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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent advances in the understanding of vascular disease genesis suggest that atherosclerosis and hypertension, primary targets of therapy in the INternational VErapamil SR/trandolapril STudy (INVEST), are closely related. A unified model for the development of cardiovascular disease (CVD) is emerging from recent advances related to atherosclerosis and hypertension. The process of vascular disease appears to begin early in life, when signs of endothelial dysfunction first appear. A primary cause of CVD progression is increased oxidative stress in the endothelium caused by multiple risk factor conditions, including heredity, dyslipidemia, smoking, diabetes, and elevated systolic blood pressure (SBP > 110 mmHg). The renin-angiotensin and kallikrein-kinin systems are important regulators of blood pressure and atherosclerosis. In the renin-angiotensin system, angiotensin-converting enzyme (ACE) mediates generation of angiotensin II (ang II) at local vascular sites and in the plasma and also degrades bradykinin. Information derived from INVEST will help to identify treatment strategies, such as those containing a calcium antagonist and an ACE inhibitor, that are targeted directly at the vascular disorder responsible for hypertension and atherosclerosis.
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PMID:The vascular biology of hypertension and atherosclerosis and intervention with calcium antagonists and angiotensin-converting enzyme inhibitors. 1171 69

Alterations in the function and structure of the blood vessel wall account for most clinical events in the coronary and cerebrovascular circulation such as myocardial infarction and stroke. Cardiovascular drugs may exert beneficial effects on the vascular wall both at the level of the endothelium and vascular smooth muscle cells. Therefore, endothelial mediators, in particular nitric oxide (NO) and endothelin (ET), are of special interest. Drugs can modulate the expression and actions of NO, a vasodilator with antiproliferative and antithrombotic properties, and of ET, a potent vasoconstrictor and proliferative mitogenic agent. The most successful drugs in this context are statins and angiotensin-converting enzyme (ACE)-inhibitors. While statins increase the expression of NO synthase. ACE-inhibitors increase the release of NO via bradykinin-mediated mechanisms. Antioxidant properties of drugs are also important, as oxidative stress is crucial in atherosclerotic vascular disease. These properties may explain part of the effects of calcium antagonists and ACE-inhibitors. Indeed, angiotensin II stimulates NAD(P)H oxidases responsible for the formation of superoxide, which inactivates NO. ACE-Inhibitors thus increase the bioavailability of NO. Newer cardiovascular drugs such as nebivolol are able to directly stimulate NO release from the endothelium both in isolated arteries and in the human forearm circulation. ET receptor antagonists may exert beneficial effects in the vessel wall by preventing the effects of ET at its receptors and by reducing ET production. In summary, cardiovascular drugs have important effects on the vessel wall, which may be clinically relevant for the prevention and treatment of cardiovascular disease.
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PMID:Vascular effects of newer cardiovascular drugs: focus on nebivolol and ACE-inhibitors. 1181 90

Angiotensin-converting enzyme (ACE) inhibitors are well established as first-line therapy for patients with left ventricular dysfunction, diabetic patients with hypertension or renal disease, and patients recovering from myocardial infarction. Angiotensin II and bradykinin regulate cellular proliferation, inflammation, and endothelial function, thus playing an important role in the pathogenesis of atherosclerosis. A large body of experimental evidence reporting that ACE inhibitors limit these effects has formed the rationale for major clinical trials of these drugs in the management of atherosclerotic vascular disease. The first trial to be completed demonstrated that ACE inhibition improves the prognosis of patients who have, or are at risk of, atherosclerotic vascular disease, independent of its effects on left ventricular function and hypertension. Expanding the indications for ACE inhibitors is now evidence driven, although the choice of agent for these new indications remains to be determined by further research.
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PMID:Potential indications for angiotensin-converting enzyme inhibitors in atherosclerotic vascular disease. 1183 51

