Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bradykinin, an endogenous nonapeptide produced by activation of the kallikrein-kinin system, promotes neuronal tissue damage as well as disturbances in blood-brain barrier function through activation of B2 receptors. In a rat model of focal cerebral ischemia, blockade of B2 receptors before initiation of ischemia with the B2 receptor antagonist, LF 16-0687 Ms, afforded substantial neuroprotection. In order to assess the potential clinical value of this approach, we evaluated the effect of LF 16-0687 Ms given at reperfusion following focal cerebral ischemia on local cerebral blood flow (LCBF), neurological outcome, and infarct size. Sprague-Dawley rats were subjected to MCA occlusion for 90 min by an intraluminal filament. Animals were assigned to one of four treatment arms (n = 7 each): (1) vehicle, (2) LF 16-0687 Ms (1.0 mg/kg/day), (3) LF 16-0687 Ms (3.0 mg/kg/day), or (4) LF 16-0687 Ms (10.0 mg/kg/day) given at reperfusion and repetitively over 2 days. Neurological recovery was examined daily, and infarct volume was assessed histologically on day 7 after ischemia. Physiological parameters and local CBF were not influenced by the treatment. Significant improvement of neurological outcome was observed on postischemic day 3 in animals receiving 1.0 and 3.0 mg/kg/day of LF 16-0687 Ms (P < 0.05). Inhibition of B2 receptors significantly reduced infarct volume in all treated animals predominantly in the cortex. B2 receptor blockade with LF 16-0687 Ms showed neuroprotective effectiveness even when therapy was initiated upon reperfusion, i.e. 90 min after induction of ischemia. Therefore, blockade of B2 receptors seems to be a promising therapeutic approach after focal cerebral ischemia, which deserves further experimental and clinical evaluation.
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PMID:Neuroprotective effects of a postischemic treatment with a bradykinin B2 receptor antagonist in a rat model of temporary focal cerebral ischemia. 1637 3

Stroke-induced neurological deficits and mortality are often associated with timing of treatment after the onset of stroke. We showed that local delivery of the human tissue kallikrein gene into rat brain immediately after middle cerebral artery occlusion (MCAO) exerts neuroprotection. In this study, we investigated the effect of systemic delivery of the kallikrein gene 8 hr after MCAO. Expression of recombinant human tissue kallikrein after gene transfer was identified in the ischemic brain region and blood vessels. Intravenous injection of adenovirus encoding the kallikrein gene significantly reduced neurological deficit scores 2 and 7 days after gene transfer. Kallikrein gene transfer also reduced ischemia-reperfusion (I/R)-induced cerebral infarction and promoted the survival and migration of glial cells from penumbra to the ischemic core from 3 to 14 days after gene delivery. Kallikrein reduced I/R-induced apoptosis of neuronal cells and inhibited inflammatory cell accumulation in the ischemic brain. These effects were blocked by the kinin B2 receptor antagonist icatibant. In addition, kallikrein enhanced angiogenesis and promoted neurogenesis after I/R and the stimulatory effect of kinin on neuronal cell proliferation was confirmed in primary cultured neuronal cells. The protective effects of kallikrein, through the kinin B2 receptor, were accompanied by increased cerebral nitric oxide and Bcl-2 levels, Akt phosphorylation, and reduced NAD(P)H oxidase activity, superoxide production, Bax levels, and caspase-3 activity. These results indicate that delayed systemic administration of the kallikrein gene after onset of stroke protects against ischemic brain injury by inhibiting apoptosis and inflammation and by promoting angiogenesis and neurogenesis.
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PMID:Kallikrein protects against ischemic stroke by inhibiting apoptosis and inflammation and promoting angiogenesis and neurogenesis. 1645 54

