Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aging is associated with cerebrovascular dysregulation, which may underlie the increased susceptibility to ischemic stroke and vascular cognitive impairment occurring in the elder individuals. Although it has long been known that oxidative stress is responsible for the cerebrovascular dysfunction, the enzymatic system(s) generating the reactive oxygen species (ROS) have not been identified. In this study, we investigated whether the superoxide-producing enzyme NADPH oxidase is involved in alterations of neurovascular regulation induced by aging. Cerebral blood flow (CBF) was recorded by laser-Doppler flowmetry in anesthetized C57BL/6 mice equipped with a cranial window (age=3, 12, and 24 months). In 12-month-old mice, the CBF increases evoked by whisker stimulation or by the endothelium-dependent vasodilators acetylcholine and bradykinin were attenuated by 42, 36, and 53%, respectively (P<0.05). In contrast, responses to the nitric oxide donor S-nitroso-D-penicillamine or adenosine were not attenuated (P>0.05). These cerebrovascular effects were associated with increased production of ROS in neurons and cerebral blood vessels, assessed by hydroethidine microfluorography. The cerebrovascular impairment present in 12-month-old mice was reversed by the ROS scavenger Mn (III) tetrakis (4-benzoic acid) porphyrin chloride or by the NADPH oxidase peptide inhibitor gp91ds-tat, and was not observed in mice lacking the Nox2 subunit of NADPH oxidase. These findings establish Nox2 as a critical source of the neurovascular oxidative stress mediating the deleterious cerebrovascular effects associated with increasing age.
 ...
PMID:Nox2-derived reactive oxygen species mediate neurovascular dysregulation in the aging mouse brain. 1742 47

Decades of experimentation on angiotensin and bradykinin have focused on macrovascular systemic effects. However, angiotensin II and bradykinin are both angiogenic agents, highlighting their ability to also effect the microvascular circulation. Not surprisingly, inhibition of angiotensin converting enzyme, which inhibits angiotensin II synthesis and bradykinin degradation, would have different impacts on angiogenesis in vivo dependent upon what factors were present in the system. Several pathological states in which angiogenesis is important, including peripheral ischemia, stroke, retinopathy, and cancer are examined in this review with respect to activity of angiotensin II and bradykinin and the impact of angiotensin converting enzyme inhibition. Although generalizations are not without legitimate criticism, one can think about peripheral ischemia and stroke as being more dependent upon bradykinin signaling and retinopathy and cancer as more dependent upon angiotensin II signaling to drive angiogenesis. Many exceptions are found that are specific to individual animal model systems. Furthermore, cancer systems that have been examined at any depth are few. However, published data on in vitro cultures and animal models present interesting predictions about how the renin angiotensin and bradykinin systems may function in humans. Since angiotensin converting enzyme inhibitors have been widely utilized pharmaceuticals for many years, we are now accumulating epidemiological data that test our predictions. The importance of understanding which agent, angiotensin and/or bradykinin, appears to be the more important regulator of angiogenesis in a given pathology will become increasing evident as more specific angiotensin II and bradykinin receptor blocking drugs make their way into clinical use.
 ...
PMID:The renin angiotensin system in the regulation of angiogenesis. 1750 31

The angiotensin-converting enzyme (ACE) catalyzes the formation of angiotensin II and the breakdown of bradykinin into inactive products. The insertion/deletion (I/D) polymorphism affects the activity of the enzyme, with the DD genotype being responsible for the highest activity of the enzyme. Meta-analysis of 11 studies including white persons showed that the DD genotype was a risk factor for ischemic stroke. No such correlation was found in an Asian population. Studies on different etiologies or intermediate phenotypes of ischemic stroke did not bring univocal results. There are still no convincing data on whether the I/D polymorphism of the ACE gene is a risk factor for spontaneous intracerebral hemorrhage and intracranial aneurysms, ruptured or unruptured. Several pharmacogenetic studies analyzed the influence of the ACE I/D polymorphism on the response to acute stroke therapy (thrombolysis) or prevention strategies (lifestyle modification and treatment of vascular risk factors). Presently, however, there is no consensus on whether the efficacy of these therapies is affected by the ACE gene I/D polymorphism.
 ...
PMID:ACE genotype, risk and causal relationship to stroke: implications for treatment. 1760 83

