UMLS:C0004135 - FACTA Search

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Query: UMLS:C0004135 (ATM)
13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin-converting enzyme inhibitors (ACE-I) and specific nonpeptide angiotensin II (ANG II) receptor antagonists have been used extensively to treat a variety of cardiovascular disorders in experimental animals and humans. Despite their widespread use, only a limited amount of data has been published regarding the effect that renin-angiotensin system (RAS) blockade may have on ANG II receptors, and very often this information is contradictory. The present study was designed to investigate whether changes in plasma ANG II levels induced by RAS blockade could alter glomerular ANG II receptor characteristics. Captopril was employed as an ACE-I with losartan and TCV-116, two AT1 receptor antagonists of different chemical structure. Two experimental protocols were established. Protocol 1 contained 3 experimental groups: controls (Sprague-Dawley rats, 250-300 g BW), and animals treated with either captopril (0.5 g/l via drinking water) or losartan (10 mg/kg BW p.o.). In protocol 2, the animals were treated as in protocol 1 except that losartan was replaced by TCV-116 (1 mg/kg BW p.o.). At the end of treatment (3 days), all groups were killed by decapitation, blood was collected for plasma renin activity (PRA) measurement, and hearts and kidneys were excised. ANG II receptors were assessed by radioligand binding assays on membrane preparations of purified glomeruli, by displacement of 125I-[Sar1, Ile8]-ANG II with specific nonpeptide antagonists of AT1 (losartan) and AT2 (PD 123319) receptor subtypes. RAS blockade by either ACE-I or AT1 antagonists increased PRA. The binding assays showed that renal glomeruli from treated rats and controls expressed a single population (AT1) of ANG II receptors. The density of glomerular AT1 receptors was not modulated by captopril, but was significantly lower in animals treated with either losartan (Bmax: 854 +/- 169 vs. 379 +/- 79 fmol/mg protein and Kd: 59 +/- 6 vs. 45 +/- 6 nM for controls and losartan, respectively) or TCV-116 (480 +/- 72 vs. 188 +/- 16 fmol/mg protein and Kd: 45 +/- 9 vs. 37 +/- 18 nM for controls and TCV-116, respectively) than in their controls. No changes in receptor affinity (Kd) were detected. Previous membrane "acid-wash" did not modify the results. We conclude that short-term RAS blockade by AT1 antagonists, but not by ACE-I, induces true downregulation of renal glomerular ANG II receptors. No AT2 receptor subtype was detected.
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PMID:Modulation of renal glomerular angiotensin II receptors by ace inhibition and AT1 receptor antagonism. 911 Mar 82

We investigated the contribution of brain angiotensinergic mechanisms to postprandial drinking in sheep. Sheep in fluid balance were given 0.8 kg chaff for 30 min, and water intake was measured for the next hour. Intracerebroventricular infusion of the AT1 type angiotensin II (ANG II) receptor blocker losartan (1 mg/h) reduced postprandial drinking by approximately 70% (n = 7, P < 0.01) but did not affect food intake. The same losartan dose given intravenously had little or no effect on prandial drinking. Feeding increased Na+ concentrations in plasma and cerebrospinal fluid (CSF; n = 5, P < 0.05). Intracerebroventricular losartan (1 mg/h) inhibited the drinking responses to intracarotid infusion of ANG II (0.8 microg/min for 30 min, n = 4, P < 0.01) and to intracerebroventricular infusion of 0.5 M NaCl (1 ml/h for 1 h, n = 5, P < 0.05) but had no effect on drinking responses to intravenous infusion of 4 M NaCl (1.3 ml/min for 30 min). These findings indicate that a brain ANG II-dependent mechanism is involved in postprandial drinking in sheep. They suggest also that the mechanism by which increasing CSF Na+ causes thirst involves brain ANG II and is different from the mechanism subserving the drinking response to changes in blood Na+.
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PMID:Intracerebroventricular losartan inhibits postprandial drinking in sheep. 914 1

