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)

CS-866, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxy-4-(1-hydroxy-1- methylethyl)-2-propyl-1-(4-[2-(tetrazol-5-yl)-phenyl]phenyl)met hylimidazol- 5-carboxylate, a prodrug type angiotensin receptor antagonist, is deesterified to the active acid, RNH-6270. RNH-6270 inhibited [125I]angiotensin II binding to bovine adrenal cortical membranes (angiotensin AT1 receptors) with an IC50 value of 7.7 nM, but not [125I]angiotensin II binding to bovine cerebellar membranes (angiotensin AT2 receptors), indicating the selectivity of the compound for angiotensin AT1 receptors. In guinea pig aortas, RNH-6270 reduced the maximal response of the concentration-contractile curve for angiotensin II (pD'2 = 9.9), but had no effect on the contractile response induced by phenylephrine or KCl. In conscious rats, intravenously injected RNH-6270 inhibited angiotensin II-induced pressor responses in a dose-dependent manner, and orally administered CS-866 produced a long-lasting inhibition of angiotensin II pressor responses. SK&F-525A, a P-450 inhibitor, suppressed the angiotensin II inhibitory effect of losartan, but not that of CS-866. These results demonstrate that RNH-6270 is a potent and AT1-selective angiotensin receptor antagonist and that, after oral administration, CS-866 has a long-lasting angiotensin II inhibitory action which is not affected by drug metabolizing enzymes in the liver.
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PMID:Pharmacology of CS-866, a novel nonpeptide angiotensin II receptor antagonist. 856 37

So far, two angiotensin receptor subtypes, called AT1 and AT2, have been described in an animal model and in human. AT1 mediates almost all known effects of angiotensin II and its gene sequence and regulation is well studied. In contrast, only few data on function and regulation of AT2 are available. The complete mRNA sequence of AT2 has only recently been cloned and sequenced. The angiotensin receptors' receptor density and subtype distribution is organ specific. In the rat, lowest densities are found in the myocardium, followed by kidney, liver, adrenal medulla and cortex. The percentage of AT1 in the different organs amounts to 80, 85, 90, 57 and 10%. Angiotensin receptor subtypes have also been quantitated in human myocardium. There, the relatively unknown subtype AT2 dominates (67%). Myocardial receptor density is low, amounting to about 11 fmol/mg protein corresponding to 1/20-1/50 of the density of beta-adrenergic receptors. Angiotensin receptors in the human heart are present on cardiac fibroblasts and induce proliferation of these cells. Blockade of the renin angiotensin system by ACEI and AT1 antagonists in the rat downregulates angiotensin receptors in liver, kidney and adrenals to about 50% in an organ- and subtype specific manner, whereas cyclosporin A upregulates receptors twice. In end-stage human heart failure, but not in early stages, angiotensin receptors are downregulated to 1/3 of control values. Regulator mechanisms at transcriptional level have been elucidated by reporter gene assays; PMA, an activator of proteinkinase C, stimulates the transcription of the AT1 gene. The organ- and subtypespecific regulation of angiotensin receptors by pharmacological agents and/or cardiovascular diseases can contribute to the understanding of these drugs and of the pathophysiology of the corresponding diseases.
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PMID:[Angiotensin receptors--organ and subtype specific regulation in cardiovascular diseases by modulation of the renin-angiotensin system. Studies of the rat model and in human myocardium]. 858 75

