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)

Mesangial cells possess a variety of receptors for hormones and autacoids. They are also equipped with ectoenzymes whose function may be to control the availability of autacoids and hormones at their receptor sites. Several examples are considered. Receptors for angiotensin II (AII) are present both on murine and human mesangial cells. One single group of receptors has been demonstrated in each of these preparations. Mesangial cell AII receptors are linked to phospholipase C via a G protein. They belong to the AT1 subtype because (125I)AII is displaced from its binding sites preferentially by AT1 antagonists such as DUP 753 and EXP 3,174, whereas AT2 antagonists are much less potent. AT1 antagonists suppress the biological effects of AII in mesangial cells, including the stimulation of intracellular calcium concentration and the increase of prostaglandin synthesis and of (3H)leucine incorporation. Mesangial cells also have receptors for atrial natriuretic factor, but the distribution between B receptors with guanylate cyclase activity and clearance (C) receptors varies with the species. Both types are present in murine mesangial cells, whereas only C receptors are found in human mesangial cells. In contrast, human epithelial cells possess both B and C receptors. Ecto-5'-nucleotidase activity results in the production of adenosine, which acts on mesangial cells through A1 and A2 receptors. This enzyme is markedly induced in rat mesangial cells by interleukin-1, whose effect is mediated in part by prostaglandin E2 and cAMP. Various other cAMP-stimulating agents also induce 5'-nucleotidase expression in rat mesangial cells. Ectopeptidases are present in all glomerular cell types but essentially in epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cell surface receptors and ectoenzymes in mesangial cells. 131 10

The effects of angiotensin II (AII) and related peptides on the mobilization of internal Ca2+ were studied in a subclone of NG 108-15 cells. The subclone, C1, was prepared by fluorescence-activated cell cloning using a rapid response kinetics and a large response magnitude following stimulation by AII as the selection criteria. Angiotensin I, AII, and angiotensin III (AIII) stimulated Ca2+ mobilization in the C1 cells in a concentration-dependent manner (1 nM-100 microM), yielding EC50 values of 437 +/- 80 nM (n = 4; slope = 1.6 +/- 0.3), 57 +/- 8 nM (n = 12; slope = 1.5 +/- 0.3), and 36 +/- 5 nM (n = 7; slope = 1.4 +/- 0.3), respectively. AIII was significantly more potent than AII (p less than 0.05). In contrast, Des-Phe8-AII, AII-hexapeptide (AII 3-8), and p-NH2-Phe6-AII (1-10 microM) were inactive as agonists. Although the effects of AII and AIII in C1 and parent NG108-15 cells were totally inhibited by the AT1 receptor-selective nonpeptide antagonist, DUP-753 (0.3-1 microM), the AT2-selective antagonists, EXP-655 and CGP42112A (1-10 microM), failed to block the effects of AII. DUP-753 (0.3-100 nM) produced dextral shifts of the AII-induced concentration-response curves and yielded an estimated affinity constant (pA2) of 8.5 +/- 0.2 (n = 16) using single-point analysis involving different concentrations of DUP-753. These data compared well with those obtained for the inhibition of AII-induced aortic contractions by DUP-753 (pA2 = 8.5) reported previously by others.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:AT1 angiotensin receptors mobilize intracellular calcium in a subclone of NG108-15 neuroblastoma cells. 156 Feb 41

We examined the effects of U-97018, an AT1 receptor antagonist, on the pressor response to intracerebroventricularly (i.c.v.) administered angiotensin II (AII) in conscious normotensive rats in comparison to losartan, EXP 3174, EXP 655, and saralasin. In an i.c.v. study, U-97018, losartan, and EXP 3174 reduced the pressor response. EXP 655, an AT2 selective antagonist, also inhibited the pressor response to i.c.v. AII. U-97018 combined with EXP 655 did not fully eliminate the pressor response to i.c.v. AII. Moreover, saralasin, a nonselective peptide AII antagonist, also failed to abolish the pressor response to i.c.v. AII. Therefore, both AT1- and AT2-receptors probably are functional in inhibiting the pressor response to i.c.v. AII and that a part of the i.c.v. AII-induced pressor response occurs through non-AT1- and non-AT2-receptors. In an intravenous (i.v.) study, U-97018, losartan, and EXP 3174 reduced the pressor response to i.c.v. AII. At 10 mg/kg orally (p.o.), which is an antihypertensive dose in spontaneously hypertensive rats (SHR), neither U-97018 nor losartan reduced the pressor response to i.c.v. AII even at 180 min after administration. This result indicates that neither U-97018 nor losartan, at the oral antihypertensive dose, reaches the brain in sufficient amount to affect the pressor response to i.c.v. AII.
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PMID:Effects of U-97018 on pressor responses to intracerebroventricularly administered angiotensin II in conscious normotensive rats. 756 32

