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)

Cell lines established from donors with the inherited disorder ataxia-telangiectasia (A-T) exhibit exceptional sensitivity to ionizing radiation and chemicals known to produce increased levels of intracellular H2O2, suggesting a deficiency in glutathione-dependent detoxication reactions. Glutathione (GSH) biosynthesis in fibroblast and lymphoblast cultures derived from individuals known to be clinically unaffected, homozygous, or heterozygous for A-T was assessed. Following GSH depletion by diethylmaleate, fibroblasts (GM 3492) from a clinically unaffected individual resynthesized GSH at a rate approximately twice that observed in fibroblasts from known heterozygotes (GM 3488 and GM 3489). Unrelated A-T homozygote fibroblast lines GM 3487B and GM 5823 resynthesized GSH only very slowly. GM 3492 cells repleted intracellular GSH by 6 h after depletion, the heterozygote lines by 18 h. The A-T homozygotes replaced only 30% of the intracellular GSH pool by 24 h. A lymphoblast cell line from the A-T homozygote (GM 3189) also exhibited slow resynthesis after depletion. However, if these cells were permeabilized by treatment with digitonin, GSH synthesis proceeded at a rate exceeding synthesis in permeabilized or untreated normal lymphoblasts (GM 3323). The first enzyme in GSH synthesis, gamma-glutamylcysteine synthetase, was found to be elevated about 2.7-fold in A-T homozygote fibroblasts, suggesting that a substrate for GSH synthesis may be rate limiting. A-T homozygote lymphoblasts contained about 2-fold more gamma-cystathionase activity over other cell lines tested suggesting increased flux through the transsulfuration pathway for cysteine production in response to reduced cysteine supply. Transport of cysteine and cystine was found to be 8- and 5-fold slower in A-T homozygotes that did not affect fibroblasts while glutamate and methionine transport Vmax did not differ among the cell lines tested. These experiments demonstrate that cells from A-T homozygotes are deficient in cysteine transport, thus limiting GSH resynthesis after a depleting challenge such as radiation or GSH-depleting xenobiotic compounds.
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PMID:Imparied glutathione biosynthesis in cultured human ataxia-telangiectasia cells. 362 Nov 55

Superficial layer superior colliculus (SC) neurons were recorded extracellularly with multibarreled recording/ejecting micropipettes. Angiotensin II was delivered via micropressure ejection during visual stimulation (n = 215 cells), or during electrical stimulation of either the optic chiasm (OX; n = 150 cells) or visual cortex (CTX; n = 42 cells). Application of angiotensin II decreased visual responses of SC cells to 43.8% +/- 30.7% (mean +/- S.D.) and reduced responses to electrical stimulation of the OX and CTX to 58.6% +/- 34.1% and 43.8% +/- 30.7% of control values, respectively. Angiotensin II enhanced responses by at least 30% in only 6 cells (1.5%). Of the 35 neurons tested with both OX and CTX stimulation, the correlation of evoked response suppression by angiotensin II was highly significant (r = 0.69; P < 0.001). This suggests that the suppressive effects of angiotensin II were common to both pathways. To test whether the inhibitory effects of angiotensin II were presynaptic or postsynaptic, Mg2+ ions were ejected iontophoretically to abolish synaptic responses, and the neurons were activated by iontophoresis of glutamate and then tested with angiotensin II. Angiotensin II reduced the glutamate-evoked responses to an average 29.1% +/- 21.1% of control values (n = 9 cells). This suggest that the site of action of angiotensin II is most likely postsynaptic. To identify which receptors were involved in these effects, angiotensin II was ejected concurrently with the AT1 antagonist Losartan (DUP753) or with either of two AT2 antagonists, CGP42112A or PD123177. Losartan antagonized the action of angiotensin II in 65.6% of the cells tested (n = 99) and CGP42112A and PD123177 had antagonistic effects in 58% (n = 65) and 60% (n = 5), respectively. Both classes of antagonists were tested in 29 cells; and there was no significant correlation between their effectiveness. These results suggest that both AT1 and AT2 receptors may independently mediate the suppressive effects of angiotensin II, and that collicular neurons may have either or both receptor subtypes.
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PMID:Effects of angiotensin II on visual neurons in the superficial laminae of the hamster's superior colliculus. 784 Nov 24