We investigated the role of nitric oxide (NO) in the control of myocardial O2 consumption in Fischer 344 rats. In Fischer rats at 4, 14, and 23 mo of age, we examined cardiac function using echocardiography, the regulation of cardiac O2 consumption in vitro, endothelial NO synthase (eNOS) protein levels, and potential mechanisms that regulate superoxide. Aging was associated with a reduced ejection fraction [from 75 +/- 2% at 4 mo to 66 +/- 3% (P < 0.05) at 23 mo] and an increased cardiac diastolic volume [from 0.60 +/- 0.04 to 1.00 +/- 0.10 ml (P < 0.01)] and heart weight (from 0.70 +/- 0.02 to 0.90 +/- 0.02 g). The NO-mediated control of cardiac O2 consumption by bradykinin or enalaprilat was not different between 4 mo (36 +/- 2 or 34 +/- 3%) and 14 mo (29 +/- 1 or 25 +/- 3%) but markedly (P < 0.05) reduced in 23-mo-old Fischer rats (15 +/- 3 or 7 +/- 2%). The response to the NO donor S-nitroso-N-acetyl penicillamine was not different across groups (35%, 35%, and 44%). Interestingly, the eNOS protein level was not different at 4, 14, and 23 mo. The addition of tempol (1 mmol/l) to the tissue bath eliminated the depression in the control of cardiac O2 consumption by bradykinin (25 +/- 3%) or enalaprilat (28 +/- 3%) in 23-mo-old Fischer rats. We next examined the levels of enzymes involved in the production and breakdown of superoxide. The expression of Mn SOD, Cu/Zn SOD, extracellular SOD, and p67phox, however, did not differ between 4- and 23-mo-old rats. Importantly, there was a marked increase in gp91phox, and apocynin restored the defect in NO-dependent control of cardiac O2 consumption at 23 mo to that seen in 4-mo-old rats, identifying the role of NADPH oxidase. Thus increased biological activity of superoxide and not decreases in the enzyme that produces NO are responsible for the altered control of cardiac O2 consumption by NO in 23-mo-old Fischer rats. Increased oxidant stress in aging, by decreasing NO bioavailability, may contribute not only to changes in myocardial function but also to altered regulation of vascular tone and the progression of cardiac or vascular disease.
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PMID:NAD(P)H oxidase-generated superoxide anion accounts for reduced control of myocardial O2 consumption by NO in old Fischer 344 rats. 1291 88

Bradykinin is an important modulator of endothelial cell function and has also a powerful cardioprotective effect. Here we report that treatment of severely pulmonary hypertensive rats (that recapitulate several of the physiological and pathological characteristics of the human pulmonary vascular disease, including dramatic right ventricular hypertrophy, pericardial effusion and death) with a newly synthesized long-acting bradykinin B2 receptor agonist B9972 caused reduction of the pulmonary artery pressure (PAP=51+/-2.0 versus 68+/-2.8 of untreated animals) and of right ventricular hypertrophy (Rv/Lv+S=0.55+/-0.02 versus 0.73+/-0.03 of untreated rats) and activation of Akt. Long-term stimulation with B9972 in our animal model of SPH resulted in decreased expression of the B2 receptor in lung vasculature. Treatment with B9972 decreased the number of plexiform lesions in the lungs by inducing cell apoptosis in the obliterated vessels and by restoring caveolin-1 expression. B9972 also promoted eNOS activation. In vitro B9972 caused activation of caspase-3 as well as Erk and induction of prostacyclin production in rat pulmonary microvascular EC. Taken together our data suggest that a stable bradykinin B2 agonist B9972 demonstrates the capacity to reduce severe pulmonary hypertension, right ventricular hypertrophy and induce apoptosis of hyperproliferative cells in pre-capillary pulmonary arterioles.
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PMID:Treatment of severe pulmonary hypertension: a bradykinin receptor 2 agonist B9972 causes reduction of pulmonary artery pressure and right ventricular hypertrophy. 1587 94

Cardiovascular disease is the number one cause of death in the United States. Vascular smooth muscle cells (VSMC) are an important constituent of the vessel wall that can bring about pathological changes leading to vascular disease. Depending on the environment, the function of VSMC can deviate profoundly from its normal contractile role. Despite advances in research, the underlying mechanisms that activate VSMC toward vascular disease are poorly understood. For the first time, we have observed that factor XII and high-molecular-weight kininogen, constituents of the blood plasma, can bind to VSMC in a Zn2+-dependent manner. In the presence of prekallikrein, this assembly of factor XII and high-molecular-weight kininogen on VSMC leads to the activation of prekallikrein to kallikrein with a rapid formation of bradykinin. The amount of bradykinin in the culture medium then decreases, presumably because of the presence of a kininase activity. p44/42 mitogen-activated protein kinase is rapidly phosphorylated in response to in situ-generated or in vitro-added bradykinin and is inhibited by bradykinin antagonist HOE-140. Binding of factor XII to VSMC also results in a concentration-dependent phosphorylation of p44/42 mitogen-activated protein kinase. This early mitogenic signal, which is also implicated in atherogenesis, may change the metabolic and proliferative activity of VSMC, which are key steps in the progression of atherosclerosis.
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PMID:Assembly, activation, and signaling by kinin-forming proteins on human vascular smooth muscle cells. 1596 76

Since their discovery in the 1980s, angiotensin-converting enzyme (ACE) inhibitors have been shown to decrease angiotensin formation, prevent breakdown of bradykinin, and may also act on peptides of the renin-angiotensin system. They are effective in reducing the risk of heart failure, myocardial infarction, and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure, and have been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure. They may preserve endothelial function and counteract initiation and progression of atherosclerosis. Broadly, ACE inhibitors can be divided into tissue specific or serum ACE inhibitors. Tissue-specific ACE inhibitors as a group are not superior to serum ACE inhibitors in the treatment of coronary artery disease. Pending direct comparator clinical trials between a tissue ACE inhibitor and a plasma ACE inhibitor, both ramipril and perindopril can be recommended for secondary risk prevention, based on the evidence.
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PMID:Tissue angiotensin-converting enzyme inhibitors: are they more effective than serum angiotensin-converting enzyme inhibitors? 1640 97

