Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renin-angiotensin system evolved to maintain volume homeostasis and blood pressure and to prevent ischemia during acute volume loss. But in the present age, these mechanisms are redundant, and the clinical significance of angiotensin II results from its pathologic effects, which are mediated by the angiotensin II type 1 (AT(1)) receptor. Activation of AT(1) receptors has been linked to pathologic processes that contribute to atherosclerosis and ischemic events, including oxidative stress, inflammatory processes, low-density lipoprotein cholesterol trafficking, and prothrombotic states. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) program will compare the efficacy of the angiotensin II receptor blocker (ARB) telmisartan, the angiotensin-converting enzyme (ACE) inhibitor ramipril, and combination therapy with telmisartan plus ramipril for reducing cardiovascular risk. The ARB telmisartan is distinguished by its long duration of action, which compares favorably with some other ARBs and conventional antihypertensives. Ramipril was shown in the Heart Outcomes Prevention Evaluation (HOPE) study to reduce the risk for myocardial infarction (MI) and other cardiovascular events in patients at high risk for cardiovascular events but without heart failure or a low ejection fraction. The ONTARGET program consists of 2 randomized, double-blind, multicenter international trials: a principal trial, ONTARGET, and a parallel trial, Telmisartan Randomized Assessment Study in ACE-I Intolerant Patients with Cardiovascular Disease (TRANSCEND). The treatment arms for the principal ONTARGET study are telmisartan 80 mg, ramipril 10 mg, and combination therapy with telmisartan 80 mg plus ramipril 10 mg; for the parallel study TRANSCEND, the treatment arms are telmisartan 80 mg and placebo. Both trials will assess cardiovascular outcomes in patients at high risk using the same criteria as that of the HOPE study, with a single exception: the TRANSCEND trial will enroll patients who do not tolerate ACE inhibitor treatment. The primary end points in both ONTARGET and TRANSCEND are death caused by cardiovascular disease, acute MI, stroke, and hospitalization because of congestive heart failure. The secondary end points include newly diagnosed heart failure, revascularization, new-onset type 2 diabetes mellitus, nephropathy, cognitive decrease and dementia, and newly diagnosed atrial fibrillation; these will be used for hypothesis generation.
 ...
PMID:The ongoing telmisartan alone and in combination with ramipril global endpoint trial program. 1278 6

Hyperglycaemia is considered to be the key causal factor in the development of diabetic complications. Poor glycemic control a significant changes of erythrocyte membrane fluidity, erythrocyte deformability and antioxidant status. Nonenzymatic glycation and glycoxidation with cascade of free radical reactions, oxidative and carbonyl stress may play an important role in the development diabetic micro- and macrovascular complications. The serum levels of specific and nonspecific advanced glycation end products (s-AGEs) have been found elevated in type 1 and type 2 diabetic patients. Levels of s-AGEs. may serve as useful biochemical marker for monitoring progression of diabetic complications and pathological processes. Accumulation of AGEs on tissue proteins increases with pathogenesis of diabetic complications and atherosclerosis. AGEs are believed to induce cellular oxidative stress through the interaction with specific cellular receptors. Carbonyl stress-induced tissue damage is caused by AGE precursors formed by hyperglycaemia, hyperlipidemia, nonenzymatic glycation, peroxidation of lipids and metabolis processes. The toxic effects of AGE precursors can not be directly antagonized by antioxidants. Only a small number of biological carbonyl scavengers like glutathione have been identified to date. For therapeutic intervention, nucleophilic compounds as aminoguanidine, pyridoxamine, OPB-9195, 2,3-diaminophenazone, carnosine and tenilsetam give promising results. These potential therapeutics have been proposed to trap AGE precursors. Studies in vitro showed that these AGE inhibitors have also the antioxidant and chelating activity. Angiotensin converting enzyme (ACE) and angiotensin II receptor antagonists also significantly attenuate AGE production. These drugs do not trap AGE precursors, but impact on the production of AGE precursors by chelating transition metals and inhibiting various oxidative steps in the process of glycoxidation, including the formation of free radicals. Finally, supplementation with antioxidants and antioxidant systems could be a complementary treatment in diabetic patients.
 ...
PMID:[The role of nonenzymatic glycation and glyco-oxidation in the development of diabetic vascular complications]. 1282 98

