Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

The endothelial function of a coronary bypass graft is an important aspect, contributing not only to its patency but to its functional performance. To evaluate this aspect in vivo, we studied 16 patients who underwent selective catheterization of the native gastroepiploic artery (GEA). Quantitative angiography of the GEA was performed at baseline, after 2 minutes' infusion of acetylcholine in three ascending doses, and after 2 mg isosorbide dinitrate injection directly into the GEA. Mean GEA diameter was 2.02 +/- 0.38 mm at baseline. We observed dose-dependent vasodilation during acetylcholine infusion: The mean diameter increased slightly to 2.11 +/- 0.32 mm (+6%, not significant) with the second dosage and, more significantly, with the highest dosage, to 2.32 +/- 0.33 mm (+18%, p < 0.001). More important vasodilation was observed after administration of nitrates (+36%, p < 0.001). We found no difference between patients with and without coronary artery disease and no relationship with risk factors for atherosclerosis. A positive correlation was seen between the vasodilation observed after nitrate administration and the highest dose of acetylcholine (r = 0.728, p = 0.002). In conclusion, the GEA demonstrates a notable vasodilatory response to nitrates (non-endothelium-dependent) and a dose-related dilator response to acetylcholine, reflecting preserved endothelial function. This sensitivity should affect favorably the hemodynamic performance of grafts performed with GEA, as well as these grafts' long-term patency rate.
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PMID:Evaluation in vivo of the endothelial function of the native gastroepiploic artery. 945 34

Under basal conditions, nitric oxide (NO) modulates vascular tone, serves as an antithrombotic agent, and inhibits vascular smooth muscle cell proliferation. NO deficiency has been implicated in the pathophysiology of several vascular disorders, including hypertension, atherosclerosis, and restenosis, and provides a plausible biologic basis for the use of NO replacement therapy in these conditions. Treatment with conventional nitrate preparations is limited by a short therapeutic half-life, systemic absorption with potentially adverse hemodynamic effects, and drug tolerance. To overcome these limitations, novel delivery systems and novel NO donors have been developed that offer selective effects, a prolonged half-life, and a reduced incidence of tolerance.
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PMID:New developments in nitrosovasodilator therapy. 954 68

Endothelial function has been shown to be impaired in patients with essential hypertension. The purpose of the present study was to determine whether antihypertensive drug therapy improves impaired endothelium-dependent renal vasorelaxation in essential hypertensive patients without atherosclerosis. We evaluated the effects of intravenous infusion of L-arginine (500 mg/kg given over 30 minutes) on systemic and renal hemodynamics in 27 patients with mild to moderate essential hypertension who were randomly assigned to treatment with either the angiotensin-converting enzyme inhibitor imidapril or the calcium antagonist amlodipine for 12 weeks in a double-blind fashion. After the 12 weeks, the decrease in blood pressure was similar in the imidapril (n=14) and amlodipine (n=13) groups. The increase in renal plasma flow was also similar in both groups. L-Arginine-induced renovascular relaxation was increased by imidapril (renal plasma flow, 9.6+/-5.1% to 14.4+/-7.4%; renal vascular resistance, -10.4+/-8.1% to -16.7+/-9.2%, P<0.05, respectively) but not by amlodipine. Urinary excretion of nitrite/nitrate in response to L-arginine was significantly increased by imidapril (90+/-29% to 134+/-63%, P<0.05) but remained unchanged by amlodipine. These findings suggest that angiotensin-converting enzyme inhibition improves the impaired endothelium-dependent renovascular relaxation in patients with essential hypertension due to the increase in nitric oxide production and that the reduction in blood pressure with a calcium antagonist does not play a major role in the potentiation of L-arginine/nitric oxide-mediated effects.
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PMID:Angiotensin-converting enzyme inhibition, but not calcium antagonism, improves a response of the renal vasculature to L-arginine in patients with essential hypertension. 967 32

