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)

Although sarpogrelate HCl is widely used for the prevention of arterial thrombosis, its effect on atherosclerosis is unknown. Accordingly, we here investigated the effects of sarpogrelate HCl on a rabbit model of atherosclerosis. Male rabbits were fed a 0.5% cholesterol diet (HCD) (Gp 1), HCD with vitamin E (Gp 2), HCD with vitamin E and sarpogrelate (Gp 3), or HCD with sarpogrelate alone (Gp 4) for 8 weeks. The atherosclerotic area was decreased by feeding of vitamin E and sarpogrelate (16.9+/-2.0% in Gp 1 vs. 8.2+/-2.0% in Gp 3). Tone-related basal NO release was higher in Gps 3 and 4. Acetylcholine-induced relaxation tended to be improved in Gp 3. The amount of eNOS mRNA was increased in Gp 4, and aortic cyclic GMP concentration showed the same tendency. O(2)(-) release tended to be decreased in Gps 2 and 3. The matrix metalloproteinase-1 (MMP-1)-positive area was decreased, and the percentage ratio of cell numbers of smooth muscle cells/macrophages in the plaque was increased in Gp 3. The results demonstrated that sarpogrelate HCl retards the progression of atherosclerosis in rabbits, and that this effect is enhanced by concomitant administration of vitamin E. Although upregulation of eNOS may play a role as one of the underlying mechanisms, our results suggest that an additional mechanism-possibly involving the antiproliferative effects of sarpogrelate HCl on smooth muscle cells and macrophages-may also play an important role.
Atherosclerosis 2003 May
PMID:Sarpogrelate HCl, a selective 5-HT2A antagonist, retards the progression of atherosclerosis through a novel mechanism. 1273 83

We used mesenteric arterial beds from normal rats and beef tallow-fed rats (hypercholesterolemic model) to study the interaction between the effects of viscosity-induced shear stress and agonists mesenteric vasoreactivity. Mesenteric arterial beds were perfused under constant-flow conditions (5 ml/min) via a peristaltic pump using warm oxygenated modified Krebs-Henseleit solution containing either 4% BSA to increase viscosity or 300 microM L-arginine, a NO synthase substrate. Whether beds were perfused with BSA alone or L-arginine alone as pretreatment, the methoxamine-induced contractile responses were similar to those in normal beds. However, methoxamine-induced contractile responses were significantly reduced following pretreatment with L-arginine plus BSA. These reduced responses underwent significant recovery when either tyrphostin A23 (30 microM, a tyrosine kinase inhibitor) or wortmannin (300 nM, a PI3K inhibitor) was present. The dose-response curve for methoxamine was shifted to the right and the maximum contractile response was reduced in mesenteric arterial beds from beef tallow-fed rats, but the modulation of this response induced by L-arginine plus BSA was preserved. In beef tallow-fed rats, the ACh-induced endothelium-dependent vasodilation was attenuated in both thoracic aortic strips and mesenteric arterial beds. These results suggest that in hypercholesterolemic rats, agonist-induced endothelial function is impaired, while shear stress-induced responses (tyrosine kinase- and PI3K-mediated NO production) are preserved. These abnormal vascular responses may contribute to hypertension in beef tallow-fed hypercholesterolemic model rats.
Atherosclerosis 2004 Jul
PMID:Modulations of shear stress-induced contractile responses and agonist-induced vasodilation in hypercholesterolemic rats. 1518 44