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are recognized primarily for their use in hypertension, in heart failure, and after myocardial infarction. New evidence, particularly with ACE inhibitors, has shown their ability to reduce acute coronary events associated with atherosclerosis in patients without a history of the aforementioned cardiac conditions. This is likely due to inhibitory effects on the renin-angiotensin system--a system that adversely influences fibrinolytic balance, vascular endothelial function, and vascular inflammation, all key components of atherosclerotic progression and adverse coronary outcomes. Results of various studies suggest favorable effects of ACE inhibitors and ARBs on markers of these components, including effects on plasminogen activator inhibitor-1, endothelin-1, and nitric oxide by ACE inhibitors, and effects on vascular cell adhesion molecule-1 and C-reactive protein by ARBs. Although early evidence suggests that ACE inhibitors may provide a greater beneficial effect on some of these markers compared with ARBs, and that certain ACE inhibitors may provide greater vascular benefits than others, further investigation is required to verify such findings. Overall, understanding the distinct coronary vascular benefits of these agents will emphasize the importance of using them, particularly ACE inhibitors, to improve outcomes in patients with coronary atherosclerotic disease.
 ...
PMID:Pharmacologic blockade of the renin-angiotensin system: vascular benefits beyond commonly understood pharmacologic actions. 1452 46

As a result of oxidative and carbonyl stress, advanced glycation end products (AGEs) are involved in the pathogenesis of severe and frequent diseases and their fatal vascular/cardiovascular complications, i.e. diabetes mellitus and its complications (nephropathy, angiopathy, neuropathy and retinopathy, renal failure and uremic and dialysis-associated complications), atherosclerosis and dialysis-related amyloidosis, neurodegenerative diseases, and rheumatoid arthritis. They are formed via non-enzymatic glycation which is specifically enhanced through the presence of oxidative and carbonyl stress, and their ability to form glycoxidation products in peptide and protein structures finally modulating or inducing biological reactivity. Food can be another source of AGEs; however, high serum AGEs in hemodialysis patients might reflect nutritional status better. Several methods of renal replacement therapy have been studied in connection with the AGE removal, but unfortunately the possibilities are still unsatisfactory even if high flux dialysis, hemofiltration, or hemodiafiltration give better results than conventional low flux dialysis. AGEs are currently being studied in the patients on peritoneal dialysis as their precursors can be formed in the dialysis fluid. AGEs can cause damage to the peritoneum and so a loss of ultrafiltration capacity. Many compounds give promising results in AGE inhibition (inhibition of formation of AGEs, inhibition of their action or degradation of AGEs), are tested for these properties, and eventually undergo clinical studies (e.g. aminoguanidine, OPB-9195, pyridoxamine, antioxidants, N-phenacylthiazolium bromide, antihypertensive drugs, angiotensin-converting enzyme inhibitors and angiotensin II receptor-1 antagonists).
 ...
PMID:Advanced glycation end products in clinical nephrology. 1467 11

Proliferation of vascular smooth muscle cells (VSMC) stimulated by oxidative stresses and reactive oxygen species (ROS) may play a pivotal role in the pathogenesis of atherosclerosis. Antiatherosclerotic effects of angiotensin II receptor blockers, angiotensin converting enzyme inhibitors, HMG CoA reductase inhibitors, calcium channel blocker and epalrestat were studied with an in vitro guinea-pig basilar artery smooth muscle cell (GBa-SM3) culture system over 3 days incubated with 0 to 10% of fetal bovine serum. Results demonstrated that simvastatin (0.1 mM), fluvastatin (0.3 mM), amlodipine (0.2 mM) and epalrestat (1 mM) elicited significant (p < 0.05 or 0.01) antiproliferative effects, whereas losartan (1 mM), valsartan (1 mM), enalapril (0.1 mM), captopril (1 mM), trandolapril (0.01 mM), pravastatin (0.7 mM) did not. In conclusion, the present in vitro VSMC culture system may serve as a comprehensive screening method for pleiotropic effects of commonly used therapeutic agents.
 ...
PMID:[Effects of angiotensin II receptor blockers, angiotensin converting enzyme inhibitors, 3-hydroxy-3-methyl glutaryl (HMG) CoA reductase inhibitors, amlodipine and epalrestat on cultured basilar artery smooth muscle cell proliferation]. 1504 34