The present studies were conducted to examine the roles of angiotensin II, angiotensin IV, and the angiotensin receptor subtypes in the cerebral circulation. The effects of angiotensin II, the selective AT1 receptor antagonist losartan, and the selective AT2 receptor ligands, PD 123319 and CGP 42112, on cerebral blood flow autoregulation, were studied during increases and decreases in blood pressure in normotensive rats. Cerebrocortical blood flow was measured by laser-Doppler flowmetry, while systemic blood pressure was either increased by phenylephrine infusion, or decreased by controlled haemorrhage. The effects of angiotensin II, and AT1 and AT2 receptor ligands on the contractility of rat anterior cerebral artery in vitro, were studied using cannulated, perfused vessel segments. The effect of angiotensin IV on cerebral blood flow after experimental subarachnoid haemorrhage, and possible involvement of nitric oxide, was studied in rat. Subarachnoid haemorrhage was simulated by injecting 0.3 ml arterial blood into the cisterna magna, while cerebral blood flow was measured by laser-Doppler flowmetry. The main findings in the present studies were that angiotensin II, the AT1 antagonist losartan, and the AT2 ligands PD 123319 and CGP 42112, shifted the cerebral blood flow autoregulatory range towards higher blood pressures. PD 123319 and CGP 42112 acted as AT2 receptor agonists. In vitro, angiotensin II elicited an AT1 receptor mediated contraction of rat anterior cerebral artery. Angiotensin IV was able to reverse the acute CBF reduction after subarachnoid haemorrhage. No evidence was found to support the involvement of nitric oxide in this response. In conclusion, there is strong evidence supporting a role for the AT2 receptor in the regulation of cerebral circulation. The role of the AT1 receptor is questionable, and the losartan induced autoregulatory shift is possibly mediated indirectly through AT2 receptor stimulation. Although AT1 receptors mediate the angiotensin II induced contraction of rat anterior cerebral artery in vitro, this effect does not explain the effect of losartan on CBF autoregulation. Angiotensin IV increases cerebral blood flow after experimental subarachnoid haemorrhage possibly by dilating cerebral vessels through stimulation of the AT4 receptor.
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PMID:The role of angiotensin receptor subtypes in cerebrovascular regulation in the rat. 861 May 1

Angiotensin-(1-7) [Ang-(1-7)] was recently recognized to have novel biological functions that are distinct from those of Ang II. In these studies, we determined the vasoactive effects of Ang-(1-7) together with the endothelium-dependent mediator(s) of these responses in canine coronary arteries. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2 at 37 degrees C. Ang-(1-7) caused significant concentration-dependent vascular relaxation (2.73 +/- 0.58 micromol/L, EC50) of rings precontracted with the thromboxane A2 analogue U46,619. Pretreatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (1 mol/L) abolished the vasodilator response to Ang-(1-7), whereas treatment with the cyclooxygenase inhibitor indomethacin (10 micromol/L) was without effect. The vasodilator response produced by Ang-(1-7) was blocked by 75% with the bradykinin B2 receptor antagonist Hoe 140 (1 micromol/L) or by 80% with the nonselective Ang II antagonist [Sar1,Thr8]-Ang II (1 micromol/L). In contrast, the selective AT1 or AT2 Ang II antagonists CV 11974 (1 micromol/L), and PD 123319 (1 micromol/L), respectively, were ineffective in inhibiting the Ang-(1-7)-elicited vasodilation. Furthermore, pretreatment of the coronary rings with 2 micromol/L Ang-(1-7) markedly potentiated the bradykinin response. These results suggest that Ang-(1-7) elicits coronary vasodilation that is specifically mediated by the endothelium-dependent release of nitric oxide. These responses involve a B2 bradykinin receptor and a non-AT1, non-AT2, angiotensin receptor. These data suggest that increases in circulating levels of Ang-(1-7) accompanying long-term administration of converting enzyme inhibitors or Ang II receptor blockers may contribute to the cardioprotective actions of these drugs.
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PMID:Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. 861 97

Characterization and regulation of angiotensin II (AII) receptor binding sites was performed in rat membrane preparations from nonadipose (liver, lung) and adipose (interscapular (ISBAT) and periaortic (PA) brown adipose tissue; epididymal (EF) and retroperitoneal (RPF) white adipose tissue). In membrane preparations from brown and white adipose sources, [125I]AII saturation binding revealed a single, high affinity (Kd range of 0.3 -0.6 nM) binding site with a modest AII receptor density (Bmax range of 17-120 fmol/mg protein) comparable to rat lung (130 fmol/mg protein). White adipose tissue contained a greater number of AII receptor sites than brown adipose tissue. Competition displacement studies demonstrated the AT1 receptor is the only angiotensin receptor subtype localized in adipose tissue, with the rank order for competition of [125I]AII binding in all adipose tissues examined AIII > AII > losartan > angiotensin I (AI) > PD123319. The AT2 specific receptor antagonist, PD123319, was ineffective at displacing [125I]AII binding in all adipose tissues examined. Since components of the renin-angiotensin system are regulated in adipose tissue, we determined if the AII receptor is also regulated in the obese state. AII receptor binding characteristics were determined in liver, lung, ISBAT and EF membrane preparations from adult Zucker obese (fa/fa) and lean (Fa/?) rats. AII receptor density was decreased in liver from obese rats. In contrast, the affinity for [125I]AII binding was not altered in tissues from obese rats. In a separate group of obese and lean rats, regulation of the AII receptor by phenobarbital (PB) was examined. Administration of PB restored AII receptor density in liver from obese rats to levels obtained in lean rats. In summary, these results demonstrate the presence of AT1 receptor sites in brown and white adipose tissue. Moreover, AII receptor density is decreased in tissues from obese rats, with restoration of receptor density by administration of PB. Future studies will determine if PB regulates the AT1 receptor at the level of gene expression.
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PMID:Characterization and regulation of angiotensin II receptors in rat adipose tissue. Angiotensin receptors in adipose tissue. 872 84

