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)

Hypercholesterolemia, before atherosclerosis, is known to reduce agonist- (e.g., acetylcholine) mediated nitric oxide (NO) production within 2 weeks of a cholesterol-enriched diet. However, no data exist on the effect of hypercholesterolemia on the basal release of NO from blood vessels. We studied the basal release of NO in rabbit coronary arteries by addition of the NO synthase blocker NG-nitro-L-arginine-methyl ester (L-NAME). Basal release of NO was markedly attenuated 2 weeks after introduction of a 0.5% cholesterol addition to the diet. One week later, the adherence of neutrophils to the coronary endothelium was significantly enhanced (i.e., threefold; p < 0.01 different from control). The increased adhesiveness could be attributed to enhanced endothelial adhesion rather than to changes in the properties of the leukocytes. Both phenomena could be reversed by addition of L-arginine to isolated coronary arteries. Administration of 10 mg/day lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, markedly attenuated both the reduced basal NO production and the increased adhesiveness of the endothelium. These results support the concept that NO is an important protective agent produced by the endothelium to preserve the integrity of the endothelium and may protect it against atherogenesis.
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PMID:Decreased basal nitric oxide release in hypercholesterolemia increases neutrophil adherence to rabbit coronary artery endothelium. 768 5

So far pharmacological consequences of inhibition of thromboxane A2 (TXA2) synthase by imidazole derivatives (e.g., camonagrel or dazoxiben) were linked to suppression of platelet activity. Here we report that in patients with peripheral atherosclerosis or in cats with extracorporeal thrombogenesis treatment with camonagrel is associated with activation of fibrinolysis or thrombolysis. These phenomena seem to be related to the camonagrel-induced shift in metabolism of prostaglandin endoperoxides from TXA2 to prostacyclin (PGI2), although in an in vitro model the involvement of the L-arginine/nitric oxide pathway cannot be excluded. In cats camonagrel (10 mg/kg i.v.) produced not only a fall in TXB2 but also a rise in 6-keto-PGF1 alpha and no change in cyclic-GMP plasma levels. This points to PGI2 rather than to nitric oxide as an in vivo mediator of camonagrel-induced thrombolysis. The crucial role of endogenous PGI2 in the thrombolytic response to camonagrel in cats was evidenced by its blockade following pretreatment of animals with a megadose of aspirin (50 mg/kg i.v.) and lack of any effect on pretreatment with L-NAME (100 micrograms/kg/min, i.v.). Obviously TXA2 synthase inhibitors (e.g., camonagrel) and cyclo-oxygenase inhibitors (e.g., aspirin) antagonize each other in their anti-thrombotic actions and must not be administered at the same time. Furthermore, in patients camonagrel (800 mg orally) suppressed TXA2 generation by 99.5% and doubled the plasma level of 6-keto-PGF1 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The mechanism of anti-thrombotic, thrombolytic and fibrinolytic actions of camonagrel--a new thromboxane synthase inhibitor. 777 18

Reduced epicardial coronary arterial distensibility associated with early atherosclerosis may be mediated in part by reduced nitric oxide (NO) release. To directly assess the contribution of endogenous NO to coronary arterial distensibility, we examined the effect of intracoronary N omega nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, and L-arginine, its natural substrate, on the circumflex artery in seven anesthetized dogs. We also used intracoronary acetylcholine to examine the effect of pharmacologically induced NO release on coronary distensibility. Electrocardiographically gated measurements of epicardial coronary lumen area were made by a blinded observer from images obtained with a 4.3F, 30 MHz intravascular ultrasound catheter. Aortic root pressure was continuously monitored, and neither systemic arterial pressure nor pulse pressure changed significantly with intracoronary drug administration. Change in lumen area (delta LA) from end systole to end diastole was measured, and an arterial distensibility index was calculated. Delta LA increased with acetylcholine from 8.2% +/- 0.5% at baseline to 16.3% +/- 2.8% (10(-6) mol/L; p < 0.001), with increases in both end-systolic and end-diastolic lumen area and decreased delta LA to 3.1% +/- 1.3% (p < 0.01). Lumen area and delta LA were both restored to baseline by L-arginine (10(-4)). The calculated distensibility index of the epicardial coronary artery was enhanced by acetylcholine, reduced below baseline by L-NAME, and restored to baseline by L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Contribution of endothelium-derived nitric oxide to coronary arterial distensibility: an in vivo two-dimensional intravascular ultrasound study. 790 Jun 24