Monocyte-derived microparticles play an important role in the pathogenesis of diabetic vasculopathy, and angiotensin II receptor blocker and statin have been shown to have a beneficial effect on the angiopathies of hypertension and hyperglycemia in patients with type 2 diabetes mellitus. However, the interaction between angiotensin II receptor blocker and statin, and monocyte-derived microparticles in atherosclerosis is poorly understood. The effects of losartan and simvastatin on circulating concentrations of monocyte-derived microparticles, chemokines, and soluble adhesion markers were studied in hypertensive patients with or without type 2 diabetes mellitus. Monocyte-derived microparticles were measured by flow cytometry, and levels of serum chemokines (MCP-1 and RANTES) and soluble adhesion markers (sP-selectin and sVCAM-1) were measured by enzyme-linked immunosorbent assay. Losartan decreased both the systolic and diastolic blood pressure in hypertensive patients with and without type 2 diabetes mellitus. The concentrations of monocyte-derived microparticles, chemokines, and soluble adhesion molecules were higher in hypertensive patients who also had type 2 diabetes mellitus vs. those who did not. The administration of angiotensin II receptor blocker decreased the circulating concentration of all these markers. In addition, all markers were decreased by combination therapy, and monocyte-derived microparticles were decreased more with combination therapy with losartan and simvastatin than monotherapy with losartan. The administration of angiotensin II receptor blocker inhibited monocyte-derived microparticle generation and suggests that angiotensin II is intimately related to vascular changes that occur in type 2 diabetes mellitus. Combination therapy with a statin and angiotensin II receptor blocker might be valuable as anti-atherosclerotic therapy in patients with type 2 diabetes mellitus and nephropathy.
 ...
PMID:Effects of losartan and simvastatin on monocyte-derived microparticles in hypertensive patients with and without type 2 diabetes mellitus. 1509 33

Diabetes mellitus and impaired glucose tolerance (IGT) are common disorders, and their prevalence is predicted to increase over the next several decades. The major serious complication of these disorders is large vessel atherosclerosis leading to myocardial infarction and stroke. Aggressive control of hypertension and dyslipidemia can significantly reduce risk for cardiovascular events, but a large amount of residual cardiovascular disease remains. A major remaining question is the potential role of aggressive glucose control for reducing macrovascular event rates in patients with diabetes. An ongoing trial addresses this issue, and a large number of other concurrent trials address several novel therapeutic strategies to reduce further the cardiovascular complications of diabetes or IGT. Many of these strategies test approaches that may directly target the vessel wall. Therapeutic modalities currently being evaluated include thiazolidinediones, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers. Most of these trials will report their findings in the next 5 years. It is likely that the results of ongoing trials will significantly improve our approach to managing cardiovascular risk in patients with diabetes and IGT.
 ...
PMID:Strategies in ongoing clinical trials to reduce cardiovascular disease in patients with diabetes mellitus and insulin resistance. 1517 14