We investigated the effect of losartan, a nonpeptide angiotensin II (Ang II)-type 1 (AT1) receptor antagonist, on the responses evoked by Ang II and L-glutamate (L-Glu) in the rostral ventrolateral medulla (RVLM). Adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were anesthetized with halothane and artificially ventilated. Responses of mean arterial pressure (MAP), heart rate (HR) and splanchnic sympathetic nerve activity (SNA) to microinjection of Ang II (100 pmol) or L-Glu (2 nmol) into the RVLM were examined following microinjection of losartan (10 pmol-10 nmol). Ang II increased MAP (16 +/- 1 mmHg in SHR and 16 +/- 1 mmHg in WKY) and SNA (9 +/- 1% and 10 +/- 1%, respectively), which were significantly (P < 0.01) attenuated by pretreatment with losartan (100 pmol-10 nmol) in both strains. In addition, the pressor and sympathoexcitatory responses evoked by L-Glu were attenuated by losartan in a dose-dependent manner. The increases of MAP evoked by L-Glu (53 +/- 6 mmHg in SHR and 39 +/- 3 mmHg in WKY) were suppressed to 5 +/- 3 mmHg (P < 0.01) and 4 +/- 2 mmHg (P < 0.01), respectively, in the presence of 10 nmol of losartan. The increase of SNA was also markedly inhibited by higher doses of losartan.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Losartan, nonpeptide angiotensin II-type 1 (AT1) receptor antagonist, attenuates pressor and sympathoexcitatory responses evoked by angiotensin II and L-glutamate in rostral ventrolateral medulla. 789 60

The selective angiotensin (ANG) II antagonists losartan (AT1) and CGP-42112A (AT2) were used to determine the receptor subtype and neuronal pathways that mediate the hypotension and bradycardia produced by 200 fmol of ANG II microinjected into the dorsal medial nucleus tractus solitarii (NTS) or dorsal motor nucleus of the vagus (dmnX) in anesthetized rats. At dorsal medial NTS sites (0.3 mm below the surface) where L-glutamate microinjections produced maximal decreases in mean arterial pressure (MAP) and heart rate (HR), ANG II (200 fmol, 50 nl, n = 16) elicited hypotension (-22 +/- 1 mmHg) and bradycardia (-26 +/- 2 beats/min). Although L-glutamate also suppressed respiration, ANG II injections in the medial NTS did not alter respiration. Losartan injected at the medial NTS site caused a dose-dependent reduction of ANG II-induced decreases in MAP and HR. At 2 pmol, the AT1 antagonist attenuated the response to ANG II, whereas 100 pmol abolished the effects of ANG II microinjections. In contrast, the AT2 antagonist CGP-42112A (100 pmol) had no effect on the responses to ANG II. Neither ANG II antagonist altered the cardiovascular effects of L-glutamate injections. Losartan injected into the dmnX blocked hypotension and bradycardia produced by ANG II at that site but did not prevent responses to subsequent ANG II injections in the medial NTS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of angiotensin-induced hypotension and bradycardia in the medial solitary tract nucleus. 791 65