The purpose of the present study was to test the hypothesis that hypertension induced by reduced renal mass (RRM) upregulates gene expression of the type 1 angiotensin II (Ang II) receptor (AT1) in the thoracic aorta and heart through an Ang II-dependent mechanism. Three groups of rats were given 1% NaCl water and subjected to RRM, RRM plus captopril (RRM+Cap, 30 mg/kg per day), or sham surgery. Tail-cuff systolic blood pressure was significantly elevated in RRM and RRM+Cap rats compared with sham-operated rats. The ratios of the medial wall area of the thoracic aorta and heart weight to body weight were significantly elevated in RRM and RRM+Cap rats compared with sham-operated rats. Northern blot analysis indicated that the ratio of AT1 to GAPDH mRNA in the aorta was significantly higher in RRM (1.85 +/- 0.52) compared with sham-operated (0.21 +/- 0.04) and RRM+Cap (0.55 +/- 0.20) rats. In contrast, the ratio of AT1 to GAPDH mRNA in the heart was significantly increased in both RRM (1.09 +/- 0.23) and RRM+Cap (1.00 +/- 0.09) compared with sham-operated (0.34 +/- 0.06) rats. Thus, RRM hypertension upregulates AT1 mRNA expression in both the hypertrophied aorta and heart. Captopril treatment without altering blood pressure in RRM rats prevents the increase in AT1 mRNA in the aorta but not the heart. These results suggest that different tissue-specific mechanisms of AT1 gene regulation exist; ie, in aorta, an Ang II-or kinin-dependent mechanism is operant, whereas in heart, RRM-induced upregulation of AT1 mRNA may be pressure dependent.
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PMID:Distinct mechanisms of modulation of angiotensin II type I receptor gene expression in heart and aorta. 914 73

We determined the effects of DuP753 and PD123319 (both nonpeptides and selective antagonists of the AT1 and AT2 angiotensin receptors, respectively), and [Sar1, Ala8]ANG II(a non-selective peptide antagonist of angiotensin receptors) on water and 3% NaCl intake induced by administration of angiotensin II (ANG II) into the paraventricular nucleus (PVN) of sodium-depleted Holtzman rats weighing 250-300 g. Twenty hours before the experiments, the rats were depleted of sodium using furosemide (10 ng/rat, sc). The volume of drug solution injected was 0.5 microliters over a period of 10-15 sec. Water and sodium intake were measured at 0.25, 0.5, 1.0 and 2.0 h. Pre-treatment with DuP753 (14 rats) at a dose of 60 ng completely abolished the water intake induced by injection of 12 ng of ANG II (15 rats) (6.4 +/- 0.6 vs 1.4 +/- 0.3 ml/2 h), whereas [Sar1, Ala8] ANG II (12 rats) and PD123319 (10 rats) at the doses of 60 ng partially blocked water intake (6.4 +/- 0.6 vs 2.9 +/- 0.5 and 2.7 +/- 0.2 ml/h, respectively). In the same animals, [Sar1, Ala8]ANG II, DuP753, and PD123319 blocked the sodium intake induced by ANG II (9.2 +/- 1.6 vs 3.3 +/- 0.6, 1.8 +/- 0.3, and 1.4 +/- 0.2 ml/2 h respectively). These results indicate that both DuP753 and PD123329, administered into the PVN, blocked the water and sodium intake induced by administration of ANG II into the same site.
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PMID:Paraventricular nucleus administration of DuP753 or PD123319 inhibits the effects of angiotensin on water and sodium intake. 919 52

Experiments in cattle compared the effects of intracerebroventricular (i.c.v.) infusions of losartan and PD-123319 on water intake caused by water restriction, i.c.v. infusion of hypertonic NaCl, or i.c.v. infusion of angiotensin II (ANG II). The effects of these receptor antagonists on sodium intake caused by sodium depletion were also examined. Losartan infusion caused dose-dependent inhibition of the high water intake caused by the physiological stimulus of water restriction or by ANG II infusion but did not affect salt appetite. PD-123319 infused at equimolar or greater (in ANG II experiments) doses did not affect water intake or salt intake due to sodium depletion. The results of these i.c.v. infusion experiments confirm our earlier proposal that the physiological regulation of water intake in cattle may be mediated by ANG II acting centrally via AT1 receptors. The dose of losartan that inhibited thirst in cattle did not inhibit sodium appetite, nor did an equimolar dose of PD-123319.
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PMID:Central infusion of the AT1 receptor antagonist losartan inhibits thirst but not sodium appetite in cattle. 922 11

