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)

1. Bradykinin (BK) appears to play an important role in the development and maintenance of inflammation. Here, we assessed the role of the BK B(2) receptor for the injuries that occur after ischemia and reperfusion (I/R) of the territory irrigated by the superior mesenteric artery. 2. Tissue (lung and duodenum) kallikrein activity increased after ischemia with greater enhancement after reperfusion. A selective inhibitor of tissue kallikrein, Phenylacetyl-Phe-Ser-Arg-N-(2,3-dinitrophenyl)-ethylenediamine (TKI, 0.001-10 mg ml(-1)), inhibited kallikrein activity in a concentration-dependent manner in vitro. In vivo, pretreatment with TKI (30 mg kg(-1)) prevented the extravasation of plasma and the recruitment of neutrophils. 3. Similarly, the bradykinin B(2) receptor antagonists, HOE 140 (0.01-1.0 mg kg(-1)) or FR173657 (10.0 mg kg(-1)), inhibited reperfusion-induced increases in vascular permeability and the recruitment of neutrophils in the intestine and lungs. 4. In a model of more severe I/R injury, HOE 140 (1.0 mg kg(-1)) inhibited the increase in vascular permeability, neutrophil recruitment, haemorrhage and tissue pathology. Furthermore, HOE 140 significantly inhibited the elevations of TNF-alpha in tissue and serum and partially prevented lethality. This was associated with an increase in the concentrations of IL-10 in tissue and serum. 5. Thus, our results demonstrate that, following intestinal I/R injury, there is an increase in tissue kallikrein activity and activation of BK B(2) receptors. B(2) receptor activation is essential for the development of inflammatory tissue injury and lethality. These results contrast with those of others showing that BK mostly exerts a protective role during I/R injury.
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PMID:Role of the bradykinin B2 receptor for the local and systemic inflammatory response that follows severe reperfusion injury. 1274 31

Arterial Hypertension (AH) is characterized by reduced nitric oxide (NO) biosynthesis, activation of the Renin-Angiotensin-Aldosteron-System (RAAS), vasoconstriction, and microvascular rarefaction. The latter contributes to target organ damage, especially in left ventricular hypertrophy, and may partially be due to impaired angiogenesis. Angiogenesis, the formation of new microvessels and microvascular networks from existing ones, is a highly regulated process that arises in response to hypoxia and other stimuli and that relieves tissue ischemia. In AH, angiogenesis seems impaired. However, blood pressure alone does not affect angiogenesis, and microvascular rarefaction is present in normotensive persons with a family history for AH. Normal or increased NO in several processes and diseases enables or enhances angiogenesis (e.g. in portal hypertension) and reduced NO biosynthesis (for example, in a rat model of AH, in other disease models in vivo, and in endothelial NO Synthase knock out mice) impairs angiogenesis. Angiogenic growth factors such as Vascular Endothelial Growth Factor (VEGF) and Fibroblast Growth Factor (FGF) induce NO and require NO to elicit an effect. Effector molecules and corresponding receptors of the RAAS either induce (Bradykinin, Angiotensin II) or perhaps inhibit angiogenesis. The pattern of Bradykinin- and Angiotensin II-receptor expression and the capacity to normalize NO biosynthesis may determine whether ACE-inhibitors, Angiotensin II-receptor antagonists and other substances affect angiogenesis. Reconstitution of a normally vascularized tissue by reversal of impaired angiogenesis with drugs such as ACE inhibitors and AT1 receptor antagonists may contribute to successful treatment of hypertension-associated target organ damage, e.g. left ventricular hypertrophy.
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PMID:Hypertension and angiogenesis. 1287 Dec 5