Bradykinin is considered an important mediator of the inflammatory response in both the peripheral and the central nervous system and it has attracted recent interest as a potential mediator of brain injury following stroke. Bradykinin is recognized to play an important role in ischemic brain. We investigated the effect of bradykinin postconditioning on ischemic damage after 8 min of ischemia (four-vessel occlusion) and 3 days of reperfusion. Bradykinin was administered after 2 days of reperfusion at a dose of 150 microg/kg (i.p.). Catalase (CAT) activity was significantly increased in all examined regions (cortex, hippocampus and striatum) 3 days after 8 min of ischemia, but postconditioning decreased this activity below the control values. The total activity of superoxide dismutase (SOD) 3 days after ischemia was at control level with or without postconditioning. However, the analysis of individual SODs separately revealed interesting differences; while the activity of CuZnSOD was significantly decreased 3 days after ischemia, the activity of MnSOD was significantly increased compared to control levels. In both cases, postconditioning returned SOD activity to control levels. These findings are interesting because MnSOD is a mitochondrial enzyme and its activity in the cytosol suggests that a possible mechanism of protection provided by postconditioning could include prevention of release of mitochondrial proteins to the cytoplasm, resulting in protection against the mitochondrial pathway of apoptosis. 8 min of ischemia alone caused the degeneration of 52.37% neurons in the hippocampal CA1 region 3 days later. Bradykinin used as postconditioning 2 days after the same interval of ischemia enabled the survival of more than 97% of CA1 neurons. This study demonstrated that bradykinin postconditioning induces protection against ischemic brain injury and promotes neuronal survival.
 ...
PMID:Effects of bradykinin postconditioning on endogenous antioxidant enzyme activity after transient forebrain ischemia in rat. 1808 Jan 86

The paper presents a comparison of the influence of angiotensin-converting enzyme (ACE) with high (perindopril) or low (enalapril) affinity to the endothelial renin-angiotensin-aldosterone system on the dynamics of the content of humoral endothelial dysfunction markers in patients with essential hypertension (EH) complicated by ischemic cerebral stroke. The subjects of the study were patients with EH complicated by acute cerebral ischemia, who received hospital treatment with perindopril (52 patients) or enalapril (58 patients). Changes in the physical properties of the cytoplasmatic membrane and phosphatidylserine exterialization were studied in peripheral blood on lymphocyte model. In peripheral blood plasma, the dynamics of sPECAM-1 titre and antiphospholipid antibodies (APLA) were studied. All the patients had high contents of blebbing and Annexin-positive lymphocytes, as well as high sPECAM-1 and APLA titres on the 1st day of hospital treatment. These variables decreased by the 20th day of hospital stay. In patients receiving perindopril the contents of endothelial dysfunction markers under study decreased more prominantly vs. patients in the other group. The elevation of endothelial dysfunction markers is a result of its progression and oxidative stress effect. Endothelial dysfunction can be corrected, which is proved by the decrease in the level of its markers by the 20th day of hospital treatment. The most prominent therapeutic effect of perindopril is a result of its high affinity to endothelial ACE and the inhibition of bradykinin degradation.
 ...
PMID:[The therapy of complicated forms of essential hypertension with the ACE inhibitor perindopril]. 1821 59