The actions of angiotensin II in the cardiovascular system are transmitted by two known and possibly some unknown angiotensin receptor types. AT1 and AT2 both correspond to G-protein-coupled receptors with seven hydrophobic transmembrane domains, several N-glycosylation sites and a potential G-protein binding site. Cloning of coding regions and promoter sequences contributed to the understanding of receptor protein function and regulation. Angiotensin receptors with atypical binding properties for the known AT1- and AT2-specific ligands are expressed on human cardiac fibroblasts and in the human ulcrus. In several animal models, receptors with high affinity for angiotensin (1-7) have been described. AT1 stimulation is mediated by the generation of phospholipid-derived second messengers, activation of protein kinase C, the MAPkinase pathway and of immediate early genes. Recently, phosphorylation and dephosphorylation of tyrosine kinases have been associated with AT1- and AT2-mediated signal transduction. ATR are regulated by phosphorylation, internalization, modification of transcription rate and mRNA stability. Regulation is highly cell and organ specific and includes upregulation of ATR in some pathophysiological situations where the renin angiotensin system is activated. Whereas the function of AT1 in the cardiovascular system is relatively well established, there is little information regarding the role of AT2. Recent hypotheses suggest an antagonism between AT1 and AT2 at the signal transduction and the functional level. Transgenic animal models, particularly with targeted disruption of the AT1 and AT2 genes, suggest the contribution of both genes to blood pressure regulation. Genetic polymorphisms have been described in the AT1 and AT2 gene or neighbored regions and are used to analyze the association between gene defects and cardiovascular diseases. AT1 antagonists are now being introduced into the treatment of hypertension and potentially heart failure, and more interesting pharmacological developments are expected from the ongoing basic studies.
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PMID:Molecular biology of angiotensin receptors and their role in human cardiovascular disease. 877 61

In this study I attempted to assess, in rats, the role of AT1 and AT2 angiotensin receptor subtypes in the phenomenon of improved learning and memory after an intracerebroventricular (icv) injection of angiotensin II (Ang II) and Ang II (3-7). Selective AT1 (losartan, 1 mg) or AT2 (CGP 42112 A, 2 micrograms) receptor antagonist was dissolved in 2 microliters of saline and given to the left cerebral ventricle 5 min before 1 nmol Ang II or Ang II (3-7) injected in the same volume of saline to the right ventricle. Consequently, there were 9 experimental groups which underwent 3 memory oriented and 3 auxiliary tests. Ang II and Ang II (3-7) significantly improved retention of the passive avoidance and recognition memory. These effects were abolished by losartan or CGP 42112 A. Better, after Ang II and Ang II (3-7), acquisition of conditioned avoidance responses was unchanged by losartan and abolished by CGP 42112 A. None of the treatments significantly changed rats motor behaviour in open field. Losartan as well as CGP 42112 A abolished significant enhancement of apomorphine (1 mg/kg, i.p.) stereotypy caused by Ang II and Ang II (3-7). The results suggest considerable involvement of AT1 and AT2 angiotensin receptors in the cognitive enhancement produced by angiotensins.
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PMID:The contribution of AT1 and AT2 angiotensin receptors to its cognitive effects. 878 10