Cardiovascular responses to intracerebroventricular angiotensin II (ANG II) were measured in conscious rats, chronically instrumented for the measurement of regional hemodynamics, over 4 consecutive days in the absence and presence of either the AT2 receptor antagonist, PD 123319 (experiment 1), or the AT1 receptor antagonist, EXP-3174 (experiment 2). Intracerebroventricular ANG II had pressor and bradycardic effects, which were associated with marked mesenteric and hindquarters vasoconstriction, and a small transient renal vasoconstriction. Both PD 123319 and EXP-3174, given intracerebroventricularly, abolished the cardiovascular response to intracerebroventricular ANG II, although the profiles of activity of the compounds were different. PD 123319 caused a slowly developing, but remarkably prolonged (1-2 days) inhibition of the effects of ANG II, whereas EXP-3174 caused an immediate inhibition of the effects of ANG II, although responses to ANG II had returned to control levels by the following day. These data suggest that the hemodynamic effects of ANG II may involve concurrent, and interdependent, activation of AT1 and AT2 receptors or that PD 123319 undergoes a unique biotransformation in the brain to some product(s) with AT1 receptor antagonist activity.
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PMID:Central administration of PD 123319 or EXP-3174 inhibits effects of angiotensin II. 767 56

The aim of the present report was to examine the effect of several agents on angiotensin II (ANG II) and losartan receptors using 125I-[Sar1,Ala8]ANG II and [3H]losartan as radiolabeled ligand, respectively. ANG II receptors were downregulated in glomeruli from rats infused with ANG II during 3 wk or rats receiving losartan orally during 1 wk. The number of sites (Bmax) was reduced, but the dissociation constant (Kd) value was unchanged. Losartan receptors were downregulated in glomeruli from rats receiving losartan, but remained unchanged in glomeruli from rats infused with ANG II. Since in vivo administration of losartan results in increase of plasma ANG II and formation of metabolites, in vitro studies using human mesangial cells were performed to better analyze the present findings. Treatment of mesangial cells during 4 days by ANG II, losartan, or its metabolite, EXP-3174, also produced downregulation of 125I-[Sar1,Ala8]ANG II binding sites with a decreased Bmax and unchanged Kd value. Only treatment of mesangial cells by ANG II or EXP-3174 produced downregulation of [3H]losartan binding sites. In contrast, exposure of these cells to losartan resulted in upregulation of [3H]losartan binding sites. Under all conditions, only Bmax was modified. Whereas internalization of [3H]losartan in mesangial cells was negligible under all experimental conditions, there was an increase of the percentage of internalized 125I-[Sar1,Ala8]ANG II after exposure of the cells to ANG II or AT1 antagonists. No change was observed in mesangial cell AT1 receptor mRNA levels. This study demonstrates that 1) AT1 mRNA is expressed in human mesangial cells; 2) the characteristics of 125I-[Sar1,Ala8]ANG II and [3H]losartan binding sites in rat glomeruli and human mesangial cells are different, with Kd and Bmax values greater in both preparations when [3H]losartan was utilized; 3) both types of binding sites obey different regulations, and the effects of losartan in vivo are due in part to the associated increase in plasma ANG II levels and the transformation of the drug into its metabolite, EXP-3174; 4) downregulation of AT1 receptors does not depend on changes in mRNA expression but is associated with increased relative internalization.
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PMID:Differential regulation of angiotensin II and losartan binding sites in glomeruli and mesangial cells. 816 Jul 86

In spontaneously hypertensive rats (SHR) 15-18 weeks old, the intracerebroventricular (icv) administration of peptide angiotensin II (Ang) antagonists results in a short (30-60 min) decrease (15-25 mmHg) of blood pressure (BP). Both EXP-3174, a known metabolite of Losartan and AT1 selective, and PD-123177, a receptor AT2 specific compound, do not affect SHR BP following icv administration. The receptor AT1 selective non-peptide Ang antagonists, Losartan and L-158809, induce long-lived (days) significant BP reductions (< or = 40 mmHg) in SHR, but only 18 h after icv injection. The slow development of BP reduction and its persistence might be due to the formation of an active metabolite, different from EXP-3174, a Losartan metabolite. In older SHR (25-28 weeks), the hypotensive effect of Losartan and L-158809 is not significant. These results suggest that in the CNS of the young SHR, an active Renin-Ang-System is implicated in the establishment of the hypertensive state, and that the receptor for this function is different from AT1 and AT2, since it has a selectivity profile different from AT1 and AT2 receptor types.
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PMID:The neurogenic origin of hypertension in SHR may be mediated by angiotensin II through a receptor different from AT1 and AT2. 821 May 22

In conscious, chronically instrumented, male Long-Evans rats, we showed previously that central administration (intracerebroventricular) of the AT1-receptor antagonist EXP-3174 (1 microgram) caused a rapid-onset marked, but transient, blockade of the regional hemodynamic responses to intracerebroventricular angiotensin II (ANG II). In contrast, the AT2-receptor antagonist PD-123319 (80 micrograms) caused a slow-onset, but marked and persistent, antagonism of the effects of intracerebroventricular ANG II. In the present study we attempted to mimic the actions of PD-123319 by giving a supramaximal dose of EXP-3174 (10 micrograms), and we also assessed the effects of PD-123177 (80 micrograms), an AT2-receptor antagonist that differs from PD-123319 only by a dimethyl group. The higher dose of EXP-3174 did not exert prolonged antagonistic effects against responses to intracerebroventricular ANG II, and PD-123177 was without inhibitory effects in this model. The results indicate important functional differences between putative AT2-receptor antagonists, when assessed in vivo, that are not apparent from binding studies.
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PMID:Differential blockade of central effects of angiotensin II by AT2-receptor antagonists. 834 37

