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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This article summarizes the main mechanisms responsible for the ischemia-induced neovascularization. Growth factors and inflammatory agents are the most powerful actors in the neo-vascularization process. Numerous other factors have been shown to modulate blood vessel growth. Among these, we have tested the potential effect of angiotensin II in several in vivo models of angiogenesis. Angiotensin II has pro-angiogenic effects via its AT1 subtype receptor whereas the AT2 angiotensin II receptor has pro-apoptotic and anti-angiogenic properties. Besides its effect on angiotensin II formation, some angiotensin-converting-enzyme inhibitors have pro-angiogenic effect by increasing the local concentration of bradykinin in ischemic tissues and, thus, by activation of its B2 receptor and then NO release. These besides the "classical" gene and cellular therapies designed for the treatment of pathological tissue ischemia, alternative strategies using new pharmacological properties of drugs acting on the renin angiotensin system are likely to be possible.
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PMID:[The renin-angiotensin system and post-ischemic angiogenesis]. 1558 84

Several lines of clinical and experimental evidence suggest an important role of the renin-angiotensin system in ischemic brain injury although the cellular regulation of the angiotensin AT1 and AT2 receptors and their potential relevance in this condition have not yet been clearly defined. We first assessed the regulation of brain AT1 and AT2 receptors in response to transient unilateral medial cerebral artery occlusion in rats by real-time RT-PCR, Western blot, and immunofluorescence labeling. AT2 receptors in the peri-infarct zone were significantly upregulated 2 days after transient focal cerebral ischemia. Increased AT2 receptors, which were abundantly distributed in a large number of brain regions adjacent to the infarct area including cerebral frontal cortex, piriform cortex, striatum, and hippocampus, were exclusively expressed in neurons. By contrast, AT1 receptors, which remained unaltered, were mainly expressed in astrocytes. In neurons of ischemic striatum, increased AT2 receptors were associated with intense neurite outgrowth. Blockade of central AT2 receptors with PD123177 abolished the neuroprotective effects of central AT1 receptor blockade with irbesartan on infarct size and neurological outcome. In primary cortical neurons, stimulation of AT2 receptors supported neuronal survival and neurite outgrowth. Our data indicate that cerebral AT2 receptors exert neuroprotective actions in response to ischemia-induced neuronal injury, possibly by supporting neuronal survival and neurite outgrowth in peri-ischemic brain areas.
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PMID:Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. 1566 34

The cardiovascular role of angiotensin-(1-7), especially in the functional and metabolic alterations associated with ischemia-reperfusion (IR), is still not clearly defined. Our objective was to evaluate the cardiac effects of angiotensin-(1-7), the receptors involved, and their relationships with NADPH oxidase activation under non-ischemic conditions and, during an ischemia-reperfusion sequence. Isolated perfused rat hearts underwent 45 min of non-ischemic perfusion, or 30 min of global ischemia followed by 30 min of reperfusion. Angiotensin-(1-7) and/or AT1 receptor blocker losartan or angiotensin-(1-7) receptor antagonist (D-Ala7)-angiotensin-(1-7) were perfused. Our results showed that angiotensin-(1-7) was without effect at low concentrations (10(-10) to 10(-7) M). At a pharmacological concentration, 0.5 microM angiotensin-(1-7) induced vasoconstriction, which was antagonised by losartan. After ischemia, we noted a partial recovery of functional parameters, which was not modified by any of the treatments. The expression of AT1 receptor mRNA was increased by ischemia-reperfusion, except in (D-Ala7)-angiotensin-(1-7) treated hearts. Angiotensin-(1-7) further increased the AT1 expression. NADPH oxidase activity was enhanced in 0.5 microM angiotensin-(1-7)-treated hearts subjected to ischemia-reperfusion, this effect was totally reversed by losartan. This is the first time that it has been shown that, in the heart, angiotensin-(1-7) at pharmacological concentration activates NADPH oxidase, an enzyme thought to be involved in several angiotensin II effects.
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PMID:Pharmacological concentration of angiotensin-(1-7) activates NADPH oxidase after ischemia-reperfusion in rat heart through AT1 receptor stimulation. 1568 Apr 76