We investigated the cardioprotective effect of acute and chronic sodium hydrogen exchanger 1 (NHE-1) inhibition with cariporide under pathological conditions in rabbits fed an atherogenic diet (0.25% cholesterol, 3% coconut oil), an experimental model of atherosclerosis. New Zealand White rabbits were fed over 4 weeks with normal diet or with atherogenic diet and randomized in 3 subgroups (n=7 in each group); placebo, acute cariporide (0.3 mg/kg, 10 min. before occlusion of left anterior descending coronary artery and chronic cariporide (4 weeks 0.1% in chow). In the final infarction experiments the animals were subjected to 30 min. of myocardial ischaemia by occlusion of a branch of the left anterior descending coronary artery followed by 2 hr of reperfusion. Infarct mass was evaluated by triphenyl-tetrazolium chloride staining and the infarct size expressed as a percentage of area at risk. Besides the assessment of aortic endothelium-dependent function aortic and cardiac vessels were inspected for atherosclerotic lesions. In cholesterol-fed rabbits, the infarct size was significantly increased when compared with normal diet animals (63+/-3% versus 41+/-3%). Acute cariporide treatment reduced the infarct size in normal diet rabbits to 14%+/-3% (66% decrease, P<0.05) as well as in atherogenic diet rabbits to 22+/-3% (65% decrease, P<0.05). Chronic treatment with cariporide also reduced the infarct size significantly: normal diet 19+/-2% (53% decrease, P<0.05), atherogenic diet 32+/-3% (49% decrease, P<0.05). Total cholesterol serum levels in rabbits with atherogenic diet were significantly higher (15.3+/-2.7 mmol/l) than those on a standard diet (0.65+/-0.08 mmol/l). Chronic cariporide treatment significantly attenuated the increase of serum cholesterol (7.9+/-1.9 mmol/l) and improved the lipoprotein pattern. Although the aortas and heart vessels of hypercholesterolaemic animals were without any histological evidence of atherosclerosis they developed endothelial dysfunction (reduced endothelium-dependent relaxation by ACh), which was prevented by chronic cariporide treatment. Acute and chronic treatment with the NHE-1 inhibitor cariporide significantly reduced infarct mass. This effect was associated with improved endothelial function.
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PMID:Effects of acute and chronic treatment with the sodium hydrogen exchanger 1 (NHE-1) inhibitor cariporide on myocardial infarct mass in rabbits with hypercholesterolaemia. 1524 73

Acetylcholine esterase (AChE) and paraoxonase 1 (PON1) are both serum ester hydrolases, which are associated with the prevalence of myocardial infarction. Both genes are located in close proximity on chromosome 7q21-22. As PON1 was suggested to protect against cardiovascular diseases secondary to its ability to break down oxidized lipids and to inhibit LDL oxidation, we examined AChE capacity to protect LDL against oxidation. Preincubation of LDL with AChE retarded the onset of copper ion-induced LDL oxidation in a concentration-dependent manner. AChE significantly reduced the formation of lipid peroxides and TBARS during the course of LDL oxidation, by up to 45%. This effect was associated with AChE-mediated hydrolysis of lipid peroxides, which accounts for the inhibition in the onset of LDL oxidation, the oxidative propagation phase, and aldehyde formation. We conclude that AChE, similar to PON1, can hydrolyze lipid peroxides and thus may prevent the accumulation of oxidized LDL and attenuate atherosclerosis development.
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PMID:Acetylcholine esterase protects LDL against oxidation. 1533 59

Endothelial dysfunction is a feature of atherosclerosis and is associated with CHD (coronary heart disease) risk factors. This study aimed to determine the relationship between the degree of endothelial dysfunction and calculated cardiovascular risk. Endothelial function, as determined by the ACh/NP (acetycholine/sodium nitroprusside response) ratio on brachial plethysmography, was compared with cardiovascular risk as calculated from the Framingham, PROCAM (Prospective Cardiovascular Munster) and MRFIT (Multiple Risk Factor Intervention Trial) algorithms in 246 (187 male) patients, including 44 (22%) with established CHD. Endothelial dysfunction correlated with the total number of risk factors (r2=0.22; P=0.002) and was related to LDL (low-density lipoprotein)-cholesterol in men and triacylglycerols (triglycerides) in women. The ACh/NP ratio correlated with the occurrence of diabetes, CHD and the LDL-cholesterol concentration (r2=0.58; P<0.001). Endothelial dysfunction was associated with presence of CHD on receiver-operating characteristic plot analysis (area=0.706+/-0.04; P=0.001). There was no correlation between ACh/NP ratio and CHD risk calculated with the Framingham algorithm in men, although both ACh and NP response correlated separately with risk in women. The endothelial ACh/NP ratio correlated with absolute risk in the PROCAM algorithm (r2=0.41; P<0.005). Intermediate results were obtained with MRFIT. Individual risk factors make different contributions to endothelial dysfunction compared with their role in risk calculators. The stronger relationship of endothelial dysfunction with PROCAM risk reflects the contribution of male sex, LDL-cholesterol and triacylglycerols to risk calculated by this algorithm.
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PMID:Cardiovascular risk factors and endothelial dysfunction. 1545 2

