproteins affected all parameters measured in this study. Oxidized LDL produced reversible and irreversible alterations to the membrane and the [Ca2+]i. All changes associated with LDL were abolished by vitamin E. Such modifications in the physicochemical properties of the membrane and [Ca2+]i could be involved in the initiation of the atherosclerotic process.
Atherosclerosis 1995 Apr 24
PMID:Oxidized-LDL induced changes in membrane physico-chemical properties and [Ca2+]i of bovine aortic endothelial cells. Influence of vitamin E. 760 87

Hyperlipidemia contributes to the development of intimal hyperplasia and subsequent accelerated atherosclerosis in vein bypass grafts. This study examines the effect of dietary supplementation with L-arginine on the development of intimal hyperplasia and the vasomotor function of vein grafts in hypercholesterolemic animals. Thirty male New Zealand White rabbits had a right carotid vein bypass graft and were sacrificed at 28 days postoperatively. Twenty animals received a 1% cholesterol diet for 4 weeks prior to surgery and this diet was continued until harvest. Of these, 10 also received L-arginine (2.25%, 2 g/kg, p.o.) 7 days preoperatively and thereafter until harvest. The last 10 animals were controls. Vein grafts were harvested either for morphology or for in vitro isometric tension studies. Cumulative dose-response curves to norepinephrine, serotonin, and bradykinin were recorded, and following norepinephrine precontraction, relaxation to acetylcholine and sodium nitroprusside were determined. After in situ pressure fixation, intimal thicknesses of the vein grafts were measured by videomorphometry. The addition of L-arginine doubled the serum arginine concentrations. Intimal hyperplasia of both groups of hypercholesterolemic vein grafts contained foam cells and lipid-laden endothelial and smooth muscle cells. There was a 24% reduction in the intimal thickness of vein graft intimal hyperplasia in the L-arginine group compared to that in the hypercholesterolemia group (P < 0.05). All hypercholesterolemic vein grafts were two-fold thicker than in the control group. L-arginine supplementation resulted in the preservation of acetylcholine-mediated relaxation but did not change hypercholesterolemia-induced contractile agonist supersensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Control of accelerated vein graft atheroma with the nitric oxide precursor: L-arginine. 763 Jan 34

Nitric oxide (NO) synthesised by endothelial cells, plays a key role in the control of vascular tone. Its synthesis from L-arginine is assured by NO-synthase, the activity of which is dependent on intracellular calcium concentrations, which are themselves modulated by pharmacological (acetylcholine, serotonin, bradykinin...) or physical factors (shearing forces exerted by blood flow). NO acts by stimulating a soluble guanylate-cyclase of the smooth muscle cells in the vessel wall. Its vasodilator effect is therefore mediated by an increase in intracellular cyclic GMP concentration. The synthesis or liberation of NO by the endothelium may be decreased or abolished during many pathological processes (hypercholesterolaemia, atherosclerosis, systemic or pulmonary hypertension...). The significance of this abnormality of NO-mediated endothelium-dependent vasodilation in different pathological conditions has not been established. However, it is probably significant in view of the different properties of NO: vaso-relaxation, antiaggregant and inhibition of vascular smooth muscle growth. It is not yet known whether this abnormality is a cause or a consequence of the underlying disease. From the therapeutic point of view, NO is an active metabolite of nitrate derivatives, sodium nitroprussiate and molsidomine which therefore share the same mode of action as the so-called "endothelium-dependent" vasodilatoe agents. The inhalation of NO, which is increasingly used in neonatal and adult intensive care units, is an alternative therapeutic approach in many conditions associated with pulmonary hypertension.
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PMID:[Nitric oxide, from vascular physiology to therapeutics]. 778 35

Several classes of antihypertensive drugs, including beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, alpha 1-blockers, and a combined calcium antagonist/alpha 1-blocker, have been shown to reduce atherosclerosis in hypercholesterolemic animals. Although the exact mechanism of action of these drugs has not been described, certain findings are of particular interest. All of these drugs have the ability to inhibit cellular growth. ACE inhibitors appear to be antiatherosclerotic in several species including the low density lipoprotein (LDL)-deficient Watanabe heritable hyperlipidemic rabbit, and their effects appear to be mediated through both angiotensin II inhibition and bradykinin enhancement. Calcium antagonists may influence primarily the development of new atherosclerotic lesions and their action may be species specific and, at least in part, dependent on the integrity of the LDL receptor. The action of alpha 1-blockers and of a combined calcium antagonist/alpha 1-blocker in hypercholesterolemic animals is probably related in part to their cholesterol-lowering properties. Whether any of the antihypertensive drugs can affect atherosclerosis in humans remains to be determined. Clinical trials are in progress to examine their effects on the course of coronary heart disease and on surrogate endpoints of atherosclerosis such as those demonstrable by angiography and Doppler-ultrasound techniques. Although the results of trials involving such surrogate markers will be of great interest, the findings will need to be interpreted with caution because they may not necessarily be predictive of either the course of atherosclerosis or its clinical complications.
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PMID:Can antihypertensive drugs reduce atherosclerosis and its clinical complications? 782 61