We examined whether prostaglandin (PG) H2, as an endothelium-dependent contracting factor, or the disturbed production of endothelium-derived relaxing factor, impairs endothelium-dependent relaxation and whether long-term inhibition of nitric oxide (NO) synthesis aggravates atherosclerosis in hypercholesterolemic rabbits. Male New Zealand White rabbits were fed one of the following diets: (1) standard chow; (2) 2% cholesterol-supplemented chow; (3) standard chow with 80 micrograms/mL N omega-nitro-L-arginine methylester (L-NAME), an NO synthetase inhibitor, in their drinking water; or (4) 2% cholesterol-supplemented chow with 80 or 160 micrograms/mL L-NAME in their drinking water. The rabbits were fed these diets for 8 or 12 weeks. Then aortic rings were obtained, and changes in isometric tension were recorded. Intimal atherosclerotic areas of the thoracic aortas were subsequently measured by planimetry. The cholesterol-supplemented diet significantly impaired endothelium-dependent aortic relaxation to acetylcholine. Pretreatment with the thromboxane A2/PGH2 receptor antagonist ONO-3708 did not reverse this impaired response. Vessels from both normocholesterolemic and hypercholesterolemic rabbits given L-NAME showed more impaired endothelium-dependent relaxation than those from their dietary counterparts not given L-NAME. Morphometric analysis revealed marked enlargement of intimal atherosclerotic areas in aortas from L-NAME-treated hypercholesterolemic rabbits compared with those from untreated hypercholesterolemic rabbits. These findings suggest that PGH2 does not contribute to impaired endothelium-dependent relaxation and that long-term administration of L-NAME promotes atherosclerosis by inhibition of NO synthesis in the hypercholesterolemic rabbit thoracic aorta.
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PMID:Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta. PGH2 does not contribute to impaired endothelium-dependent relaxation. 817 41

To characterize alterations of renal vessels occurring during systemic hypertension elicited in rats by 5, 10, and 25 days of treatment by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME)(20 mg/kg daily), preglomerular vasculatures, consisting of arcuate arteries and their branches, interlobular arteries, and afferent arterioles, were isolated by HCl maceration. Blockade of nitric oxide synthase significantly increased tail-cuff systolic blood pressure by 21 +/- 2% and 42 +/- 3% after 5 and 25 days, respectively. Medias of hypertensive arcuate arterial branches and interlobular arteries but not of afferent arterioles had focal deposits of Sudan black-positive lipid droplets. At 25 days, vessel wall thickness increased by 72 +/- 6% along the sudanophilic areas. Immunostaining of sudanophilic lesions with a panel of antibodies unveiled medial cell proliferation, macrophage invasion, immunoreactive vascular cell adhesion molecule-1, and low-density lipoprotein. The frequency of sudanophilic lesions increased with time to affect 26 +/- 2% and 36 +/- 3% of arcuate arterial branches and interlobular arteries, respectively, at 25 days. Hypertensive L-NAME-treated rats developed glomerular injury probed by albuminuria and glomerular immunostaining for alpha-smooth muscle actin. Administration of the nonselective endothelin antagonist bosentan (30 mg/kg daily) blunted the development of sudanophilic lesions during L-NAME treatment without affecting arterial hypertension or degree of glomerular injury. Therefore, L-NAME hypertension leads to rapid development of focal, inflammatory, proliferative, and sudanophilic lesions along preglomerular vessels, suggesting atherosclerosis-like processes. Furthermore, endothelin is a likely mediator in the development of these lesions.
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PMID:Preglomerular sudanophilia in L-NAME hypertensive rats: involvement of endothelin. 869 42