Current concepts for the explanation of endothelial dysfunction and accelerated atherosclerosis in uremia propose a reduced vascular bioavailability of nitric oxide (NO). The aim of the present study was to test the contributions of NO and NO/prostacyclin (PGI(2))-independent mechanisms to both baseline vascular tone and agonist-induced endothelium-dependent vasodilation in patients on hemodialysis (HD). In 10 HD patients and eight matched healthy control subjects, forearm blood flow (FBF) was measured at rest and during intrabrachial infusions of norepinephrine (NE; endothelium-independent vasoconstrictor, 60, 120, and 240 pmol/min) and N-monomethyl-L-arginine (blocker of NO synthases, 16 micromol/min). After inhibition of cyclo-oxygenase by ibuprofen (1200 mg orally), endothelium-dependent and -independent vasodilation was assessed by infusion of acetylcholine (ACh; 1, 5, 10, 50, 100, and 300 nmol/min) and sodium-nitroprusside (2.5, 5, and 10 microg/min). NO/PGI(2)-independent vasodilation was tested by equal infusions of ACh during NO clamp. N-monomethyl-L-arginine reduced resting FBF to a comparable degree in both groups. Vascular responses to ACh were reduced in HD (P = 0.003 versus control by ANOVA), whereas those to sodium nitroprusside were mainly at control level. Infusion of ACh during NO clamp caused a similar increment of FBF in both groups. NO-mediated vasodilation as calculated by the difference between ACh-induced responses without and with NO clamp was substantially impaired in HD (P < 0.001) compared with control. In HD patients, baseline NO-mediated arteriolar tone is at control level. This study provides first evidence that endothelial dysfunction of uremic patients as shown by reduced agonist-induced endothelium-dependent vasodilation is attributable to reduced stimulation of NO, whereas the NO/PGI(2)-resistant portion of ACh-mediated vasodilation is unaffected.
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PMID:Reduced agonist-induced endothelium-dependent vasodilation in uremia is attributable to an impairment of vascular nitric oxide. 1572 85

Aldosterone may be involved in the pathogenesis of atherosclerosis. We investigated the effect of eplerenone, a selective mineralocorticoid receptor blocker, on atherosclerosis in monkeys fed a high-cholesterol diet. Monkeys fed a high-cholesterol diet for 9 months were divided into 3 groups: those treated with a low dose of eplerenone (30 mg/kg per day); those treated with a high dose of eplerenone (60 mg/kg per day); and the placebo-treated group. The normal group consisted of monkeys fed a normal diet. There were no significant differences in blood pressure and cholesterol levels between the placebo- and eplerenone-treated groups. On the other hand, monocyte chemoattractant protein-1 and malondialdehyde-modified LDL were significantly higher in the placebo-treated group than in the normal group, whereas they were suppressed in the eplerenone-treated groups. The ratio of intimal volume to total volume by intravascular ultrasound analysis imaging of the aortas was dose-dependently lower in the eplerenone-treated groups than in the placebo-treated group. Acetylcholine-induced vasorelaxation was significantly weaker in the placebo-treated group than in the normal group, but the vasorelaxation was strengthened in the eplerenone-treated groups. A significant upregulation of angiotensin-converting enzyme activity was observed in the placebo-treated group, but the activity was suppressed in the eplerenone-treated groups. In conclusion, eplerenone may strengthen the endothelium-dependent relaxation and suppress angiotensin-converting enzyme activity in the vasculature, thus preventing the development of atherosclerosis in nonhuman primates.
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PMID:Eplerenone inhibits atherosclerosis in nonhuman primates. 1643 23