The endothelium regulates vascular function by releasing the vasodilator autacoid nitric oxide (NO) and the vasoconstrictor peptide endothelin-1 (ET-1). Impaired activity of NO as well as excessive activity of ET-1 have been demonstrated in hypercholesterolemia and atherosclerosis. Because dietary L-arginine can restore NO function and improve abnormal endothelium-dependent relaxation in hypercholesterolemic rabbits, we examined the effects of dietary supplementation with L-arginine in cholesterol-fed rabbits on endothelium-dependent vascular relaxation and ET-1-induced vascular contraction, as well as the systemic synthesis of ET-1. Rabbits were initially fed a diet enriched with 1% cholesterol for 4 weeks, followed by 0.5% cholesterol alone or supplemented with 2% L-arginine in drinking water during the next 12 weeks. Cholesterol feeding impaired endothelium-dependent relaxation of rabbit aortic rings ex vivo and increased urinary immunoreactive ET-1 excretion, along with decreased urinary nitrate excretion, an index of NO production. L-Arginine partially restored endothelium-dependent relaxation in parallel to increased urinary nitrate excretion and decreased urinary immunoreactive ET-1 excretion. Selective inhibition of ET-A receptors with BQ123 partially restored endothelium-dependent relaxation in hypercholesterolemic rabbits but had no effect on arterial rings from rabbits supplemented with L-arginine or from control animals. The contractile vascular response of aortic rings to exogenous ET-1 was increased in rabbits fed a high-cholesterol diet; this enhanced contractility to ET-1 was completely reversed by L-arginine. These data suggest that L-arginine restores endothelial function and normalizes the synthesis and vasoconstrictor response to ET-1 in hypercholesterolemia.
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PMID:Dietary L-arginine normalizes endothelin-induced vascular contractions in cholesterol-fed rabbits. 970 Sep 94

Pentaerythritol tetranitrate is an organic nitrate ester that undergoes metabolization to pentaerythritol, pentaerythritol trinitrate, pentaerythritol dinitrate and pentaerythritol mononitrate. Recent data suggested that pentaerythritol tetranitrate is endowed with vasoprotective activities in experimental atherosclerosis. This study was undertaken to gain insight into the underlying mechanism. The basic mechanism of action of all pentaerythritol nitrates was evaluated by measuring liberation of nitric oxide (NO), stimulation of human soluble guanylate cyclase and vasorelaxation in rabbit aorta. A subsequent in vivo study in New Zealand White rabbits was performed to investigate the effects of a 4 months lasting nonintermittent oral treatment with 6 mg pentaerythritol tetranitrate kg(-1) day(-1) on vascular superoxide production, endothelium dependent vasorelaxation and vasorelaxation to pentaerythritol tetranitrate itself. The formation rates of NO from the pentaerythritol nitrates (100 microM, n = 5) in presence of 5 mM cystein were (in nM min(-1)): 62.1 +/- 3.2 (pentaerythritol tetranitrate), 21.3 +/- 0.9 (pentaerythritol trinitrate), 6.4 +/- 0.6 (pentaerythritol dinitrate) and 3.2 +/- 0.4 (pentaerythritol mononitrate). Similarly, the pD2 values (-log M) for half-maximal activation of soluble guanylate cyclase decreased from pentaerythritol tetranitrate (3.391 +/- 0.09, n = 4) to pentaerythritol mononitrate (2.655 +/- 0.04, n = 3) as did the pD2 values (in -log M) for half-maximal relaxation of rabbit aortic rings (n = 7) from pentaerythritol tetranitrate (8.3 +/- 0.17) to pentaerythritol mononitrate (5.0 +/- 0.11). Significant correlations were found between the NO formation rates and the pD2 values for enzyme stimulation (r = 0.98, P = 0.002) and vasorelaxation (r = 0.90, P = 0.049) suggesting that these effects of the pentaerythritol nitrates were mediated by NO. The results of the in vivo study showed that aging induces a significant increase of aortic superoxide production (median values, n = 10) from 2.45 nM mg(-1) min(-1) (age 7 months) to 3.39 nM mg(-1) min(-1) (age 11 months, P < 0.01) that was prevented by concurrent treatment with pentaerythritol tetranitrate (2.76 nM mg(-1) min(-1)). In vitro vasorelaxation to pentaerythritol tetranitrate was identical in all groups indicating absence of nitrate tolerance. Endothelium-dependent vasorelaxation was also identical in all groups. These data suggest that oral treatment with pentaerythritol tetranitrate reduces vascular oxidant stress by an NO-dependent pathway, which may contribute to the vasoprotective activity of pentaerythritol tetranitrate in experimental atherosclerosis.
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PMID:Effects of nonintermittent treatment of rabbits with pentaerythritol tetranitrate on vascular reactivity and superoxide production. 975 35