1. The function of endogenous nitric oxide (NO) at the level of vascular smooth muscle, was assessed in a popular experimental model of accelerated atherosclerosis, the cholesterol-fed rabbit. 2. Endothelium-dependent vasorelaxation in response to acetylcholine (ACh, 1 microM) was significantly impaired in the carotid artery from rabbits maintained on a 1% (W/W) cholesterol diet for 8-10 weeks. Furthermore, the ability of an inhibitor of nitric oxide synthase (NOS), NG-nitro-L-arginine methyl ester (L-NAME, 1-300 microM), to enhance the contractile reactivity to a submaximal concentration of noradrenaline (NA, 3 microM), was significantly attenuated in hypercholesterolaemia. 3. A significant linear correlation between the maximal contractile effect of L-NAME (300 microM) and maximal vasorelaxation to ACh (1 microM) was determined in the carotid artery from control rabbits. In contrast, no such linear correlation was found in the carotid artery from hypercholesterolaemic rabbits. 4. We conclude that there are lesions both in agonist-stimulated, endogenous NO-dependent vasorelaxation and in the regulation of vasoconstrictor reactivity by endogenous NO in the hypercholesterolaemic rabbit carotid artery. Furthermore, the normal linear relationship between the contractile effect of L-NAME and vasorelaxation to ACh is lost after cholesterol-feeding.
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PMID:Investigation of endogenous nitric oxide vascular function in the carotid artery of cholesterol-fed rabbits. 873 Jul 41

L-arginine, the precursor of endogenous nitric oxide (NO), has been shown to enhance endothelial function and to reduce intimal plaque area in cholesterol (Chol)-fed rabbits. We have studied endogenous NO production in such animals in vitro (endothelium-dependent relaxations) and in vivo (assessed by urinary NO3- excretion) before and during chronic oral administration of L-arginine and inhibitor of NO synthesis, L-NAME. Vascular superoxide anion (O2-) production of aortic rings was measured under basal conditions and following exposure to phorbol-myristate-acetate (PMA). Cholesterol feeding reduced endothelium-dependent relaxations and decreased urinary NO3- excretion. These effects were potentiated by administration of L-NAME. L-arginine partly restored endothelium-dependent relaxations and increased NO3- excretion. PMA-stimulated O2- production was increased in aortic rings from rabbits given cholesterol ( +159 +/- 28%; mean +/- S.E.M.) or cholesterol + L-NAME ( +149 +/- 37%) as compared with controls ( -22 +/- 7%). In rabbits given cholesterol + L-arginine, O2- production was decreased to control levels ( +14 +/- 17%; P < 0.05). We conclude that the systemic synthesis of NO is impaired in cholesterol-fed rabbits, as indicated by the decreased urinary excretion of NO3-. Enhanced O2- production may further contribute to the decreased biological activity of NO in hypercholesterolaemia. L-arginine restores endothelial function in hypercholesterolaemia by enhancing NO production and by protecting NO from early breakdown by O2-.
Atherosclerosis 1995 Oct
PMID:Supplementation of hypercholesterolaemic rabbits with L-arginine reduces the vascular release of superoxide anions and restores NO production. 880 73

1. Cytomegalovirus (CMV) is a major pathogen in immunocompromised individuals and may participate in the pathogenesis of atherosclerosis in the general population. We evaluated whether CMV-infection alters the function of arterial smooth muscle. 2. Blood pressure (BP) and arterial reactivity were recorded in immunosuppressed rats that had been infected with CMV (10(5) plaque forming units i.p.). Furthermore, the reactivity of isolated arteries was compared between CMV-infected rats and rats injected with bacterial endotoxin (LPS). 3. Initially resting BP and heart rate (HR) were not modified in CMV-infected rats, but baroreflex control of HR was impaired. By the eighth day post-CMV, BP dropped precipitously and could no longer be raised by phenylephrine (PHE). 4. In mesenteric resistance arteries, isolated at this stage from CMV-infected rats, contractile responses to nerve stimulation, noradrenaline, PHE and 5-hydroxytryptamine (5-HT) were virtually absent while those to high potassium and vasopressin (AVP) were not modified. In aortae of CMV-infected rats, responses to 5-HT and AVP were impaired while those to PHE or potassium were hardly affected. Reduced contractile responses could not be restored by NG-nitro-L-arginine methyl ester (L-NAME). 5. Continuous treatment of CMV-infected rats with prazosin (0.1 mg kg-1 day-1) prevented blood pressure lowering and resistance artery changes. 6. Observations in arteries of LPS-treated rats (5-10 mg kg-1, i.p.) differed markedly from those in vessels of CMV-infected animals. The contractile reactivity of their mesenteric resistance arteries was not altered while in their aortae, responses to PHE, 5-HT and AVP were reduced. With the exception of the AVP responses, this was more pronounced in the presence of 1-arginine and reversed by L-NAME. 7. These findings indicate that CMV-infection results in a reduction of resistance artery reactivity and hypotonia. This seems not to involve cytokine-mediated induction of NO synthase in the vascular wall but may be due to alterations of excitation-contraction coupling in arterial smooth muscle in response to increased sympathetic nervous input.
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PMID:Impaired arterial reactivity following cytomegalovirus infection in the immunosuppressed rat. 890 36