Though ischaemia/reperfusion injury induces renin-angiotensin systemic (RAS) activation and increased heart angiotensin production, the effects of blockade of the two main angiotensin II receptors, AT1 and AT2, are not definitively established. Using a Langendorff heart preparation, effects of Valsartan 10(-7)M (AT1 receptor blocker), PD 123319 10(-7)M (AT2 receptor blocker) or both in the presence of a controlled concentration of angiotensin II (10(-8)M) in order to reproduce systemic RAS activation were studied in adult male Wistar rat hearts submitted to ischaemia/reperfusion. Ischaemia/reperfusion impaired both systolic and diastolic function through a no-reflow phenomenon. Presence of a controlled concentration of angiotensin in the perfusate, enough to produce a significant AT1-induced vasoconstriction before ischaemia, has no relevant influence on ischaemia/reperfusion injury. Only blockade of both AT1 and AT2 receptors significantly improved recovery from ischaemia; better ventricle function paralleled better perfusion. The results suggest that blockade of angiotensin II receptors is cumulative since blockade of AT1 and AT2 receptors is more effective than blockade of just one of them.
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PMID:Cumulative effects of AT1 and AT2 receptor blockade on ischaemia-reperfusion recovery in rat hearts. 1582 28

1. There are two Angiotensin II systems in the brain. The discovery of brain Angiotensin II receptors located in neurons inside the blood brain barrier confirmed the existence of an endogenous brain Angiotensin II system, responding to Angiotensin II generated in and/or transported into the brain. In addition, Angiotensin II receptors in circumventricular organs and in cerebrovascular endothelial cells respond to circulating Angiotensin II of peripheral origin. Thus, the brain responds to both circulating and tissue Angiotensin II, and the two systems are integrated. 2. The neuroanatomical location of Angiotensin II receptors and the regulation of the receptor number are most important to determine the level of activation of the brain Angiotensin II systems. 3. Classical, well-defined actions of Angiotensin II in the brain include the regulation of hormone formation and release, the control of the central and peripheral sympathoadrenal systems, and the regulation of water and sodium intake. As a consequence of changes in the hormone, sympathetic and electrolyte systems, feed back mechanisms in turn modulate the activity of the brain Angiotensin II systems. It is reasonable to hypothesize that brain Angiotensin II is involved in the regulation of multiple additional functions in the brain, including brain development, neuronal migration, process of sensory information, cognition, regulation of emotional responses, and cerebral blood flow. 4. Many of the classical and of the hypothetical functions of brain Angiotensin II are mediated by stimulation of Angiotensin II AT1 receptors. 5. Brain AT2 receptors are highly expressed during development. In the adult, AT2 receptors are restricted to areas predominantly involved in the process of sensory information. However, the role of AT2 receptors remains to be clarified. 6. Subcutaneous or oral administration of a selective and potent non-peptidic AT1 receptor antagonist with very low affinity for AT2 receptors and good bioavailability blocked AT1 receptors not only outside but also inside the blood brain barrier. The blockade of the complete brain Angiotensin II AT1 system allowed us to further clarify some of the central actions of the peptide and suggested some new potential therapeutic avenues for this class of compounds. 7. Pretreatment with peripherally administered AT1 antagonists completely prevented the hormonal and sympathoadrenal response to isolation stress. A similar pretreatment prevented the development of stress-induced gastric ulcers. These findings strongly suggest that blockade of brain AT1 receptors could be considered as a novel therapeutic approach in the treatment of stress-related disorders. 8. Peripheral administration of AT1 receptor antagonists strongly affected brain circulation and normalized some of the profound alterations in cerebrovascular structure and function characteristic of chronic genetic hypertension. AT1 receptor antagonists were capable of reversing the pathological cerebrovascular remodeling in hypertension and the shift to the right in the cerebral autoregulation, normalizing cerebrovascular compliance. In addition, AT1 receptor antagonists normalized the expression of cerebrovascular nitric oxide synthase isoenzymes and reversed the inflammatory reaction characteristic of cerebral vessels in hypertension. As a consequence of the normalization of cerebrovascular compliance and the prevention of inflammation, there was, in genetically hypertensive rats a decreased vulnerability to brain ischemia. After pretreatment with AT1 antagonists, there was a protection of cerebrovascular flow during experimental stroke, decreased neuronal death, and a substantial reduction in the size of infarct after occlusion of the middle cerebral artery. At least part of the protective effect of AT1 receptor antagonists was related to the inhibition of the Angiotensin II system, and not to the normalization of blood pressure. These results indicate that treatment with AT1 receptor antagonists appears to be a major therapeutic avenue for the prevention of ischemia and inflammatory diseases of the brain. 9. Thus, orally administered AT1 receptor antagonists may be considered as novel therapeutic compounds for the treatment of diseases of the central nervous system when stress, inflammation and ischemia play major roles. 10. Many questions remain. How is brain Angiotensin II formed, metabolized, and distributed? What is the role of brain AT2 receptors? What are the molecular mechanisms involved in the cerebrovascular remodeling and inflammation which are promoted by AT1 receptor stimulation? How does Angiotensin II regulate the stress response at higher brain centers? Does the degree of activity of the brain Angiotensin II system predict vulnerability to stress and brain ischemia? We look forward to further studies in this exiting and expanding field.
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PMID:Brain angiotensin II: new developments, unanswered questions and therapeutic opportunities. 1607 77

