Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of peripherally administered angiotensin II (AII) on blood flow to choroid plexuses was examined in pentobarbital-anesthetized rats. The indicator fractionation method with 123I- or 125I-N-isopropyl-p-iodoamphetamine as the marker was employed to measure blood flow. Basal blood flow to choroid plexus of the lateral cerebral ventricle (LVCP) (3.19 +/- 0.23 ml g-1 min-1) was lower than that to choroid plexuses of the third (3VCP) and fourth (4VCP) ventricles (3.90 +/- 0.38 and 3.95 +/- 0.36 ml g-1 min-1, respectively). The effect of AII on choroidal blood flow varied depending on peptide dose and anatomical location of the choroidal tissue. AII infused intravenously at rates of 30 and 50 ng kg-1 min-1 decreased blood flow to both LVCP and 4VCP by 12-20%. Both lower (10 ng kg-1 min-1) and higher (100 and 300 ng kg-1 min-1) AII doses did not alter blood flow to LVCP and 4VCP. Blood flow to the 3VCP was not affected by any dose of the peptide used. In comparison, blood flow to cerebral cortex increased by 33% during intravenous AII infusion at a rate of 300 ng kg-1 min-1. The choroidal blood flow-lowering effect of moderate AII doses was abolished by both AT1 (losartan) and AT2 (PD 123319) receptor subtype antagonists (3 mg kg-1 i.v.). To determine whether the hemodynamic changes observed in choroid plexuses with moderate AII doses influence CSF formation, the ventriculocisternal perfusion was performed in rats (under the experimental conditions described) with Blue Dextran 2000 as the indicator.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cereb Blood Flow Metab 1995 Jan
PMID:The role of angiotensin II in the regulation of blood flow to choroid plexuses and cerebrospinal fluid formation in the rat. 779 32

The effects of the angiotensin II AT2 receptor ligands CGP 42112 and PD 123319, the AT1 antagonist losartan, and the nonselective angiotensin II antagonist Sar1,Ile8-angiotensin II on the upper limit of CBF autoregulation were studied in pentobarbital-anesthetized rats. Blood pressure was increased by intravenous phenylephrine infusion, while CBF was measured continuously from the parietal cortex by laser-Doppler flowmetry. Intravenous infusions of CGP 42112 (0.1 and 1 mg kg-1 min-1) and PD 123319 (0.36 and 1 mg kg-1 min-1) shifted the upper limit of CBF autoregulation toward higher blood pressures without affecting baseline CBF. Sar1,Ile8-angiotensin II (4 micrograms kg-1 min-1) had no effect on baseline CBF or CBF autoregulation but antagonized the effect of CGP 42112 and PD 123319. Losartan (10 mg/kg i.v. bolus) reduced baseline blood pressure and CBF and shifted the autoregulation curve toward higher blood pressures. Sar1,Ile8-angiotensin II blocked the effect of losartan on baseline CBF but not on CBF autoregulation. These results suggest that both CGP 42112 and PD 123319 exert their effects on CBF autoregulation through stimulation of angiotensin II AT2 receptors. The mechanism by which losartan affects CBF remains unclear.
J Cereb Blood Flow Metab 1994 Jan
PMID:Angiotensin II AT2 receptor stimulation extends the upper limit of cerebral blood flow autoregulation: agonist effects of CGP 42112 and PD 123319. 826 56