Vascular endothelium releases nitric oxide (NO), an important vasodilator that is continuously synthesised by the constitutive enzyme, endothelial nitric oxide synthase (NOS). This maintains a constant vasodilator tone which is diminished in adult hypertension, due to reduced endothelium-dependent vascular relaxation, which is NO dependent. In childhood, however, hypertension is often secondary, and normalisation of blood pressure by removal of cause (e.g. renal artery stenosis, catecholamine-producing tumour) suggests reversibility of endothelial dysfunction, if it is present. Raised plasma levels of endogenous inhibitors have been found, especially in children with secondary hypertension due to renal parenchymal and renovascular disease, and may contribute to hypertension by more than just inhibition of vascular NO release; e.g. by reduction of glomerular filtration rate and promotion of salt and water retention. These inhibitors also modulate renin release, which may be of relevance in cardiovascular physiology, and may also interfere with the anti-platelet properties of NO, increasing the likelihood of vascular thrombotic events. NO inhibitors also promote endothelial activation, with increased expression of adhesion molecules that may form seedlings of atherosclerosis. In chronic renal impairment, accumulation of NO inhibitors may contribute to hypertension. Efficient long-session dialysis helps better interdialysis control of blood pressure in these subjects, independent of salt and water removal, suggesting that removal of such vasoactive agents may be important for efficient blood pressure control. There are a few studies assessing NO generation in hypertensive children via plasma nitrite and nitrate, the NO end products, which suggest normal or increased production as opposed to a reduction, perhaps as a compensatory phenomenon. In the treatment of hypertension, nitroprusside and nitrates exert their actions via NO donation. Excessive production of NO (usually via inducible NOS) or excessive administration (nitrovasodilators) can be cytotoxic and may cause hypotension and shock, as in severe sepsis. NOS inhibitors and NO therefore appear to play a crucial role in aetiology, complications and therapy of childhood hypertension.
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PMID:Vascular endothelium and nitric oxide in childhood hypertension. 981 94

This study investigated whether endothelin-1 (ET-1), a potent vasoconstrictor, which also stimulates cell proliferation, contributes to endothelial dysfunction and atherosclerosis. Apolipoprotein E (apoE)-deficient mice and C57BL/6 control mice were treated with a Western-type diet to accelerate atherosclerosis with or without ETA receptor antagonist LU135252 (50 mg/kg/d) for 30 wk. Systolic blood pressure, plasma lipid profile, and plasma nitrate levels were determined. In the aorta, NO-mediated endothelium-dependent relaxation, atheroma formation, ET receptor-binding capacity, and vascular ET-1 protein content were assessed. In apoE-deficient but not C57BL/6 mice, severe atherosclerosis developed within 30 wk. Aortic ET-1 protein content (P < 0.0001) and binding capacity for ETA receptors was increased as compared with C57BL/6 mice. In contrast, NO-mediated, endothelium-dependent relaxation to acetylcholine (56 +/- 3 vs. 99 +/- 2%, P < 0.0001) and plasma nitrate were reduced (57.9 +/- 4 vs. 93 +/- 10 micromol/liter, P < 0.01). Treatment with the ETA receptor antagonist LU135252 for 30 wk had no effect on the lipid profile or systolic blood pressure in apoE-deficient mice, but increased NO-mediated endothelium-dependent relaxation (from 56 +/- 3 to 93 +/- 2%, P < 0.0001 vs. untreated) as well as circulating nitrate levels (from 57.9 +/- 4 to 80 +/- 8.3 micromol/liter, P < 0.05). Chronic ETA receptor blockade reduced elevated tissue ET-1 levels comparable with those found in C57BL/6 mice and inhibited atherosclerosis in the aorta by 31% without affecting plaque morphology or ET receptor-binding capacity. Thus, chronic ETA receptor blockade normalizes NO-mediated endothelial dysfunction and reduces atheroma formation independent of plasma cholesterol and blood pressure in a mouse model of human atherosclerosis. ETA receptor blockade may have therapeutic potential in patients with atherosclerosis.
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PMID:Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice. 982 6