1. Bradykinin promotes neuronal damage and brain edema through the activation of the B(2) receptor. The neuroprotective effect of LF 16-0687 Ms, a B(2) receptor antagonist, has been described when given prior to induction of transient focal cerebral ischemia in rat, but there are no data regarding the consequence of a treatment when given after injury. Therefore, in a murine model of transient middle cerebral artery occlusion (MCAO), we evaluated the effect of LF 16-0687 Ms given prior to and/or after the onset of ischemia on neurological deficit, infarct volume and inflammatory responses including cerebral edema, blood-brain barrier (BBB) disruption and neutrophil accumulation. 2. LF 16-0687 Ms (1, 2 and 4 mg kg(-1)) administered 0.5 h before and, 1.25 and 6 h after MCAO, decreased the infarct volume by a maximum of 33% and significantly improved the neurological recovery. 3. When given at 0.25 and 6.25 h after MCAO, LF 16-0687 Ms (1.5, 3 and 6 mg kg(-1)) decreased the infarct volume by a maximum of 25% and improved the neurological score. 4. Post-treatment with LF 16-0687 Ms (1.5 mg kg(-1)) significantly decreased brain edema (-28%), BBB disruption (-60%) and neutrophil accumulation (-65%) induced by ischemia. Physiological parameters were not modified by LF 16-0687 Ms. 5. These data emphasize the role of bradykinin B(2) receptor in the development of infarct lesion, neurological deficit and inflammatory responses resulting from transient focal cerebral ischemia. Therefore, B(2) receptor antagonist might represent a new therapeutic approach in the pharmacological treatment of stroke.
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PMID:LF 16-0687 Ms, a bradykinin B2 receptor antagonist, reduces ischemic brain injury in a murine model of transient focal cerebral ischemia. 1292 42

Bradykinin is a potent vasoactive peptide that is known to elicit a number of biological responses. A number of peptidases have been identified to possess kininase activity, the inhibition of which increases the availability and effectiveness of kinins. We wished to determine the cardioprotective actions of an aminopeptidase P inhibitor, apstatin alone and in combination with enalapril/lisinopril/ramipril in an in vivo rat model of acute ischemia (30 min) and reperfusion (4 h). Myocardial infarction was produced by occlusion of the left anterior descending coronary artery for 30 min followed by 4 h of reperfusion. Infarct size was measured by using the staining agent 2,3,5-triphenyl tetrazolium chloride (TTC). Lipid peroxide levels in serum and in heart tissue were estimated spectrophotometrically. A lead II electrocardiogram was monitored at various intervals throughout the experiment. Infarct size was reduced to a greater extent with apstatin and with combined inhibition it was further reduced. Infarct size reduction obtained with the combined inhibition came to normal with the prior administration of B2 bradykinin antagonist HOE140 suggests the involvement of bradykinin in the cardioprotective actions of apstatin.
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PMID:Infarct size limiting effect of apstatin alone and in combination with enalapril, lisinopril and ramipril in rats with experimental myocardial infarction. 1452 19

Bradykinin is a potent endothelium-dependent vasodilator in the coronary vascular bed. Endothelial mediators released by bradykinin include nitric oxide, prostacyclin and as yet unidentified endothelium-derived hyperpolarising factors. We wished to determine the involvement of nitric oxide and prostaglandin pathways in the cardioprotective actions mediated by bradykinin via the combined inhibition of ACE and aminopeptidase P (APP) in an in vivo rat model of acute ischemia (30 min) and reperfusion (4h). Myocardial infarct size was measured by using the staining agent 2,3,5-triphenyl tetrazolium chloride (TTC). Lipid peroxide levels in serum and in heart tissue were estimated spectrophotometrically. A lead II electrocardiogram was monitored at various intervals throughout the experiment. Infarct size reduction obtained with the combined inhibition of enalapril and apstatin, lisinopril and apstatin was blocked partially but significantly with the prior administration of L-NAME (Nomega-nitro-L-arginine methyl ester) or aspirin, suggesting the involvement of both nitric oxide and prostaglandin pathways in the cardioprotective actions mediated by bradykinin.
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PMID:Involvement of nitric oxide and prostaglandin pathways in the cardioprotective actions of bradykinin in rats with experimental myocardial infarction. 1459 48