1. In cats anaesthetized with a mixture of alpha-chloralose (40 mg/kg) and urethane (400 mg/kg) and in rats anaesthetized with a mixture of alpha-chloralose (60 mg/kg) and urethane (800 mg/kg), changes in systemic arterial pressure (SAP), heart rate (HR) and sympathetic activities of vertebral (VNA) and renal (RNA) nerves were determined following the microinjection of angiotensin II (AngII; 0.16 mmol/L; 50 nL) into the pressor and depressor sites of the pontomedulla previously reacted to a microinjection of monosodium L-glutamate (Glu; 0.1 mol/L; 50 nL). Pressor sites included gigantocellular tegmental field (FTG) and dorsal medulla (DM) and rostral ventrolateral medulla (VLM). The depressor site was the caudal VLM (CVLM). The effects of losartan (1 mmol/L; 50 nL), a specific AT1 receptor non-peptide antagonist for AngII, on responses induced by AngII in the VLM, DM and CVLM were also determined. 2. In 30% of pressor sites in the FTG, 55% in the VLM and 67% in the DM and in 76% of depressor sites in the CVLM previously exposed to Glu, microinjection of AngII to the same site produced pressor or depressor responses similar to that of Glu, but smaller in magnitude, particularly in the pressor VLM. Changes in both VNA and RNA induced by AngII were also smaller than those induced by Glu, particularly RNA from DM activation. 3. In the dorsal motor nucleus of the vagus, AngII, as Glu, produced marked bradycardia, but again this was smaller in magnitude than the bradycardia produced by Glu. 4. In rats, in the DM near or around the nucleus of the solitary tract where Glu increased SAP, microinjection of AngII (0.8 mmol/L; 60 nL) produced a depressor response, while the microinjection of 1.6 mmol/L (60 nL) AngII produced a pressor response. 5. Losartan blocked the increase in SAP induced by AngII in the VLM and DM. Decreases in SAP induced by AngII in the CVLM, however, were only slightly decreased by losartan. 6. Our data suggest that a significant portion of pressor and depressor sites of the pontomedulla contain neurons responsive to both AngII and Glu. In neurons in the VLM and DM, AngII produced pressor responses that were primarily mediated through AT1 receptors, while the depressor actions of AngII in the CVLM were not mediated by AT1 receptors.
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PMID:Angiotensin II activates pressor and depressor sites of the pontomedulla that react to glutamate. 871 81

Evidence continues to accumulate that strengthens the proposal of heterogeneity within both the AT1 and the AT2 receptor subtypes. Pharmacologic, biochemical and immunological studies of AT2 receptors expressed in N1E-115 cells strengthen the hypothesis of AT2 receptor heterogeneity. However, it is important to reassess these studies, especially in terms of how these results correlate with other reports of AT2 receptor heterogeneity. For example, AT2 receptor immunoreactivity was absent in some neuronal regions which have previously been proposed to express the AT2 receptor subtype. In particular, AT2 receptor staining was not seen in the inferior olive, a region which is known to express a high density of AT2 receptors. Upon first examination, these results were somewhat troubling. However, when compared with earlier reports, these results should not have been unexpected. For instance, Tsutsumi and Saaverdra previously have shown that AT2 receptors in the locus coeruleus are sensitive to the actions of guanine nucleotides, while AT2 receptors in the inferior olive are insensitive (21). These antisera were raised against a population of AT2 receptors which are sensitive to GTP gamma S and therefore, the lack of AT2 receptor staining in the inferior olive, as well as the presence of AT2 receptor immunoreactivity in the locus coeruleus, confirms and extends these earlier reports. In addition the AT2 receptors expressed in the locus coeruleus have been shown to be functionally distinct from AT2 receptors in the inferior olive. In this regard, Ang II has been shown to depress glutamate-induced EPSPs in the locus coeruleus, an effect which is mediated through the AT2 receptor (19). Conversely, AT2 receptors have been shown to increase the firing rate of neurons in the inferior olive (20). Collectively, these results would predict that staining should be absent in the inferior olive using these AT2-directed antisera. Indeed, in view of these earlier physiological and pharmacological studies, the presence of AT2 receptor immunoreactivity in the inferior olive would have been surprising. The most convincing example of AT2 receptor heterogeneity is the characterization of AT2 receptors present in N1E-115 cells. Separation of solubilized N1E-115 membranes by heparin-Sepharose chromatography generates two populations of AT2 receptors which are pharmacologically and biochemically distinct. In particular, CGP42112A was approximately 2 orders of magnitude more selective for Peak III AT2 receptors than was PD123319. Binding activity of Peak I and Peak III AT2 receptor populations also differed in their responses to GTP gamma S and DTT treatment. Lastly, the AT2-directed antisera, raised against the Peak I population of AT2 receptors, were not able to immunodetect the Peak III population of AT2 receptors in immunoblot analysis, or immunoprecipiatate AT2 binding activity from Peak III material. Pharmacological, biochemical and immunological analysis of the AT2 receptor clone isolated from N1E-115 cells revealed that it has the identical characteristics or properties of the Peak III receptor. The AT2 receptor isolated from N1E-115 cells exhibited a similar pharmacology as the Peak III AT2 receptor, in that CGP42112A was more effective at displacing 125I-Ang II binding activity than was PD123319. The AT2 receptor clone was also shown to be insensitive to the actions of GTP gamma S, as well as demonstrated increased binding activity in the presence of DTT, identical to the Peak III AT2 receptor. Lastly, immunoblot analysis of membranes prepared from COS-1 cells transfected with the AT2 receptor cDNA from N1E-115 cells did not demonstrate any immune-specific bands with the AT2-directed antisera. Characterization of an AT2 receptor cDNA isolated from N1E-115 cells reveals that this clone is identical to the Peak III type of AT2 receptor.
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PMID:Heterogeneity of angiotensin type 2 (AT2) receptors. 872