Endothelium-derived relaxing and contracting factors play an important role in atherosclerosis, re-stenosis and graft survival. Internal thoracic artery (ITA) and saphenous vein (SV) are used as conduit vessels in coronary artery bypass graft surgery (CABG). The long-term graft patency rate is higher with ITA than SV. Effects of nitric oxide and superoxide on vascular relaxation in isolated rings of ITA and SV from patients undergoing CABG were investigated. NG-nitro-L-Argenine methylester (L-NAME) was used to block nitric oxide synthesis and superoxide dismutase (SOD) and tiron to scavenge superoxide. Responses to carbachol were taken as a measure of stimulated nitric oxide release and increased responses to phenylephrine after addition of L-NAME as a measure of basal nitric oxide release. Immunocytochemical demonstration of endothelial nitric oxide synthase was performed using anti-endothelial nitric oxide synthetase (anti-eNOS) NOS antibody. Stimulated nitric oxide release was observed in ITA and SV but basal release was reduced or absent in SV. Treatment with SOD and tiron potentiated carbachol stimulated relaxation in ITA and SV. Tiron treatment resulted in a significant increase in basal nitric oxide in veins. eNOS immunoreactivity was more intense in ITA than SV, compatible with reduced nitric oxide production in veins. This may contribute to the reduced patency of venous grafts.
Atherosclerosis 1997 Aug
PMID:Effects of nitric oxide and superoxide on relaxation in human artery and vein. 925 10

The purpose of this study was to investigate whether endothelium-derived nitric oxide (NO) is involved in the plasma lipid-independent antiatherogenic effect of estrogen and levormeloxifene, a partial estrogen receptor agonist. 85 rabbits were ovariectomized and balloon-injured in the middle thoracic aorta. The rabbits were fed a cholesterol-enriched diet supplemented with 17beta-estradiol, levormeloxifene, or placebo, either alone, or together with 160 microg/ml NG-nitro- -arginine methyl ester (-NAME), an NO synthase inhibitor, in their drinking water for 12 wk. Plasma cholesterol was maintained at 25-30 mmol/liter by individualized cholesterol feeding. In the undamaged aorta, the extent of atherosclerosis in the estrogen group was only one-third that in the placebo group. Simultaneous administration of -NAME, however, significantly reduced the antiatherogenic effect of estrogen (P < 0.01). There was no significant difference between the placebo group given -NAME and the group treated with placebo alone. At the previously endothelium-denuded site, estrogen had no effect on atherosclerosis development, whereas -NAME combined with estrogen significantly increased atherogenesis (P < 0.05). The effects of levormeloxifene were almost similar to those of estrogen. Active vascular concentrations of -NAME were demonstrated in an additional study, in which maximal aortic/coronary endothelium-dependent relaxation was significantly inhibited in rabbits given -NAME. Thus, in this study a considerable part of the plasma lipid-independent antiatherogenic effect of estrogen was mediated through its effect on endothelial NO in cholesterol-fed rabbits. The results for levormeloxifene suggest a common mechanism of action for estrogen and partial estrogen receptor agonists on atherogenesis.
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PMID:Significant reduction of the antiatherogenic effect of estrogen by long-term inhibition of nitric oxide synthesis in cholesterol-clamped rabbits. 925 81


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