All the components of the kallikrein-kinin system are located in the cardiac muscle, and its deficiency may lead to cardiac dysfunction. In recent years, numerous observations obtained from clinical and experimental models of diabetes, hypertension, cardiac failure, ischemia, myocardial infarction and left ventricular hypertrophy have suggested that the reduced activity of the local kallikrein-kinin system may be instrumental for the induction of cardiovascular-related diseases. The cardioprotective property of the angiotensin converting enzyme inhibitors is primarily mediated via kinin-releasing pathway, which may cause regression of the left ventricular hypertrophy in hypertensive situations. The ability of kallikrein gene delivery to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating hypertension, cardiovascular and renal diseases. In addition, stable kinin agonists may also be available in the future as therapeutic agents for cardiovascular and renal disorders.
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PMID:Role of tissue kallikrein-kininogen-kinin pathways in the cardiovascular system. 1651 76

We have studied the effect of DX-88, a selective recombinant inhibitor of human plasma kallikrein, in transient or permanent focal brain ischemia (with or without reperfusion, respectively) induced in C57BL/6 mice. Twenty-four hours after transient ischemia, DX-88 administered at the beginning of ischemia (pre) induced a dose-dependent reduction of ischemic volume that, at the dose of 30 microg/mouse, reached 49% of the volume of saline-treated mice. At the same dose, DX-88 was also able to reduce brain swelling to 32%. Mice treated with DX-88 pre had significantly lower general and focal deficit score. Fluoro-Jade staining, a marker for neuronal degeneration, showed that DX-88-treated mice had a reduction in the number of degenerating cells, compared with saline-treated mice. Seven days after transient ischemia, the DX-88 protective effect was still present. When the inhibitor was injected at the end of ischemia (post), it was still able to reduce ischemic volume, brain swelling, and neurological deficits. DX-88 efficacy was lost when the inhibitor was given 30 min after the beginning of reperfusion (1 h post) or when reperfusion was not present (permanent occlusion model). This study shows that DX-88 has a strong neuroprotective effect in the early phases of brain ischemia preventing reperfusion injury and indicates that inhibition of plasma kallikrein may be a useful tool in the strategy aimed at reducing the detrimental effects linked to reperfusion.
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PMID:Selective inhibition of plasma kallikrein protects brain from reperfusion injury. 1670 80

The kallikrein/kinin system is beneficial in ischemia/reperfusion injury in heart, controversial in brain, but detrimental in lung, liver, and intestine. We examined the role of the kallikrein/kinin system in acute ischemia/reperfusion renal injury induced by 40 min occlusion of the renal artery followed by reperfusion. Rats were infused with tissue kallikrein protein 5 days before (pretreated group) or after (treated group) ischemia. Two days later, the pretreated group exhibited the worst renal dysfunction, followed by the treated group, then the control group. Kallikrein increased tubular necrosis and inflammatory cell infiltration with generation of more tumor necrosis factor-alpha and monocyte chemoattractant protein-1. Reactive oxygen species (ROS), malondialdehyde, and reduced/oxidized glutathione measurement revealed that the oxidative stress was augmented by kallikrein administration in both ischemic and reperfusion phases. The groups with more ROS generation also had more apoptotic renal cells. The deleterious effects of kallikrein on ischemia/reperfusion injury were reversed by cotreatment with bradykinin B2 receptor (B2R) antagonist, but not B1 receptor antagonist, and were not associated with hemodynamic changes. We conclude that early activation of B2R augmented ROS generation in ischemia/reperfusion renal injury, resulting in subsequent apoptosis, inflammation, and tissue damage. This finding suggests the potential application of B2R antagonists in acute ischemic renal disease associated with bradykinin activation.
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PMID:Early activation of bradykinin B2 receptor aggravates reactive oxygen species generation and renal damage in ischemia/reperfusion injury. 1701 77