Stroke is one of the leading causes of disability and death worldwide and is a more common cause of cardiovascular morbidity and mortality than myocardial infarction among patients with hypertension. Identifying and modifying key risk factors is crucial to reduce morbidity and mortality from stroke. Hypertension is the most important modifiable risk factor for ischemic stroke, and antihypertensive treatment is of paramount importance to reduce the incidence of stroke mortality and morbidity. Perindopril is a third-generation long acting, once-daily lipophilic angiotensin-converting enzyme inhibitor with high tissue angiotensin-converting enzyme affinity, lowering angiotensin II and potentiating bradykinin. Its efficacy, safety and tolerability are well established in the treatment of hypertension and heart failure. The purpose of this article is to review the evidence from clinical trials as well as from recent patents that has been gathered in regard to perindopril, demonstrating not only its efficacy in reducing blood pressure, but also to other cardiovascular protective properties that act in addition to the obvious blood-pressure-lowering effect in the prevention of stroke in patients with essential hypertension, with particular attention paid to the results from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS).
 ...
PMID:Role of perindopril in the prevention of stroke. 1822 Oct 93

ACE inhibition is now recognized as superior to placebo on outcomes in stable coronary artery disease (CAD), including total and cardiovascular mortality, fatal and nonfatal myocardial infarction, heart failure, revascularization and stroke. This review examines clinical evidence for the mode of action of ACE inhibitors in CAD, which is dominated by the results of a single trial, EUROPA, and its substudies. The generally accepted mode of action for ACE inhibitors in CAD is blood pressure reduction. However, the EUROPA data demonstrate that endothelial protection, with the effect of arresting or reducing the processes of atherosclerosis is also important. Chronic overexpression of tissue ACE in CAD disrupts the angiotensin II/bradykinin balance with a net result of endothelial dysfunction. ACE inhibitors reduce production of angiotensin II, which prevents vasoconstriction, reduces adhesion molecules and growth factors, decreases oxidative stress and prevents apoptosis. A concomitant decrease in the degradation of bradykinin as a result of ACE inhibition raises levels of this kinin, leading to vasodilation and an antiapoptotic action, as well as opposition of the negative actions of angiotensin II. We now have clinical trial evidence of these processes in CAD patients participating in the EUROPA study by measurement of markers of endothelial function, including nitric oxide synthase (eNOS), the rate of apoptosis and levels of von Willebrand factor (vWf). Serum from CAD patients was found to significantly downregulate eNOS protein expression and activity versus that of healthy controls (p < 0.01), most probably as a result of upregulation of tissue ACE. One year of treatment with perindopril upregulated eNOS protein expression and activity (19% and 27% vs placebo; p < 0.05). Similarly, vWf was elevated at baseline and significantly reduced after 1 year of treatment with perindopril (p < 0.001). Increased endothelial apoptosis by serum of CAD patients was accompanied by excess angiotensin II and tumour necrosis factor-alpha and a reduction in bradykinin; all of these parameters were reversed by treatment. We therefore have clinical results showing that perindopril normalizes the angiotensin II/bradykinin balance, reduces inflammation and prevents endothelial apoptosis. Accumulating preclinical evidence for the absence of a class effect for ACE inhibitors includes differences in terms of effect on eNOS and rate of endothelial apoptosis. These differences appear to be related to tissue affinity, penetration of atherosclerotic plaque and affinity for the target enzyme. Consideration of these features is important when administering ACE inhibition as secondary prevention in CAD patients. In this context, current European guidelines for stable angina pectoris recommend prescription of agents and doses with proven efficacy in secondary prevention.
 ...
PMID:Insight into the mode of action of ACE inhibition in coronary artery disease: the ultimate 'EUROPA' story. 1927 71