Angiotensin II receptor blockers could prevent the development of atherosclerosis beyond reducing blood pressure in monkeys fed a high-cholesterol diet. However, it has been unclear whether hypotensive effects improve atherosclerosis in primates. We investigated whether antihypertensive agents, an angiotensin II receptor antagonist, candesartan, and a calcium channel blocker, amlodipine, prevent areas of atherosclerotic lesions in the aorta of monkeys fed a high-cholesterol diet. Seventeen male monkeys fed a high-cholesterol diet for 6 months were grouped as follows: a high-cholesterol diet group (n=5), a candesartan-treated group (1 mg/kg per day, n=6) and an amlodipine-treated group (5 mg/kg per day, n=6). Candesartan and amlodipine showed a similar hypotensive effect by decreasing the systolic blood pressure approximately 20 mmHg, while these agents did not affect serum cholesterol levels. The ratio of atherosclerotic area to total area in thoracic aorta was significantly decreased by treatment with candesartan, but the ratio tended to be decreased by treatment with amlodipine. Although the angiotensin-converting enzyme activity in plasma was not changed by treatment with candesartan or amlodipine, the angiotensin-converting enzyme activity in the thoracic aorta was obviously reduced by treatment with candesartan, but not with amlodipine. Therefore, a blockade of angiotensin II action rather than a hypotensive effect may play an important role in preventing the development of atherosclerosis in primates.
 ...
PMID:Comparative effects of candesartan and amlodipine in a monkey atherosclerotic model. 1530 89

Since endothelial dysfunction may significantly contribute to the pathophysiology of hypertension and its complications, its modification seems to be a very attractive means to favourably affect the development of atherosclerosis and cardiovascular events in hypertensive patients. However, not all antihypertensive drugs consistently improve endothelial dysfunction. While first-generation beta-blockers showed contrasting or null effects on endothelial function, newer beta-blockers of the third generation, such as carvedilol and nebivolol, seem to be provided with specific endothelium-mediated vasodilating effects. Calcium channel blockers are generally able to increase endothelium-dependent vasodilation in several vascular beds, in patients with essential hypertension, probably through multiple mechanisms. Most studies have shown thatACE inhibitors favourably affect endothelial function mainly in the subcutaneous, epicardial and renal circulation, not only by inhibiting the effects of angiotensin II on the endothelium, but also by enhancing bradykinin-induced vasodilation, probably a hyperpolarization-related effect. On the other hand, discordant evidence is available about the effects of angiotensin II receptor type I blockers on endothelial function in patients with essential hypertension, atherosclerosis or diabetes.There are data suggesting that an increased activity of the endothelin- I system may play a role in the blunted endothelium-dependent vasorelaxation of hypertensive patients, an effect that could be contrasted by the use of endothelin-I receptor antagonists. However, to date no substantial clinical efficacy of endothelin-I receptor blockers has been shown in patients with essential hypertension. Finally, other possibly useful compounds in restoring impaired endothelial function in hypertension are some antioxidant agents such as vitamin C, folic acid, the cofactor tetrahydrobiopterin (BH4), L-arginine and the drugs of the statin class.
 ...
PMID:Different effects of antihypertensive drugs on endothelial dysfunction. 1552 63

Angiotensin II is a potent vasoconstrictor that is implicated in the pathogenesis of hypertension, heart failure and atherosclerosis. In the present study, angiotensin II receptor mRNA expression levels were quantified by real-time polymerase chain reaction and the vasocontractile responses to angiotensin II were characterised by in vitro pharmacology in endothelium-denuded human coronary arteries. Angiotensin II type 1 (AT(1)) and type 2 (AT(2)) receptor mRNA expression levels were significantly down-regulated in arteries from patients with heart failure as compared to controls. The angiotensin II-induced vasoconstriction diminished with increasing age in patients with heart failure (r(2)=0.31, P<0.05). Also, the AT(1) receptor mRNA expression levels decreased with increasing age in patients with heart failure (r(2)=0.74, P<0.05), while no such correlation could be shown in the control group (r(2)=0.04, P=n.s.). The AT(2) receptor mRNA expression levels did not correlate with age in patients with heart failure or controls. In conclusion, the diminished angiotensin II vasoconstriction with age in heart failure patients is most likely due to a lower density of AT(1) receptors and may result from a longer period of exposure to heart failure in older patients.
 ...
PMID:Angiotensin II receptor mRNA expression and vasoconstriction in human coronary arteries: effects of heart failure and age. 1556 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>