The area postrema (AP) has been repeatedly implicated in cardiovascular regulation. Microinjection and single unit recording studies in vivo have suggested specific actions for angiotensin II (ANG) and glutamate (GLU) in controlling the excitability of AP neurons. The present study was therefore designed to examine the responsiveness of AP neurons to bath administration of these substances. Of the 133 AP neurons tested with ANG (10(-8)-10(-6) M) 40% were excited, 13% inhibited and the remainder unresponsive. The excitatory effects of ANG on AP neurons were dose-dependent. Following blockade of synaptic transmission with a low calcium high magnesium solution excitatory responses were maintained in 12 of 15 cells tested. Pretreatment of slices with the AT1 receptor antagonist losartan blocked the excitatory effects of ANG in all cells (5/5) tested. The effects of GLU on AP neurons were also examined. Of the 71 AP cells tested, 40% were excited, 10% inhibited, 8% showed excitatory responses followed by periods of inhibition while the remaining cells were unaffected. Excitatory effects of GLU were maintained in all AP neurons (7/7) tested during perfusion with low calcium, high magnesium solutions. Similar responses to NMDA were observed in four of four cells tested, suggesting these GLU actions are mediated through NMDA receptors. These data demonstrate direct excitatory actions of ANG and GLU on AP neurons which are likely mediated through the AT1 and NMDA receptors, respectively.
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PMID:Angiotensin II and glutamate influence area postrema neurons in rat brain slices. 883 16

In order to evaluate the role played by vasopressin on pressor responses elicited by stimulation of the periaqueductal gray (PAG) area by excitatory amino acids we carried out in vivo studies in genetically vasopressin deficient rats (Brattleboro). Microinjections of 1-glutamic acid (glutamate, 0.6 to 60 nmol/rat) or N-methyl-d-aspartic acid (NMDA, 0.07 to 7 nmol/rat) into the PAG area of freely moving Brattleboro rats induced increases of arterial blood pressure values significantly lower than those obtained in Long Evans rats (control) (glutamate in Brattleboro rats: from +2+/-1 mmHg to 16+/-3 mmHg; glutamate in Long Evans rats: from +16+/-2 mmHg to +36+/-4 mmHg; NMDA in Brattleboro rats: from +5+/-2 mmHg to +34 +/-8 mmHg; NMDA in Long Evans rats: from +18+/-7 mmHg to 80+/-9 mmHg; n=5). Similarly, in anaesthetized Brattleboro rats (urethane 1.2 g/kg i.p.) pressor responses to NMDA microinjections (0.7 nmol/rat) into the PAG area were significantly lower than in Long Evans rats (controls) (+15+/-3 mmHg vs +24+/-4 mmHg). In Long Evans rats NMDA injection also reversed blood pressure decrease induced by ganglionic blocker, hexamethonium and/or losartan (3 mg/kg i.v.), an AT1 receptor antagonist. In Brattleboro rats, NMDA injection did not reverse blood pressure decreases induced by hexamethonium (5 mg/kg i.v.). Moreover, hexamethonium induced blood pressure decrease was not reversed by acetylcholine injection (137 nmol/rat) into the PAG area of anaesthetized Long Evans rats, but if injected before hexamethonium, acetylcholine was able to increase blood pressure (+25+/-3 mmHg). Our results document: i) the importance of the PAG area in the control of cardiovascular system; ii) the involvement of excitatory amino acids in the neural control of vasopressin release; iii) the close relationship between glutamate and vasopressin in the central blood pressure regulation.
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PMID:Role of vasopressin on excitatory amino acids mediated pressor responses in the periaqueductal gray area. 965 Aug 3