We investigated the effect of angiotensin AT1 and AT2 receptor blockade on the upper limit of CBF autoregulation in pentobarbital-anesthetized rats. CBF was measured by laser-Doppler flowmetry from the parietal cortex and MABP was increased by intravenous phenylephrine infusion. Neither the AT1 antagonist losartan nor the AT2 ligand PD 123319 nor angiotensin II (ANG II) in the presence of losartan affected baseline CBF. When the blood pressure was increased in the control group, CBF remained fairly constant up to 145 mm Hg and increased steeply after 150 mm Hg. Both PD 123319 (7-10 mg/kg) and losartan (1-10 mg/kg) shifted the upper limit of CBF autoregulation toward higher pressures. Intravenous infusion of PD 123319 was more effective than bolus injection. The losartan effect was dose dependent. Selective stimulation of AT2 receptors with an intravenous ANG II infusion (0.54 micrograms/min) in the presence of losartan did not reverse the effect of losartan on CBF autoregulation, but, on the contrary, appeared to further shift the upper limit of autoregulation toward higher pressures. The results implicate a role for both AT1 and AT2 angiotensin receptors in the regulation of CBF.
J Cereb Blood Flow Metab 1993 Mar
PMID:Nonpeptide angiotensin AT1 and AT2 receptor ligands modulate the upper limit of cerebral blood flow autoregulation in rats. 843 22

Inhibition of angiotensin II AT1 receptors protects against stroke, reducing the cerebral blood flow decrease in the periphery of the ischemic lesion. To clarify the mechanism, spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were pretreated with the AT1 receptor antagonist candesartan (0.3 mg. kg.(-1) d(-1)) for 28 days, a treatment identical to that which protected SHR from brain ischemia, and the authors studied middle cerebral artery (MCA) and common carotid morphology, endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), and protein expression in cerebral microvessels, principal arteries of the Willis polygon, and common carotid artery. The MCA and common carotid artery of SHR exhibited inward eutrophic remodeling, with decreased lumen diameter and increased media thickness when compared with WKY rats. In addition, there was decreased eNOS and increased iNOS protein and mRNA in common carotid artery, circle of Willis, and brain microvessels of SHR when compared with WKY rats. Both remodeling and alterations in eNOS and iNOS expression in SHR were completely reversed by long-term AT1 receptor inhibition. The hemodynamic, morphologic, and biochemical alterations in hypertension associated with increased vulnerability to brain ischemia are fully reversed by AT1 receptor blockade, indicating that AT1 receptor activation is crucial for the maintenance of the pathologic alterations in cerebrovascular circulation during hypertension, and that their blockade may be of therapeutic advantage.
J Cereb Blood Flow Metab 2003 Mar
PMID:Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition. 1262 12

In the present study, we investigate whether a long-term blockade of brain AT1 receptors in male Wistar rats before and after ischemic injury exerts neuroprotective effects and modulates apoptosis and inflammatory responses, which are associated with the post-ischemic progression of brain damage. The AT1 receptor antagonist irbesartan was continuously infused intracerebroventricularly using osmotic minipumps over a 5-day period before and for 3 or 7 days after middle cerebral artery occlusion (MCAO) for 90 minutes. Neurologic status was evaluated daily, starting 24 hours after MCAO. After MCAO (3 and 7 days), brains were removed for the measurement of infarct size and immunohistochemical evaluation of apoptosis and accumulation of reactive microglia and macrophages. Treatment with irbesartan before ischemia improved motor functions, whereas post-ischemic treatment improved sensory functions. Blockade of brain AT1 receptors reduced the infarct size on days 3 and 7 after MCAO. In the peri-infarct cortex, irbesartan treatment decreased the number of apoptotic cells on day 3 and attenuated the invasion of activated microg-lia and macrophages on days 3 and 7 after ischemia. Long-term blockade of brain AT1 receptors improves the recovery from cerebral ischemia. Antiapoptotic mechanisms and inhibition of post-ischemic inflammation are involved in the AT1 receptor blockade-induced neuroprotective effects in ischemic brain tissue.
J Cereb Blood Flow Metab 2004 May
PMID:Sustained blockade of brain AT1 receptors before and after focal cerebral ischemia alleviates neurologic deficits and reduces neuronal injury, apoptosis, and inflammatory responses in the rat. 1512 86