Cardiovascular complications are the leading cause of morbidity and mortality in patients with diabetes mellitus; up to 80% of deaths in patients with diabetes are closely associated with vascular disease. The ability of the organism to form a collateral network of blood vessels constitutes an important response to vascular occlusive disease and determines to a large part the clinical consequences and severity of tissue ischemia. The development of new vessels is significantly reduced in diabetic patients with coronary or peripheral artery disease. This probably contributes to the severe course of limb ischemia in diabetic patients, in which peripheral artery disease often results in foot ulceration and lower extremity amputation. Diabetic retinopathy remains one of the major causes of acquired blindness in developed nations. This is true despite the development of laser treatment, which can prevent blindness in the majority of those who develop macular edema or proliferative diabetic retinopathy. The hallmark of diabetic retinopathy is the lack of microvessels in the macula, leading to hypoxia, associated with peripheral retinal neovascularization that may ultimately cause severe vitreous cavity bleeding and/or retinal detachment. The factors that stimulate retinal blood vessel growth have not been fully defined, but there is accumulating evidence that the renin-angiotensin-bradykinin system may be involved in a number of retinal vascular disorders, including retinopathy of prematurity and proliferative diabetic retinopathy. Only a few studies have specifically evaluated the effect of diabetes on angiogenesis in ischemic vascular disease and in the retina. Moreover, the mechanisms by which diabetes could both limit the formation of new blood vessels in most organs and simultaneously induce proliferative diabetic retinopathy remain largely undefined. In the present review, we aimed to briefly describe the main molecular mechanisms involved in the ischemia-induced angiogenesis, and their alterations in diabetes. Possible therapeutic strategies to restore angiogenesis in diabetic patients are also listed.
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PMID:[Diabetes and peripheral arterial occlusive disease: therapeutic potential and pro-angiogenic strategies]. 1670 93

The main pathologic hallmark of systemic sclerosis (SSc) is endothelial derangement; the pathologic alterations of the vessel wall in SSc are strikingly similar to the modification detected in the atherosclerotic lesions, and it is now evident that SSc is also characterized by accelerated macrovascular disease. Peptides related to angiotensin II, the final product of the renin-angiotensin system (RAS), play a role as regulators of endothelial cell function. Angiotensin-converting enzyme (ACE), the key enzyme in the RAS, is the predominant pathway of angiotensin II formation in blood and tissues. In intron 16 of the gene encoding for ACE an insertion/deletion (I/D) polymorphism, consisting of the presence or absence of a 287-base pair Alu sequence, has been identified. This polymorphism has been related to ACE enzyme levels, and data from experimental studies reported a functional role for this polymorphism in modulating the angiotensin II levels. We previously documented a high ACE D allele frequency in SSc patients and its role in increasing the risk of SSc, thus suggesting that the I/D polymorphism might be a useful genetic marker to identify SSc patients at risk to develop a severe vascular disease, frequently leading to gangrene. Moreover, our preliminary data, besides supporting the role of ACE I/D polymorphism as a predisposing factor to SSc, demonstrated its involvement in accelerated macrovascular disease by increasing the intima media thickness. Therefore, in SSc, not only endothelial dysfunction, but also vascular damage, linked to ACE I/D polymorphism, may significantly contribute to accelerated macrovascular disease, as the ACE D allele, by regulating both the production of angiotensin II and the degradation of bradykinin, contributes to mechanisms involved in the induction and maintenance of vessel wall modification.
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PMID:Angiotensin-converting enzyme in systemic sclerosis: from endothelial injury to a genetic polymorphism. 1685 31

Endothelium-dependent relaxations are due to the release by the endothelial cells of potent vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO), from 1-arginine by the constitutive endothelial NO synthase. In arterial smooth muscle, NO stimulates soluble guanylate cyclase which leads to the accumulation of cyclic GMP. Endothelial cells also release substances (EDHF) that hyperpolarize vascular smooth muscle. The release of NO from the endothelium can be mediated by both Gi (catecholamines, serotonin, thrombin) and Gq (adenosine diphosphate, bradykinin) G-proteins. In arteries with regenerated endothelium and/or atherosclerosis, there is a selective loss of the Gi mechanism of No-release which favours the occurrence of vasospasm, thrombosis and cellular growth. In addition to relaxing factors, the endothelial cells can produce contracting-substances (EDCF) which include superoxide anions, endoperoxides, thromboxane A2 and endothelin-1. The propensity to release EDCFs is maintained or even augmented in diseased blood vessels. The switch from a normally predominant release of NO to that of EDCF may play a crucial role in vascular disease.
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PMID:[Endothelial dysfunction and vascular pathology]. 1750 29


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