We studied angiotensin II (ANG II) receptor subtype expression in selected brain nuclei and pituitary gland after water deprivation by in vitro receptor autoradiography using 125I-labeled [Sar1]ANG II and by in situ hybridization using 35S-labeled AT1A, AT1B, and AT2 receptor-specific riboprobes. In control rats we found binding to AT1 receptors in the subfornical organ, paraventricular nucleus, median eminence, and anterior pituitary; AT1A mRNA expression in the subfornical organ and paraventricular nucleus; and AT1B mRNA expression in the anterior pituitary. No receptor mRNA was found in the median eminence. AT1 receptors and AT1A receptor mRNA levels were increased in the subfornical organ, and, in the anterior pituitary, AT1 receptors and AT1B receptor mRNA were increased, only after 5 days of water deprivation. No significant changes occurred after 1 or 3 days of water deprivation, and no regulation of ANG II receptor expression was detected in other brain areas. Our results show that prolonged water deprivation selectively regulates AT1 receptor expression and AT1A and AT1B receptor mRNA levels in the subfornical organ and anterior pituitary, respectively, supporting a role for these receptors during sustained dehydration.
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PMID:Water deprivation upregulates ANG II AT1 binding and mRNA in rat subfornical organ and anterior pituitary. 925 92

Glomerular influx of monocytes/macrophages (M/M) occurs in many immune- and non-immune-mediated renal diseases. The mechanisms targeting M/M into the glomerulus are incompletely understood, but may involve stimulated expression of chemokines. We investigated whether angiotensin II (ANG II) induces the chemokine RANTES in cultured glomerular endothelial cells of the rat and in vivo. ANG II stimulated mRNA and protein expression of RANTES in cultured glomerular endothelial cells. The ANG II-induced RANTES protein was chemotactic for human monocytes. Surprisingly, the ANG II-stimulated RANTES expression was transduced by AT2 receptors because the AT2 receptor antagonists PD 123177 and CGP-42112A, but not an AT1 receptor blocker, abolished the induced RANTES synthesis. Intraperitoneal infusion of ANG II (500 ng/h) into naive rats for 4 d significantly stimulated glomerular RANTES mRNA and protein expression compared with solvent-infused controls. Immunohistochemistry revealed induction of RANTES protein mainly in glomerular endothelial cells and small capillaries. Moreover, ANG II- infused animals exhibited an increase in glomerular ED-1- positive cells compared with controls. Oral treatment with PD 123177 (50 mg/liter drinking water) attenuated the glomerular M/M influx without normalizing the slightly elevated systolic blood pressure caused by ANG II infusion, suggesting that the effects on blood pressure and RANTES induction can be separated. We conclude that the vasoactive peptide ANG II may play an important role in glomerular chemotaxis of M/M through local induction of the chemokine RANTES. The observation that the ANG II- mediated induction of RANTES is transduced by AT2 receptors may influence the decision as to which substances might be used for the therapeutic interference with the activity of the renin-angiotensin system.
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PMID:Angiotensin II stimulates expression of the chemokine RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor. 927 21