Angiotensin II receptor blockers (ARBs) have a potent ability to inhibit oxidative stress and advanced glycation, in addition to their protective effects originated from blood pressure lowering and angiotensin II type 1 receptor (AT(1))-blockade. To obtain a pharmacological tool to dissect the mechanisms of ARBs' protective benefits in experimental stroke, we synthesized a novel ARB-derivative, R-147176, which is 6,700 times less potent than olmesartan in AT(1)-binding inhibition and therefore has a minimal antihypertensive effect, but retains marked inhibitory effects on oxidative stress and advanced glycation. We evaluated the effect of R-147176 (10-30 mg/kg per day), administered orally or intravenously, on brain infarct volume in transient thread occlusion and photothrombotic models in rats. The antioxidative and antiinflammatory properties were also investigated. R-147176 significantly reduced infarct volume, without influence on blood pressure, in both models. R-147176 significantly reduced the numbers of ED-1-positive cells and of TUNEL-positive cells, and protein carbonyl formation in the damaged brain. This ARB derivative, despite its significantly lower AT1 affinity and virtually no antihypertensive effect, ameliorated ischemic cerebral damage through antioxidative and antiinflammatory properties. These findings suggest potential usefulness of R-147176 as a pharmacological tool to investigate the ARBs' protective effect in experimental stroke and open new therapeutic avenues.
J Cereb Blood Flow Metab 2009 Oct
PMID:A sartan derivative with a very low angiotensin II receptor affinity ameliorates ischemic cerebral damage. 1953 69

Angiotensin II-mediated hypertension (HTN) is accompanied by a pro-inflammatory and pro-thrombotic state in the cerebral microvasculature. Whether comparable phenotypic changes are elicited in other models of HTN remains unclear. Using wild-type mice with deoxycorticosterone acetate (DOCA) salt-induced HTN and intravital microscopy, we observed significant increases in the adhesion of both leukocytes and platelets in cerebral venules, compared with uninephrectomized control mice, without an accompanying increase in blood-brain barrier permeability. The cell-cell interactions in hypertensive mice were more pronounced after ischemic stroke, but no difference in infarct size was detected. The blood cell recruitment was largely prevented in the following groups of DOCA salt mice: losartan (angiotensin II AT1 receptor blocker) treated, AT1 receptor knockout mice, tempol (a membrane-permeable oxygen radical scavenger) treated, and mito-TEMPO (a mitochondria-targeted antioxidant) treated. A similar pattern of protection was noted in mice subjected to ischemic stroke. The blunted cell recruitment responses were not accompanied by reductions in blood pressure (BP). These findings implicate mitochondria-derived oxygen radicals and angiotensin II in the cerebral inflammation associated with DOCA salt HTN and suggests that BP per se is not a critical determinant of the phenotypic changes that accompany HTN, even after ischemic stroke.
J Cereb Blood Flow Metab 2012 Feb
PMID:Cerebral microvascular inflammation in DOCA salt-induced hypertension: role of angiotensin II and mitochondrial superoxide. 2197 54

The capacity to guarantee the proper excitatory/inhibitory balance is one of the most critical steps during early development responsible for the correct brain organization, function, and plasticity. GABAergic neurons guide this process leading to the right structural organization, brain circuitry, and neuronal firing. Here, we identified the ataxia telangiectasia mutated (ATM), a serine/threonine protein kinase linked to DNA damage response, as crucial in regulating neurotransmission. We found that reduced levels of ATM in the hippocampal neuronal cultures produce an excitatory/inhibitory unbalance toward inhibition as indicated by the higher frequency of miniature inhibitory postsynaptic current events and an increased number of GABAergic synapses. In vivo, the increased inhibition still persists and, even if a higher excitation is also present, a reduced neuronal excitability is found as indicated by the lower action potential frequency generated in response to high-current intensity stimuli. Finally, we found an elevated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in heterozygous hippocampi associated with lower expression levels of the ERK1/2 phosphatase PP1. Given that the neurodegenerative condition associated with genetic mutations in the Atm gene, ataxia telangiectasia, presents a variable phenotype with impairment in cognition, our molecular findings provide a logical frame for a more clear comprehension of cognitive defects in the pathology, opening to novel therapeutic strategies.
Cereb Cortex 2016 10
PMID:New Role of ATM in Controlling GABAergic Tone During Development. 2716 72