The goals of rational antihypertensive medication should embrace the alleviation of atherosclerosis, the clinical consequences of which pose a major health problem and hence socio-economic concern for industrialized countries. Angiotensin converting enzyme (ACE) inhibitors are endowed with pharmacodynamic features which may help to attain this aim. Various animal experiments with cholesterol-fed rabbits, pigs and monkeys, as well as with rabbits with inherent disorder of lipid metabolism (WHHL-rabbit), demonstrated endothelial protection against loss of function due to hyperlipidemia and attenuation of lipid deposition in conduit blood vessels with ACE-inhibition. The alleviation of progressive atherosclerosis, which is a common feature of restenosis development following angioplasty, was shown in hypercholesterolemic rabbits and normal rats, but did not occur in clinically more relevant porcine models nor in large clinical trials. Circumstantial evidence from miscellaneous experiments is in line with the view that it is enhancement of bradykinin activity which causes the endothelial protection against the consequences of hypercholesterolemia. Furthermore, loss of relaxation of coronary resistance vessels without overt atherosclerosis despite hypercholesterolemia can be restored by augmentation of the EDRF-pathway as has been demonstrated with ramiprilat in vitro. This is being substantiated in preliminary clinical reports with different ACE-inhibitors. The possible association between improvement in both insulin sensitivity and endothelial function requires further investigation. The critical analysis of present experimental findings on a beneficial influence on both the spontaneous and the progressive development of atherosclerosis indicates ACE-inhibition to be more likely to preserve or restore the function of an intact endothelium than to interfere with the complex reaction occurring after injury of an already affected blood vessel.
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PMID:[ACE inhibition and atherosclerosis in the animal model]. 785 76

Endothelial function of epicardial arteries and coronary resistance vessels, as well as endothelial dysfunction and clinical symptoms of coronary artery disease and their therapeutic implications are reviewed including the presentation of the author's own results. Coronary endothelial vasodilator dysfunction represents a fundamental functional disturbance in vascular biology with the development of atherosclerosis. This functional alteration in coronary vascular reactivity appears to play an important integral part in the clinical presentation of coronary artery disease. Humoral and neuronal factors in favour of vasoconstrictor influences affect the balance between myocardial oxygen supply and demand, thus, facilitating the manifestation of myocardial ischemia. In order to identify more selective therapies the potential mechanisms underlying an impaired release or activity of EDRF/NO must be considered. Dysfunction of the endothelial L-arginine/NO pathway may involve decreased activity of NO synthase, increased inactivation of NO formed from its precursor L-arginine, impaired signal transduction mechanisms and reduced intracellular availability of L-arginine. Currently, initial therapeutic strategies include the supplementation of L-arginine, the use of antioxidants, as well as ACE-inhibitors. ACE-inhibitors have been shown not only to reduce vascular tone (and hypertrophy) by inhibition of angiotensin II formation, but also by increasing the endothelial production of NO and prostacyclin most likely due to the local accumulation of endothelium-derived bradykinin. Thus, ACE-inhibition appears to provide the potential to improve endothelial NO synthesis. Indeed, study results demonstrate that chronic ACE-inhibition is associated with an increased coronary blood flow response to acetylcholine suggesting an improvement in endothelial vasodilator functioning of coronary resistance vessels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Coronary endothelial vasodilator dysfunction: clinical relevance and therapeutic implications. 785 84

The pathogenesis of Raynaud's disease is unclear; an enhanced response to catecholamines has been hypothesised to contribute to this vasospastic disorder. Impaired endothelium-dependent dilation occurs in other diseases associated with vasospasm, such as coronary atherosclerosis. We investigated both endothelium-dependent and endothelium-independent venodilatory function in Raynaud's disease using the hand-vein compliance technique. Full dose-response curves to noradrenaline were constructed in 10 subjects with primary Raynaud's disease and 10 age and sex matched control subjects. The two groups did not have a different response to noradrenaline. Mean (SD) log values of ED50s (the dose producing half maximum response) were 1.00 (0.59) (geometric mean 10 ng/min) in Raynaud's disease compared with 1.29 (0.66) (20 ng/min) in control subjects (p = 0.16). The efficacy of noradrenaline as a venoconstrictor was similar in the two groups: mean maximum dilation (Emax) to noradrenaline was 81 (14)% in the Raynaud's group and 89 (8)% in the control group (p = 0.08). Full dose-response curves to the endothelium-dependent dilator bradykinin were constructed. Emax to bradykinin was significantly lower in the Raynaud's group than in the control group (65 [21] vs 91 [29%], p = 0.02). ED50 values (doses producing half maximum response) for bradykinin were similar in the two groups. Maximum dilation with nitroprusside, a direct releaser of the vasodilator nitric oxide, was not diminished in the Raynaud's group (94 [23] vs 102 [15]% in controls, p = 0.26). These results suggest that endothelium-dependent venodilation is impaired in peripheral vessels in Raynaud's disease, possibly due to diminished release of nitric oxide, and may contribute to the pathogenesis of the disorder.
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PMID:Venodilation in Raynaud's disease. 790 47

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