Bradykinin is an important endogenous trigger of myocardial ischemic preconditioning (IPC). Through simultaneous inhibition of neutral endopeptidase and angiotensin converting enzyme, omapatrilat prevents enzymatic degradation of bradykinin. The aim of this study was to investigate if omapatrilat, through its ability to augment bradykinin levels, can augment a subthreshold IPC stimulus (Sub-IPC) and to compare the action of omapatrilat with the angiotensin-converting enzyme inhibitor, captopril. Langendorff perfused rat hearts were subjected to 35 min left coronary artery occlusion and 120 min reperfusion. Full IPC was induced with 5 min global ischemia/10 min reperfusion and substantially limited infarct size (21.5 +/- 3.5% of risk zone vs 53.4 +/- 2.0% in controls, P < 0.01). Sub-IPC (2 min global ischemia/10 min reperfusion) did not limit infarct size (48.4 +/- 3.8%). Omapatrilat (10 micromol/L) or captopril (200 micromol/L) were administered alone or in conjunction with Sub-IPC. Reduced infarct size comparable to that observed with the full IPC protocol was seen when sub-IPC was combined with either omapatrilat (19.7 +/- 2.5%) or captopril (20.3 +/- 4.9%). Omapatrilat alone caused modest reduction of infarct size (34.6 +/- 1.5%, P < 0.01 v control), an effect not observed with captopril. Hoe140, a selective kinin B(2) receptor antagonist, eliminated the cardioprotective effect of omaptrilat alone or in combination with sub-IPC. We conclude that omapatrilat elicits cardioprotection via inhibition of bradykinin degradation and that dual inhibition of angiotensin-converting enzyme and neutral endopeptidase may have beneficial effects beyond standard angiotensin-converting enzyme inhibitor therapy in patients with acute coronary syndromes who are at risk of myocardial infarction.
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PMID:Omapatrilat limits infarct size and lowers the threshold for induction of myocardial preconditioning through a bradykinin receptor-mediated mechanism. 1516 74

In the rabbit heart, bradykinin and ACh trigger preconditioning by a mechanism involving ATP-sensitive potassium channel-dependent production of reactive oxygen species (ROS). Recent evidence indicates that the pathway by which bradykinin causes ROS generation includes nitric oxide synthase (NOS) and protein kinase G (PKG). On the other hand, Akt was shown to be essential for ACh to generate ROS. This study determines whether these two G-coupled receptor agonists indeed have similar signaling targets, i.e., whether Akt is involved in bradykinin's pathway and whether NOS is involved in ACh's pathway. Isolated adult rabbit cardiomyocytes were incubated for 15 min in reduced MitoTracker red, which becomes fluorescent only after exposure to ROS. Bradykinin (400 nM) and ACh (250 microM) caused a 51.4 +/- 14.8% and 39.8 +/- 11.7% increase, respectively, in ROS production (P <0.005). Coincubation of either agonist with Akt inhibitor (20 microM) or infection of cells with an adenovirus containing dominant negative Akt abolished this increase. The NO donor S-nitroso-N-acetyl penicillamine (SNAP, 1 microM) also increased the ROS signal by 40.8 +/- 15.7%, but this increase was unaffected by Akt inhibitor (39.0 +/- 6.4%), implying that Akt is upstream of NOS. ACh-induced ROS production could be abolished by either of the NOS inhibitors Nomega-monomethyl-L-arginine monoacetate (100 microM) and L-N5-(1-iminoethyl)ornithine hydrochloride (L-NIO, 5 microM). L-NIO also blocked the anti-infarct effect of ACh (550 microM) in isolated rabbit hearts exposed to 30 min of regional ischemia. We conclude that both bradykinin and ACh trigger ROS generation by sequentially activating Akt and NOS.
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PMID:Acetylcholine and bradykinin trigger preconditioning in the heart through a pathway that includes Akt and NOS. 1533 66