Hypercholesterolemia is considered a major risk factor in the development of atherosclerotic disease. The endothelium is the source of a number of vasoactive compounds which may be altered by the disease process. For example, synthesis of the arachidonic acid metabolite thromboxane A(2) (TXA(2)) increases in atherosclerosis. Non-selective blockade of vascular and platelet thromboxane (TP) receptors retards the progression of the disease in various animal models. We have previously identified a subset of NZW rabbits that lack only vascular (v) TP receptors, referred to as vTP-. These rabbits provide a unique model to elucidate the role of vascular TP receptors in hypercholesterolemia. Studies evaluated vascular responses to phenylephrine and acetylcholine in isolated aortic rings obtained from vTP- and vTP+ rabbits fed 0.5% cholesterol diet for a period of only 3 weeks. In the cholesterol-fed vTP- rabbits, contractions to phenylephrine were reduced compared to the vTP+ cholesterol-fed rabbits. Acetylcholine-induced relaxations were greater in cholesterol-fed vTP- rabbits compared to cholesterol-fed vTP+ rabbits. While the overall incidence of aortic lesions was small after only 3 weeks of cholesterol-feeding, results indicated a reduction in lesions in the vTP- compared to the vTP+ rabbits. In summary, these studies are the first to show that if rabbits lack only vascular TP receptors, impaired vascular reactivity responses normally associated with hypercholesterolemia are diminished.
Atherosclerosis 2006 Dec
PMID:Aortic thromboxane receptor deficiency alters vascular reactivity in cholesterol-fed rabbits. 1651 89

Rheumatoid arthritis (RA) is associated with greater risk of cardiovascular morbidity and mortality, the inflammatory component of RA being strongly linked to this excess risk. Endothelial dysfunction is linked to atherosclerosis and has been demonstrated in larger vessels in RA. In this pilot study, we determined for the first time whether skin microvascular function was impaired in patients with active RA and also determined its response to anti-inflammatory treatment. This was assessed non-invasively using laser Doppler imaging combined with iontophoresis of the vasodilators acetylcholine (ACh, endothelium dependent) and sodium nitroprusside (SNP, endothelium independent) to the forearm. Eight RA patients admitted for acute flare-ups were assessed before and following anti-inflammatory treatment. Standard laboratory indices were obtained along with pain perception (VAS). A control group of eight subjects was included for baseline comparison. Compared to this group, vascular function was substantially and significantly (P<0.00001) lower in RA patients. Following treatment, as CRP and VAS decreased, vascular function improved for both ACh (P<0.00001) and SNP (P=0.001), this improvement being significantly greater for ACh (P<0.001). Vascular dysfunction is evident in RA patients, even at the level of the cutaneous microcirculation, but improves as inflammation regresses. Assessment of cutaneous vascular function may be a useful, non-invasive surrogate indicator of vascular risk in RA, inclusive of myocardial microvascular abnormalities.
Atherosclerosis 2007 Jun
PMID:Inflammatory suppression rapidly attenuates microvascular dysfunction in rheumatoid arthritis. 1680 31

Paraoxonase-1 (PON1) can protect endothelial function by preventing the oxidation of low-density lipoprotein (LDL) cholesterol and retarding the development of atherosclerosis. We examined whether PON1 polymorphism influences endothelium-dependent coronary vasomotor responses. Sixty-seven patients underwent diagnostic cardiac catheterization, but showed no significant coronary artery stenosis. In all patients, PON1 genotypes (Q/Q, Q/R and R/R) were determined, and provocative testing was performed by the intracoronary administration of graded doses of bradykinin (BK; 0.2, 0.6 and 2.0 mug/min) and acetylcholine (ACh; 3, 10 and 30 mug/min). Coronary blood flow (CBF) was evaluated by a Doppler guide wire. The patients were divided into 2 groups on the basis of ACh testing: one with coronary spastic angina (CSA) and one with non-CSA. The frequencies of the PON1 genotype in the CSA group did not differ significantly from those in the non-CSA group. In the non-CSA group, the patients were subdivided into 2 groups: a group with the Q/Q or Q/R genotypes and a group with the R/R genotype. The vasoconstrictive responses of the epicardial coronary artery to ACh were comparable between the Q/Q + Q/R and R/R groups. Also, the coronary vasodilations induced by BK in the R/R group were similar to those in the QR + QQ group. There were no significant differences in the CBF responses induced by BK or ACh between the Q/Q + Q/R and R/R groups. In conclusion, as estimated by BK and ACh testing, our findings suggest that PON1 genotypes may not play a critical role in the modulation of endothelial vasomotor function in the intact coronary circulation.
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PMID:Impact of paraoxonase polymorphism (Q192R) on endothelial function in intact coronary circulation. 1694 Jul 4


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