Bradykinin coronary outflow, left ventricular performance and left ventricular dimensions of transgenic rats harboring the human tissue kallikrein-1 gene TGR(hKLK1) were investigated under basal and ischemic conditions. Bradykinin content in the coronary outflow of buffer-perfused, isolated hearts of controls and TGR(hKLK1) was measured by specific radioimmunoassay before and after global ischemia. Left ventricular function and left ventricular dimensions were determined in vivo using a tip catheter and echocardiography 6 days and 3 weeks after induction of myocardial infarction. Left ventricular type I collagen mRNA expression was analyzed by RNase protection assay. Compared to controls, basal bradykinin outflow was 3.5 fold increased in TGR(hKLK1). Ischemia induced an increase of bradykinin coronary outflow in controls but did not induce a further increase in TGR(hKLK1). However, despite similar unchanged infarction sizes, left ventricular function and remodeling improved in TGR(hKLK1) after myocardial infarction, indicated by an increase in left ventricular pressure (+34%; P<0.05), contractility (dp/dt max. +25%; P<0.05), and in ejection fraction (+20%; P<0.05) as well as by a reduction in left ventricular enddiastolic pressure (-49%, P<0.05), left ventricular enddiastolic diameter (-20%, P<0.05), and collagen mRNA expression (-15%, P<0.05) compared to controls. A chronically activated transgenic kallikrein kinin system with expression of human kallikrein-1 gene counteracts the progression of left ventricular contractile dysfunction after experimental myocardial infarction. Further studies have to show whether these results can be caused by other therapeutically options. Long acting bradykinin receptor agonists might be an alternative option to improve ischemic heart disease.
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PMID:Cardiac function and remodeling is attenuated in transgenic rats expressing the human kallikrein-1 gene after myocardial infarction. 1702 64

The aim is to show the effectiveness of inhibitors of the kallikrein-kinin system (KKS) to avoid early microcirculation impairment and low reperfusion damages in the ischemic area during systemic thrombolysis (T) in order to achieve optimal results of thrombolytic therapy (TLT) in patients with acute myocardium infarction. Patients (n=104) with acute myocardium infarction were divided into 4 groups: treatment with early TLT infusing Contrycal (Aprotinin) and Heparin (CH) during the first 2 hrs from the onset of disease (Gr. 1); treatment for isolated T at an early stage (Gr. 2); TLT with late T (in 3-6 hrs) (Gr. 3); and conventional therapy (Gr. 4). The dynamics of clinical and ECG data were evaluated for each of the groups. Before the clinical study was fully evaluated, an experimental-morphological, controlled study was carried out on dogs. These results showed improved retrograde blood flow of the acute ischemized myocardium and decrease in ischemia level, together with reduction of frequency and area of reperfused intramiocardial haemorrhages (RPIMH) in infarction areas under the TLT and CH infusion. When CH was infused a significant advantage was revealed in early T that showed high antianginal and antiarrhythmic effect, while no Q wave was observed or it was deepened non-significantly. More clinical dynamic problems with extrasystols and significant deepening of Q wave were seen in the earlier isolated T (Gr. 2) that were worse than those seen in Gr. 1 conditions, but the problems were more negative in the patients from Gr. 3 and 4. CH optimizes the situation causing suppression of the pathological activation of KKS, decreasing vessel permeability, and reducing reperfusion damage. The latest thrombolytic drugs ensure faster thromb lysing but do not prevent the reperfusion damage, as higher fibrinolytic activity at the moment of T causes enhanced activation of KKS and RPIMH development and prevents peroxide oxidation of the lipids but this may result in higher affectivity of antioxidant use. Earlier administration of KKS inhibitors optimizes the affectivity of TLT and widens the indication to the systemic and intracoronary T, minimizes complications, and may cause higher affectivity of coronary angioplasty (CAP) and aorta-coronary shunting in patients with acute myocardium infarction.
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PMID:Inhibitors of the kinin system as an alternative method of prevention or reduction reperfusive damages within thrombolytic therapy in patients with acute myocardium infarction. 1717 90