Bradykinin mediates acute inflammation by increasing microvascular permeability, vasodilation, leukocyte migration and accumulation, and the production of arachidonic acid via phospholipase A2 activation. Arachidonic acid metabolites, or eicosanoids, are potent modulators of biological functions, particularly inflammation. Bradykinin exerts its inflammatory effects via the bradykinin B2 receptor. The aim of this study was to evaluate the effect of a bradykinin B2 receptor antagonist, FR173657 (FR), on intestinal ischemia-reperfusion (I/R) injury. Twenty-eight mongrel dogs were divided into four groups (n = 7 per group). Group I underwent I/R alone, Group II underwent I/R and received FR treatment, Group III was sham operated, and Group IV was sham operated and received FR treatment. The FR treatment consisted of FR continuously from 30 min prior to ischemia to 2 hr after reperfusion. In the I/R procedure, the superior mesenteric artery (SMA) and vein were clamped for 2 hr and then released to permit reperfusion for 12 hr. The intramucosal pH (pHi), SMA blood flow, and mucosal tissue blood flow were measured during the reperfusion period. The serum thromboxane B2 and 6-keto-prostaglandin F1alpha levels were determined, and tissue samples were examined histologically. Results showed that tissue blood flow, pHi, and SMA blood flow after reperfusion were maintained in Group II in comparison with Group I. Histopathological examination showed less severe mucosal damage after reperfusion in Group II than in Group I. The serum thromboxane B2 and 6-keto-prostagland in F1alpha levels were significantly lower in Group II than in Group I (P < 0.05). We conclude that FR treatment appears to have clear protective effects on small bowel I/R injury by inhibiting the release of eicosanoids.
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PMID:Bradykinin B2 receptor antagonist FR173657 ameliorates small bowel ischemia-reperfusion injury in dogs. 1571 33

We recently reported that Na+/H+ exchanger isoform 1 (NHE1) activity in astrocytes is stimulated and leads to intracellular Na+ loading after oxygen and glucose deprivation (OGD). However, the underlying mechanisms for this stimulation of NHE1 activity and its impact on astrocyte function are unknown. In the present study, we investigated the role of the ERK1/2 pathway in NHE1 activation. NHE1 activity was elevated by approximately 75% in NHE1+/+ astrocytes after 2-h OGD and 1-h reoxygenation (REOX). The OGD/REOX-mediated stimulation of NHE1 was partially blocked by 30 microM PD-98059. Increased expression of phosphorylated ERK1/2 was detected in NHE1+/+ astrocytes after OGD/REOX. Moreover, stimulation of NHE1 activity disrupted not only Na+ but also Ca2+ homeostasis via reverse-mode operation of Na+/Ca2+ exchange. OGD/REOX led to a 103% increase in intracellular Ca2+ concentration ([Ca2+]i) in NHE1+/+ astrocytes in the presence of thapsigargin. Inhibition of NHE1 activity with the NHE1 inhibitor HOE-642 decreased OGD/REOX-induced elevation of [Ca2+]i by 73%. To further investigate changes of Ca2+ signaling, bradykinin-mediated Ca2+ release was evaluated. Bradykinin-mediated intracellular Ca2+ transient in NHE1+/+ astrocytes was increased by approximately 84% after OGD/REOX. However, in NHE1-/- astrocytes or NHE1+/+ astrocytes treated with HOE-642, the bradykinin-induced Ca2+ release was increased by only approximately 34%. Inhibition of the reverse mode of Na+/Ca2+ exchange abolished OGD/REOX-mediated Ca2+ rise. Together, our data suggest that ERK1/2 is involved in activation of NHE1 in astrocytes after in vitro ischemia. NHE1-mediated Na+ accumulation subsequently alters Ca2+ homeostasis via Na+/Ca2+ exchange.
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PMID:Stimulation of astrocyte Na+/H+ exchange activity in response to in vitro ischemia depends in part on activation of ERK1/2. 1590

Bradykinin is recognized to play an important role in heart ischemia tolerance, and it is expressed in ischemic brain. We hypothesized that bradykinin might play a role in the regulation of tolerance to ischemic brain when administered prior to the ischemic episode. We investigated the effects of bradykinin preconditioning on ischemic damage using an in vivo model of 2-h ischemia and 24-h reperfusion focal cerebral ischemia in rats. Prior to ischemia, bradykinin was pumped into the brain via external carotid artery at a dose of 10 microg/kg/min for 15 min. A significant reduction of 41.20% in infarct size was noted in rats pretreated by bradykinin 15 min prior to ischemia. Brain edema and permeability of blood-brain barrier were also decreased. Immunohistochemical and Western blot analysis of brains revealed a significant increase in basic fibroblast growth factor protein levels. The study demonstrated that bradykinin preconditioning induces protection against ischemic brain injury, and this protection is likely due to the protection of cerebral vasculature and the promotion of neuronal survival.
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PMID:Bradykinin preconditioning induces protective effects against focal cerebral ischemia in rats. 1618 59


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