Vascular oxidative stress brought about by superoxide radicals and oxidized low-density lipoproteins (oxLDL) is a major factor contributing to decreased NO-dependent vasodilator function in hypercholesterolemia and atherosclerosis. We investigated whether chronic administration of L-arginine (2% in drinking water) or of alpha-tocopherol (300 mg/day) improves endothelium-dependent vasodilator function and systemic NO production, reduces vascular oxidative stress, and reduces the progression of atherosclerosis in cholesterol-fed rabbits with pre-existing hypercholesterolemia. Systemic NO production was assessed as urinary nitrate excretion; oxidative stress was measured by urinary 8-iso-PGF2alpha excretion in vivo, by lucigenin-enhanced chemiluminescence of isolated aortic rings ex vivo, and by copper-mediated LDL oxidation in vitro. Endothelium-dependent relaxation was almost completely abrogated in cholesterol-fed rabbits. Urinary nitrate excretion was reduced by 46+/-10%, and 8-iso-PGF2alpha excretion was increased by 61+/-18% as compared to controls (each P <0.05). Vascular superoxide radical release stimulated by PMA ex vivo was increased by 273+/-93% in this group, and the lag time of LDL oxidation was reduced by 35+/-6% (each P <0.05). Treatment with L-arginine and alpha-tocopherol reduced intimal lesion formation (by 68+/-6 and 4+/-11%, respectively; P <0.05) and improved endothelium-dependent relaxation. Both treatments also normalized urinary 8-iso-PGF2alpha excretion. L-Arginine increased urinary nitrate excretion by 43+/-13% (P <0.05) and reduced superoxide radical release by isolated aortic rings to control levels, which was unaffected by vitamin E treatment. By contrast, vitamin E dramatically increased the resistance of isolated LDL to copper-mediated oxidation in vitro by 178+/-7% (P <0.05), which was only marginally prolonged by L-arginine. Intimal thickening was reduced by both treatments. We conclude that both L-arginine and alpha-tocopherol reduce the progression of atherosclerotic plaques in cholesterol-fed rabbits. However, while L-arginine increases NO formation and reduces superoxide release, alpha-tocopherol antagonizes mainly oxLDL-related events in atherogenesis. Thus, both treatments reduce urinary isoprostane excretion and improve endothelium-dependent vasodilation via different mechanisms.
Atherosclerosis 1998 Nov
PMID:Dietary L-arginine and alpha-tocopherol reduce vascular oxidative stress and preserve endothelial function in hypercholesterolemic rabbits via different mechanisms. 986 36

We examined whether or not the oral administration of L-nitroarginine methylester (L-NAME), an inhibitor of nitric oxide (NO) synthase, promotes cholesterol-induced arteriosclerosis in the aorta and the coronary artery. Thirty-six male Japanese white rabbits were fed 0.5% cholesterol-containing laboratory chow and randomly assigned to the following three groups: (1) water, (2) 80 microg/ml L-NAME and (3) 400 microg/ml L-NAME in drinking water. The rabbits were fed a 0.5% cholesterol-containing diet for 8 months. During the 8-month period, the concentration of total cholesterol and L-nitroarginine in the serum and the mean blood pressure were measured. The concentration of NO3 in the serum was also measured. After sacrifice, the aortic surface involvement (AI%), the ratio of the thickened intima to the media and the contents of the total cholesterol of the aorta, the maximum % stenosis of the subepicardial large coronary artery, the % frequency of the nearly completely occlusive distal small coronary artery and the area of the myocardial fibrosis were all measured. We found no statistical difference among the three groups regarding the degree of arteriosclerotic lesions of the aorta and of the large coronary artery, and the area of myocardial fibrosis, as well as the serum cholesterol exposure index (the area under the curve of the serum total cholesterol concentration) and the mean blood pressure. However, the serum concentration of L-nitroarginine was approximately 50 and 200 microM/l in groups 2 and 3, respectively. The concentration of NO3 in the serum in group 1 was significantly higher than that in groups 2 and 3. We thus conclude, that the oral administration of L-NAME in the rabbits fed a cholesterol-containing diet for 8 months failed to promote arteriosclerotic lesions in the aorta and the coronary artery, even though the serum concentration of L-nitroarginine increased sufficiently to inhibit NO synthase in the arterial endothelium and the NO3 concentration in the serum decreased in the rabbits given L-NAME.
Atherosclerosis 1998 Nov
PMID:Oral administration of NO synthase inhibitor failed to promote arteriosclerotic lesions in the aorta and the coronary arteries of rabbits fed cholesterol. 986 38

Occlusive vascular disease begins with an alteration of the endothelium, which is characterized by a decrease in nitric oxide (NO) activity. Endogenous NO inhibits many key processes in atherogenesis, including monocyte adherence, platelet activation, and smooth muscle proliferation. The mechanism by which NO activity is reduced in hypercholesterolemia and in other metabolic disorders associated with atherogenesis appears to be multifactorial. It includes increased production of oxygen-derived free radicals, alterations in NO synthase, and the accumulation of endogenous inhibitors (ADMA) of NO synthase. Plasma concentrations of ADMA are elevated in hypercholesterolemic humans. Elevated ADMA concentrations are associated with impaired endothelium-dependent, NO-mediated vasodilatation and reduced urinary nitrate exertion. These effects of ADMA are counteracted by administration of the NO precursor L-arginine. It is likely that basic insights regarding the mechanisms of endothelial dysfunction will lead to new therapeutic strategies for atherosclerosis.
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PMID:Endothelial alterations in hypercholesterolemia: more than simply vasodilator dysfunction. 988 48


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