Anti-angiotensin II (Ang) antibodies could become important receptor mimicking tools if an antibody with binding properties identical to a particular Ang receptor could be generated. For this purpose, anti-Ang sera from mice were screened for antibodies with structure-affinity relationships similar or identical to a particular Ang receptor. Mice were immunized with BSA-coupled [Sar1]Ang and the sera were screened in ELISA for crossreactivity with the Ang analogues saralasin, L158,809, EXP 3147, DuP 753, DuP 532, PD 123177, PD 123319 and the non-related compounds ACTH, naloxone, and CP 96,345. All sera had at least some cross-reactivity with saralasin and some also with L158,809, a potent non-peptide Ang antagonist, selective for the AT1 site. One serum out of eight recognized most Ang analogues except the AT2 selective PD 123177 and PD 123319. ELISA detection antigens were prepared by two different BSA conjugations: [Sar1]Ang was N-terminally attached and [Sar1,Lys8]Ang was C-terminally attached. Against both detection antigens, the peptide antagonists saralasin and [Sar1,Phe(Br5)8]Ang displaced in a sigmoidal manner the antibodies with an IC50-value of 0.4 mM. L158,809 and EXP 3147 displaced also in a parallel manner, suggesting an apparently homogenous population of binding sites. The selectivity profile of the serum has some resemblance to the AT1 selectivity profile but the observed affinities are too low to suggest AT1 receptor mimicry.
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PMID:Anti-angiotensin antibodies cross-reactive with nonpeptide angiotensin antagonists as angiotensin receptor model. 838 92

Aim of this study is to carry out a genetic analysis of polymorphisms of the renin-angiotensin system in a genetically homogeneous population, in patients with and without myocardial infarction (AMI) expansion and to evaluate the influence of non genetic, mechanical factors. The study was conducted on 299 patients with first AMI. Ecocardiography studies were performed on all patients on day 1 and 3 from the onset of AMI and before discharge. Eighty-four patients were excluded because of inadequate quality of echocardiograms and 215 (163 males, 52 females) were admitted. Of these, 157 had no evidence of AMI expansion (EXP-) while 58 had expansion (EXP+). DNA was extracted by standard methods from blood samples. Age and gender had no influence on AMI expansion. Anterior infarction (p < 0.000001) and Q-wave infarction (p < 0.00002) were found more frequently in EXP+. Peak of creatine phosphokinase was higher in EXP+ than in EXP- (p < 0.00001). The percent of patients treated with thrombolysis or with hypertension and/or left ventricular hypertrophy was not significantly different in the two groups. AGT MT235 polymorphism of angiotensinogen gene, I/D polymorphism of ACE gene and AT1 A1166C of AT1 receptor of angiotensin II were not significantly different in two groups. Stratified analysis showed that in patients with anterior AMI (n = 87), with a higher risk of AMI expansion, there is a significant difference (p < 0.02) in ACE genotype between EXP- and EXP+. Odds ratio assuming the dominant effect of I allele (II+ ID < DD) was 3.35 (confidence interval 1.41-7.56) with increased risk of expansion. More extension studies are need to verify if these results can contribute to early identification of patients at higher risk and to optimize therapeutic approach.
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PMID:[Does a genetic predisposition for infarction expansion exist? Evaluation of genetic polymorphisms of the renin-angiotensin system]. 917 34

Vascular injury stimulates AT1-receptor expression and nitric oxide (NO) production in smooth muscle cells (SMCs). We examined the ability of AT1 agonists and antagonists to regulate vascular tone ex vivo in injured arteries and the possible modulation by SMC-derived NO. Rings of rat carotid arteries were isolated at day 7 after endothelial denudation and stimulated with angiotensin (Ang) II in the absence or presence of the AT1 antagonists losartan, L-158,809, or EXP-3174. Freshly denuded contralateral arteries were used as controls. AngII-induced contractions were similar in control and injured arteries. Losartan caused an insurmountable inhibition of AngII-induced contractions in injured but not control arteries. Enhanced inhibition of AngII in injured arteries also was observed in the presence of L-158,809 and EXP-3174. In the presence of the NO synthesis inhibitor nitromonomethyl-L-arginine (L-NMMA), maximal contractions to AngII were greater in injured than in control vessels, and AT1-receptor blockade with losartan was surmountable in all vessels. Mechanical removal of superficial neointimal SMCs attenuated NO production and normalized the efficacy of losartan in injured arteries. These results suggest a role for NO in reducing the biologic effects of AT1-receptor agonists and potentiating the efficacy of AT1 antagonists in vessels undergoing remodeling after injury.
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PMID:Evidence that nitric oxide regulates AT1-receptor agonist and antagonist efficacy in rat injured carotid artery. 1081 69


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