The discovery that all components of the renin-angiotensin system (RAS) are present in the central nervous system led investigators to postulate the existence of a local brain RAS. Supporting this, angiotensin immunoreactive neurons have been visualized in the brain. Two major pathways were described: a forebrain pathway which connects circumventricular organs to the median preoptic nucleus, paraventricular nucleus, and supraoptic nucleus, and a second pathway connecting the hypothalamus to the medulla oblongata. Blood-brain barrier deficient circumventricular organs are rich in angiotensin II receptors. By activating these receptors, circulating angiotensin II may act on central cardiovascular centers via angiotensinergic neurons, providing a link between peripheral and central angiotensin II systems. Among the effector peptides of the brain RAS, angiotensin II and angiotensin III have the same affinity for the two pharmacologically well-defined receptors: type 1 (AT1) and type 2 (AT2). When injected in the brain, these peptides increase blood pressure, water intake, and anterior and posterior pituitary hormone release and may modify memory and learning. The cloning of AT1 and AT2 receptor cDNAs has revealed that these receptors belong to the seven transmembrane domain receptor family. In rodents, two AT1 receptor subtypes, AT1A and AT1B, have been isolated. Using specific riboprobes for in situ hybridization histochemistry, recent studies mapped the distribution of AT1A, AT1B, and AT2 receptor mRNAs in the adult rat and found a predominant expression of AT1A and AT2 mRNA in the brain and of AT1B in the pituitary. Very limited overlap was found between the brain expression of AT1A and AT2 mRNAs. In several functional entities of the brain, such as the preoptic region, the hypothalamus, the olivocerebellary system, and the brainstem baroreflex arc, the colocalization of receptor mRNA, binding sites, and angiotensin immunoreactive nerve terminals suggests local synthesis and expression of angiotensin II receptors. In other areas, such as the bed nucleus of the stria terminalis, the median eminence, or certain parts of the nucleus of the solitary tract, angiotensin II receptors are likely of extrinsic origin. The neuronal expression of AT1A and AT2 receptors was demonstrated in the subfornical organ, the hypothalamus, and the lateral septum. By using double label in situ hybridization, AT1A receptor expression was localized in corticotropin releasing hormone but not in vasopressin containing neurons in the hypothalamus. The information is discussed together with functional data concerning the role of brain angiotensins, in an attempt to provide a better understanding of the physiological and functional roles of each receptor subtype.
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PMID:Expression of angiotensin type-1 (AT1) and type-2 (AT2) receptor mRNAs in the adult rat brain: a functional neuroanatomical review. 934 32

This study delineates the role of angiotensin II type I (AT1) receptor in the remodeling of Syrian cardiomyopathic hamsters. Twelve cardiomyopathic (T0-2) hamsters received L-158,809 treatment and libitum in their drinking water (27 micrograms/ml) and 9 cardiomyopathic and 9 normal FL-B hamsters received tap water from 1 to 4 months of age. Although pharmacologically effective with regard to complete suppression of the blood pressure response to angiotensin II infusion, L-158,809 did not diminish the progression or severity of cardiomyopathy. Heart weight/100 g body weight and left ventricular wall thickness adjusted for body weight of both L-158,809 and cardiomyopathic control hamsters did not differ and exceeded those of F1-B controls (p < 0.05). Myocardial material properties (e.g., stiffness and density) of cardiomyopathic hamsters treated with L-158,809 were not affected. Thus, the progression of fibrosis, calcification, and necrosis in T0-2 cardiomyopathic hamsters was not sensitive to AT1 receptor blockade.
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PMID:Angiotensin II receptor blockade in Syrian hamster (T0-2) cardiomyopathy does not affect microscopic cardiac material properties: implications for mechanisms of tissue remodeling. 935 56

Considerable evidence now suggests that the precursors and enzymes necessary for the formation and degradation of biologically active forms of angiotensins are present in brain tissues, accompanied by at least three specific binding sites. It also appears that several forms of angiotensin may serve as signaling agents at these sites. There is accumulating support for the notion that AngII must be converted to AngIII in order to bind at the AT1 and AT2 receptor subtypes, and AngIII must be converted to AngIV in order to activate the AT4 receptor subtype. Further, AngII(1-7) may activate a separate binding site concerned with antidiuresis, however, characterization of this site has not been completed. The AT1 site appears to mediate the classic angiotensin functions concerned with body water balance, maintenance of blood pressure, and cyclicity of reproductive hormones and sexual behaviors. This receptor site also exerts some control over the secretion of pituitary hormones. Less is known about the functional importance of the AT2 site, however, it has been implicated in vascular growth, control of blood flow, and perhaps modulation of NMDA receptors. The AT4 site is heavily distributed in neocortex, hippocampus, cerebellum, and basal ganglia structures, as well as several peripheral tissues. This site appears to mediate memory acquisition and retrieval, the regulation of blood flow, neurite outgrowth, angiogenesis, and kidney function. In addition to the well-studied functions of the brain renin-angiotensin system, additional less well investigated responses are reviewed. These include electrophysiological activation, tachyphylaxis, long term potentiation, learning and memory, and cognitive affect.
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PMID:Important role for angiotensin III and IV in the brain renin-angiotensin system. 937 53

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