The angiotensin-converting enzyme (ACE) inhibitor perindopril (Coversyl) is a long-acting lipophilic drug with a high-tissue affinity for the ACE. ACE inhibition by perindopril has two main effects: it inhibits the angiotensin II formation and potentiates bradykinin. Perindopril is one of the ACE inhibitors that has been extensively studied in randomized clinical trials within various patient populations. The clinical efficacy has been demonstrated in patients with hypertension, diabetes mellitus, cerebrovascular disease, stable coronary artery disease (CAD) and heart failure. Perindopril has a positive safety and tolerability profile. Therefore, perindopril, as an ACE inhibitor, has an established place in the major clinical treatment guidelines. This article discusses several studies that have shown that an antihypertensive treatment with perindopril reduces and prevents cardiovascular events in a large range of patients with established vascular disease. The observed cardioprotective benefits of perindopril were independent of blood pressure. The outcome of these and other trials support the concept of specific cardioprotective properties of ACE inhibition by perindopril in addition to the blood pressure-lowering effects, such as anti-atherosclerotic, anti-inflammatory and antithrombotic properties. In addition, the observed consistency of the treatment benefit across subgroups indicates that the absolute benefits conferred by treatment are mainly established by each patient's future risk of vascular complications, rather than their initial blood pressure level or other risk factors. This article describes these issues according to the main studies with perindopril or perindopril-based regimens, concluding that the blood pressure-dependent and -independent cardioprotective effects extend to all patients with vascular disease. This concept supports the provision of ACE inhibitor-based treatment, not on the basis of arbitrary cut-off points for blood pressure but rather on assessment of vascular risk, which is raised in patients with stable CAD, diabetes and stroke.
 ...
PMID:Angiotensin-converting enzyme inhibition by perindopril in the treatment of cardiovascular disease. 1937 59

Blood-brain barrier disruption and brain edema are detrimental in ischemic stroke. The kallikrein-kinin system appears to play an important role in the regulation of vascular permeability and is invoked in edema formation. The effects of kinins are mediated by bradykinin receptors B1R and B2R. However, little is known about the exact roles of bradykinin receptors in the early stage of cerebral ischemia. In this study, we demonstrated that ischemia upregulated the level of B1R and B2R at 24h after reperfusion by immunofluorescence assays, mainly expressed in astrocytes and neurons, respectively, in the ischemic penumbra. Moreover, B2R inhibition more effectively reduced neurological severity scores, blood-brain barrier permeability and cytokines release than B1R inhibition did. Additionally, B2R inhibition also significantly suppressed B1R protein level. Therefore, blockade of B2R may be a more effective strategy for the treatment of ischemic brain injury than B1R inhibition within 24h after reperfusion.
 ...
PMID:Blockade of bradykinin B2 receptor more effectively reduces postischemic blood-brain barrier disruption and cytokines release than B1 receptor inhibition. 1964 18

The morphological and functional integrity of the microcirculation is compromised in many cardiovascular diseases such as hypertension, diabetes, stroke, and sepsis. Angiotensin converting enzyme inhibitors (ACEi), which are known to favor bradykinin (BK) bioactivity by reducing its metabolism, may have a positive impact on preventing the microvascular structural rarefaction that occurs in these diseases. Our study was designed to test the hypothesis that BK, via B2 receptors (B2R), protects the viability of the microvascular endothelium exposed to the necrotic and apoptotic cell death inducers H(2)O(2) and LPS independently of hemodynamics. Expression (RT-PCR and radioligand binding) and functional (calcium mobilization with fura-2AM, and p42/p44MAPK and Akt phosphorylation assays) experiments revealed the presence of functional B2R in pig cerebral microvascular endothelial cells (pCMVEC). In vitro results showed that the cytocidal effects of H(2)O(2) and LPS on pCMVEC were significantly decreased by a BK pretreatment (MTT and crystal violet tests, annexin-V staining/FACS analysis), which was countered by the B2R antagonist HOE 140. BK treatment coincided with enhanced expression of the cytoprotective proteins COX-2, Bcl-2, and (Cu/Zn)SOD. Ex vivo assays on rat brain explants showed that BK impeded (by approximately 40%) H(2)O(2)-induced microvascular degeneration (lectin-FITC staining). The present study proposes a novel role for BK in microvascular endothelial protection, which may be pertinent to the complex mechanism of action of ACEi explaining their long-term beneficial effects in maintaining vascular integrity.
 ...
PMID:Bradykinin protects against brain microvascular endothelial cell death induced by pathophysiological stimuli. 1978 24


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