Acute renal failure (ARF) is a clinical syndrome characterized by deterioration of renal function over a period of hours or days. The principal causes of ARF are ischemic and toxic insults that can induce tissue hypoxia. Transcriptional responses to hypoxia can be inflammatory or adaptive with the participation of the hypoxia-inducible factor 1alpha and the expression of specific genes related to oxidative stress. The production of peroxynitrites and protein nitrotyrosylation are sequelae of oxidative stress. In several clinical and experimental conditions, inflammatory responses have been related to cyclooxygenase (COX)-2, suggesting that its activation might play an important role in the pathogenesis and progression of nephropathies such as ARF. In the kidney, renin and bradykinin participate on the regulation of COX-2 synthesis. With the hypothesis that in ARF there is an increase in the expression of agents involved in adaptive and inflammatory responses, the distribution pattern and abundance of COX-2, its regulators renin, kallikrein, bradykinin B2 receptor, and oxidative stress elements, heme oxygenase-1 (HO-1), erythropoietin (EPO), inducible nitric oxide synthase (iNOS), and nitrotyrosylated residues were studied by immunohistochemistry and immunoblot analysis in rat kidneys after bilateral ischemia. In kidneys with ARF, important initial damage was demonstrated by periodic acid-Schiff staining and by the induction of the damage markers alpha-smooth muscle actin and ED-1. Coincident with the major damage, an increase in the abundance of EPO, HO-1, and iNOS and an increase in renin and bradykinin B2 receptor were observed. Despite the B2 receptor induction, we observed an important decrease in COX-2 in the ischemic-reperfused kidney. These results suggest that COX-2 does not participate in inflammatory responses induced by hypoxia.
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PMID:Effect of ischemic acute renal damage on the expression of COX-2 and oxidative stress-related elements in rat kidney. 1724 95

To explore the role of the kallikrein-kinin system in relation to ischemia/reperfusion injury in the kidney, we generated mice lacking both the bradykinin B1 and B2 receptor genes (B1RB2R-null, Bdkrb1-/-/Bdkrb2-/-) by deleting the genomic region encoding the two receptors. In 4-month-old mice, blood pressures were not significantly different among B1RB2R-null, B2R-null (Bdkrb2-/-), and WT mice. After 30 min of bilateral renal artery occlusion and 24 h of reperfusion, mortality rates, renal histological and functional changes, 8-hydroxy-2'-deoxyguanosine levels in total DNA, mtDNA deletions, and the number of TUNEL-positive cells in the kidneys increased progressively in the following order (from lowest to highest): WT, B2R-null, and B1RB2R-null mice. Increases in mRNA levels of TGF-beta1, connective tissue growth factor, and endothelin-1 after ischemia/reperfusion injury were also exaggerated in the same order (from lowest to highest): WT, B2R-null, and B1RB2R-null. Thus, both the B1 and B2 bradykinin receptors play an important role in reducing DNA damage, apoptosis, morphological and functional kidney changes, and mortality during renal ischemia/reperfusion injury.
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PMID:Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury. 1745 47

We assessed the role of nitric oxide (NO) and the kinin B2 receptor in mediating tissue kallikrein's actions in intramyocardial inflammation and cardiac remodeling after ischemia/reperfusion (I/R) injury. Adenovirus carrying the human tissue kallikrein gene was delivered locally into rat hearts 4 days prior to 30-minute ischemia followed by 24-hour or 7-day reperfusion with or without administration of icatibant, a kinin B2 receptor antagonist, or N(omega)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. Kallikrein gene delivery improved cardiac contractility and diastolic function, reduced infarct size at 1 day after I/R without affecting mean arterial pressure. Kallikrein treatment reduced macrophage/monocyte and neutrophil accumulation in the infarcted myocardium in association with reduced intercellular adhesion molecule-1 levels. Kallikrein increased cardiac endothelial nitric oxide synthase phosphorylation and NO levels and decreased superoxide formation, TGF-beta1 levels and Smad2 phosphorylation. Furthermore, kallikrein reduced I/R-induced JNK, p38MAPK, IkappaB-alpha phosphorylation and nuclear NF-kappaB activation. In addition, kallikrein improved cardiac performance, reduced infarct size and prevented ventricular wall thinning at 7 days after I/R. The effects of kallikrein on cardiac function, inflammation and signaling mediators were all blocked by icatibant and L-NAME. These results indicate that tissue kallikrein through kinin B2 receptor and NO formation improves cardiac function, prevents inflammation and limits left ventricular remodeling after myocardial I/R by suppression of oxidative stress, TGF-beta1/Smad2 and JNK/p38MAPK signaling pathways and NF-kappaB activation.
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PMID:Nitric oxide mediates cardiac protection of tissue kallikrein by reducing inflammation and ventricular remodeling after myocardial ischemia/reperfusion. 1806 96


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