Microvascular changes in the brain are significant causes of cerebral edema and ischemia injury. A number of studies suggest that angiotensin (Ang) II may be involved in the initiation and regulation of processes occurring in brain ischemia. We recently reported that Ang II injures brain microvascular endothelial cells (BMEC) partially via stimulating intercellular adhesion molecule-1 (ICAM-1) expression. However, the signaling cascade leading to Ang II-induced ICAM-1 expression in BMEC was unclear. The present study tested the hypothesis that Ang II induces ICAM-1 expression via an AT1 receptor/nuclear factor-kappaB (NF-kappaB) pathway in BMEC. Ang II directly stimulated the expression of ICAM-1 mRNA and protein in primary cultured BMEC. Ang II treatment also resulted in the degradation of IkappaBalpha and increase of NF-kappaB p65 subunit in the nucleus as well as the DNA binding activity of nuclear NF-kappaB. These effects were abolished by pretreatment with the selective AT1 receptor antagonists, losartan and compound EXP-2528, or losartan plus the AT2 receptor antagonist PD123319, but not by PD123319 alone. Moreover, there were no significant differences between the losartan and losartan plus PD123319 groups. These findings indicate that Ang II-induced ICAM-1 upregulation in brain microvascular endothelial cells may be mediated via an AT1 receptor/NF-kappaB pathway.
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PMID:Angiotensin II stimulates intercellular adhesion molecule-1 via an AT1 receptor/nuclear factor-kappaB pathway in brain microvascular endothelial cells. 1634 50

In pregnancy there is an attenuated response to vasoconstrictors and pressor agents, including Angiotensin II (Ang II). This effect is reverted in preeclampsia. We evaluated the renal pressor response induced by Ang II in an experimental model of preeclampsia based on the development of feto-placental ischemia produced by a subrenal aortic coarctation (SRAC). Dose-response curves for Ang II were obtained in an isolated perfused kidney preparation comparing groups of SRAC pregnant and non-pregnant rats in the presence and absence of losartan (AT1 antagonist) or PD123319 (AT2 antagonist). Kidneys from the experimental model of pre-eclampsia showed an enhanced response to AngII. In addition, losartan (10 nM) inhibited the vasopressor effect to Ang II in this model but not in the control group. PD 123319 (1 nM), increased the response in both groups, but the effect was more evident in the pre-eclamptic group. This suggests modifications in the relative participation of renal vascular receptors AT1/AT2 induced by an experimental model of pre-eclampsia, with an increased participation of AT1 and a decreased participation of AT2.
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PMID:Renal vascular responses in an experimental model of preeclampsia. 1641 59