The mechanism by which angiotensin-converting enzyme (ACE) inhibitors prevent proteinuria and glomerulosclerosis in experimental nephropathies is not yet clear. Experimental evidence is available that the effect of ACE inhibitors on the glomerular function depends on the inhibition of angiotensin II generation, but it is possible that inhibition of the bradykinin breakdown also plays a relevant role. To establish the mediators of the effects of ACE inhibitors in glomerular injury, we compared the effects of the ACE inhibitor lisinopril with those of a specific angiotensin receptor (AT1) antagonist (ZD7155) on the renal function in male MWF/Ztm rats. After 4 months (end of the study), the untreated animals developed hypertension and proteinuria (160 +/- 10 mm Hg and 214 +/- 92 mg/24 h, respectively). In the lisinopril- and in the ZD7155-treated rats, a comparable systolic pressure control was achieved (121 +/- 12 and 118 +/- 14 mm Hg, respectively), and proteinuria was significantly prevented (averaging only 38 +/- 23 and 30 +/- 8 mg/24h, respectively) at the end of the study. The glomerular filtration rate was comparable in control and lisinopril-treated rats and significantly increased in ZD7155-treated rats. Both treatments significantly reduced the glomerular capillary pressure and significantly increased the ultrafiltration coefficient (Kf) as compared with untreated animals. In ZD7155-treated rats the Kf was also significantly higher than in untreated animals glomerular sclerosis and tubulointerstitital damage developed. Structural changes were absent in lisinopril- and ZD7155-treated animals. These results show that the antihypertensive and renal protective effects of ACE inhibitors are shared by the angiotensin receptor antagonist. Thus, angiotensin II is the likely mediator of proteinuria and glomerulosclerosis which develop spontaneously with age in this model.
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PMID:Comparison of the effects of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade on the evolution of spontaneous glomerular injury in male MWF/Ztm rats. 878 96

There is increasing evidence that neuropeptides have trophic functions during embryogenesis. We examined the ability of angiotensin II, substance P, somatostatin-28 and luteinising hormone-releasing hormone to influence neurite outgrowth from embryonic chick sympathetic neurons in culture. Nanomolar concentrations of angiotensin II inhibited neurite outgrowth, whereas the other peptides had no effect at similar concentrations. The effect of angiotensin II on neurite outgrowth is likely to be mediated by an atypical angiotensin receptor, as it was only weakly inhibited by [sar1,ala8]angiotensin II, and was not inhibited by losartan, an inhibitor of mammalian AT1 receptors, or PD123319, an AT2 inhibitor. Neurite outgrowth was also inhibited by angiotensin III and angiotensin IV but not by angiotensinogen I1-14. The study provides further evidence that angiotensin peptides, like classical neurotransmitters, may have trophic functions during embryogenesis.
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PMID:A novel action of angiotensin peptides in inhibiting neurite outgrowth from isolated chick sympathetic neurons in culture. 880 32

Stimulation of cultured rat thoracic aorta vascular smooth muscle cells (VSMCs) with 100 nM angiotensin II (Ang II) reduces angiotensin receptor type 1 (AT1-R) gene expression. mRNA levels are reduced to approximately 30% of control levels 4 hr after the addition of Ang II to the culture medium. The loss of mRNA remains sustained for up to 24 hr after the addition of Ang II. The half-life of the AT1-R mRNA is approximately 2 hr in cells treated with a single dose of 100 nM Ang II. This represents a 3-fold reduction from its half-life of 6 hr in nonstimulated cells, as assessed by treatment with 5,6-dichlorobenzimidazole or actinomycin D to block transcription. Thus, the AT1-R mRNA is moderately unstable in VSMC and destabilized further by treatment with Ang II. Ang II-induced AT1-R mRNA destabilization is prevented by pretreatment with transcriptional inhibitors or the protein synthesis inhibitor cycloheximide, suggesting that Ang II-induced AT1-R mRNA destabilization requires the induction of an unknown factor or factors that are postulated to mediate this effect. AT1-R mRNA levels decrease more rapidly in vitro from a polyribosomal fraction isolated from VSMC exposed for 2 hr to 100 nM Ang II compared with that from vehicle-treated cells, suggesting that polyribosomal-associated AT1-R mRNA is at least one site of action for the mRNA destabilization effect of Ang II. Ang II stimulation induces a complex of polyribosomal proteins that bind specifically in the distal 350 bases of the AT1-R mRNA. Regulation of mRNA stability accounts in part for modulation of AT1-R gene expression by Ang II in VSMCs, and Ang II-induced AT1-R mRNA polyribosomal binding proteins are associated with this phenomenon.
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PMID:Enhanced angiotensin receptor type 1 mRNA degradation and induction of polyribosomal mRNA binding proteins by angiotensin II in vascular smooth muscle cells. 886 18


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