Microdialysis in the intermediolateral column (IML) was employed to examine amino acids release induced by angiotensin II (ANG II) applied into the rostral ventrolateral medulla (RVLM). Microinjection of ANG II (100 pmol, n = 11) into the RVLM significantly increased (P < 0.01) the release of aspartate (from 4.75 +/- 1.01 to 8.90 +/- 2.28 pmol/20 microliters) and glutamate (from 18.99 +/- 8.64 to 73.88 +/- 29.26 pmol/20 microliters) in the spinal cord. The increase of glutamate release was significantly attenuated (P < 0.05) by pretreatment with losartan (10 nmol, n = 8) at the same RVLM site. Immunofluorescence double labeling combined with confocal microscopic observation demonstrated that 62%-91% of the glutamatergic neurons in the RVLM were double-labeled with AT1 receptors, supporting the view that ANG II-induced glutamate release in the spinal cord may arise from the AT1 receptor-containing glutamatergic spinally projecting neurons in the RVLM.
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PMID:[Angiotensin II in rostral ventrolateral medulla mediates amino acids release from spinally projecting nerve terminals in the spinal cord]. 1183 24

1. The brain renin-angiotensin system can influence arterial baroreceptor reflex control of blood pressure (BP) through both direct and indirect effects on sympathetic premotor neurons of the rostral ventrolateral medulla (RVLM). The present study examined the direct effect of angiotensin (Ang) II applied by microiontophoresis on the ongoing activity of single RVLM neurons. 2. In 26 urethane-anaesthetized Wistar rats, recordings of single unit activities of barosensitive RVLM neurons were made from one barrel of a six-barrel micropipette assembly. The other five barrels were filled with either L-glutamate, AngII, valsartan (an AT1 receptor antagonist), PD 123177 (an AT2 receptor antagonist) and saline. All drugs were applied by microiontophoresis. 3. Mean BP was 83 +/- 3 mmHg. Application of AngII inhibited the ongoing activity of RVLM neurons, identified as barosensitive because their activity was inhibited by a phenylephrine- induced increase in BP, from 12.6 +/- 1.5 to 5.4 +/- 1.1 Hz (n=24; P < 0.001). Angiotensin II also inhibited the glutamate-evoked excitation of barosensitive RVLM neurons from 15 +/- 3 to 5.8 +/- 2.0 Hz (n=6; P < 0.001). Valsartan significantly increased neuronal activity from 9.5 +/- 2.3 to 13.5 +/- 3.2 Hz (n=7, P < 0.01), whereas PD 123177 significantly decreased neuronal activity from 13.5 +/- 3.5 to 9.9 +/- 2.8 Hz (n=13; P < 0.01). 4. The results suggest that AngII exerts a tonic inhibitory effect on barosensitive RVLM neurons, which is presumably mediated through AT1 receptor stimulation.
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PMID:Inhibitory effects of angiotensin II on barosensitive rostral ventrolateral medulla neurons of the rat. 1190 28


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