The acute phase of intestinal ischemia-reperfusion (I/R) injury is mediated by leukocytes and is characterized by oxidative stress and blood cell recruitment. Upregulation of angiotensin II type 1 receptors (AT1-R) has been implicated in the pathogenesis of conditions associated with oxidative stress. The AT1-R-antagonist Losartan (Los) attenuates leukocyte recruitment following I/R. However, the role of AT1-R in intestinal I/R injury and the associated platelet-leukocyte interactions remains unclear. The objective of this study was to define the contribution of AT1-R to I/R-induced blood cell recruitment in intestinal venules. Leukocyte and platelet adhesion were quantified by intravital microscopy in the small bowel of C57Bl/6 [wild-type (WT)] mice exposed to sham operation or 45 min of ischemia and 4 h of reperfusion. A separate WT group received Los for 7 days before gut I/R (WT-I/R + Los). AT1-R bone marrow chimeras that express AT1-R on the vessel wall but not blood cells also underwent I/R. Platelet and leukocyte adhesion as well as AT1-R expression in the gut microvasculature were significantly elevated after I/R. All of these responses were attenuated in the WT-I/R + Los group, compared with untreated I/R mice. A comparable abrogation of I/R-induced blood cell adhesion was noted in AT1-R bone marrow chimeras. I/R-induced platelet adhesion was unaltered in mice overexpressing Cu,Zn-SOD or mice deficient in NAD(P)H oxidase. These data suggest that although gut I/R upregulates endothelial expression of AT1-R, engagement of these angiotensin II receptors on blood cells is more important in eliciting the prothrombogenic and proinflammatory state observed in postischemic gut venules, through a superoxide-independent pathway.
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PMID:Angiotensin II type 1 receptors and the intestinal microvascular dysfunction induced by ischemia and reperfusion. 1646 24

Current evidence points to renin-angiotensin system as a key mediator in ischemia-reperfusion injury. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand, has recently been shown to confer cardioprotection against ischemia-reperfusion in animal models. We sought to examine the expression of ANG II receptors during PPAR-gamma-mediated cardioprotection. Male Sprague-Dawley rats (nondiabetic) were fed either regular rat chow (control diet group, n = 9) or rosiglitazone-rich diet (rosiglitazone-rich diet group, n = 9) and were subjected to 1 h of myocardial ischemia followed by 1 h of reperfusion. A third group of rats had only thoracotomy and pericardiotomy and served as a sham control group (n = 9). Hemodynamics, infarct size, and expression of ANG II type 1 and type 2 receptors (AT1 and AT2) were measured in all groups. There was a 58% reduction of infarct size in the rosiglitazone-rich diet group (P < 0.01 vs. control diet group). Increased myocardial expression of AT(1) receptors in the ischemic-reperfused myocardium was attenuated in the rosiglitazone-rich diet group (P < 0.05 vs. control diet group). Importantly, myocardial AT2 mRNA and protein expression were significantly increased (by >100-fold) in the rosiglitazone-rich diet group (P < 0.05). These changes were accompanied by inhibition of p42/44 MAPK in the rosiglitazone-rich diet group, while the Akt1 expression, believed to mediate insulin sensitization, remained similar in all three groups. The cardioprotective effects of rosiglitazone against myocardial ischemia-reperfusion injury are independent of its insulin-sensitizing properties and are associated with significant overexpression of AT2 receptors along with inhibition of p42/44 MAPK.
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PMID:Cardioprotective effects of rosiglitazone are associated with selective overexpression of type 2 angiotensin receptors and inhibition of p42/44 MAPK. 1658 19

Pre-eclampsia or pregnancy induced hypertension (PIH) affects 6-8% of all pregnancies. Although the underlying mechanism of PIH is still unknown, it is widely believed that the placenta plays an important role. It was thought that an ischemic placenta due to poor perfusion can precipitate the signs and symptoms of PIH. This study aims to investigate the possible role of Type 1(AT1) and Type 2 (AT2) angiotensin II receptor subtypes in the mechanism of PIH. AT1 receptor stimulation causes vasoconstriction and AT2 receptor stimulation causes vasodilatation. Investigating the interactions of these two receptors in the placenta provides an insight as to the balance that may exist between AT1 and AT2 receptors in normal pregnancy. Any disruption to the balance might cause a disruption of the blood flow in the placenta, leading to PIH. Placentas were collected from 11 PIH patients and 11 normal patients. Immunohistochemistry techniques were performed on the placental tissue to determine the distribution of AT1 and AT2 receptors in the placental tissue qualitatively and quantitatively. It was observed that in normal patients, the balance between AT1 and AT2 receptors is that the level of AT2 receptors is higher than the level of AT1 receptors. However in the PIH patient, it was observed that the normal balance was disrupted. In PIH patients the level of AT1 receptors was observed to be higher than the level of AT2 receptors. This study suggests that disruption of the balance between AT1 and AT2 receptors observed in PIH placentas might cause a decrease in blood flow to the placenta, causing it to be poorly perfused. This may cause placental ischemia which may lead to PIH.
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PMID:A preliminary finding: immunohistochemical localisation and distribution of placental angiotensin II receptor subtypes in normal and preeclamptic pregnancies. 1689 8


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