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)

The aim of the present study was to explore the mechanisms underlying angiotensin II AT2 receptor modulation of AT1 receptor-mediated vasoconstriction in the rat isolated uterine artery, since previous studies have suggested that AT2 receptors may oppose AT1 receptor-mediated effects. Segments of uterine artery were obtained from Sprague-Dawley rats and mounted in small vessel myographs. Concentration-response (CR) curves to angiotensin II (0.1 nm-0.1 microM) were constructed in the absence and presence of PD 123319 (AT2 antagonist; 1 microM), HOE 140 (bradykinin B2 antagonist; 0.1 microM), Nomega-nitro-l-arginine (NOLA) (NOS inhibitor; 30 microM), as well as combinations of these inhibitors. Contractile responses to angiotensin II were expressed as a percent of the response to a K+ depolarizing solution. PD 123319 (1 microM) potentiated angiotensin II-induced contractions; reflected by a significant four-fold leftward shift of the angiotensin II CR curve. HOE 140 (0.1 microM) significantly increased the pEC50 of the angiotensin II CR curve. The combination of HOE 140 plus PD 123319 did not produce additive potentiation. NOLA (30 microM) significantly enhanced sensitivity to angiotensin II, seen as a five-fold leftward shift of the curve, and an augmented maximum contractile response. Combinations of PD 123319 (1 microM) plus NOLA, and of HOE 140 (0.1 microM) plus NOLA, both induced a similar magnitude of potentiation. Cyclic GMP measurements confirmed angiotensin II-induced activation of the nitric oxide (NO) pathway. In conclusion, AT2 receptor-mediated inhibition of angiotensin II-induced contraction of the rat uterine artery involves NO production; a component of which occurs through a bradykinin B2 receptor pathway.
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PMID:Functional role of angiotensin II AT2 receptor in modulation of AT1 receptor-mediated contraction in rat uterine artery: involvement of bradykinin and nitric oxide. 1453 Feb 22

Abdominal aortic banding induces upregulation of the angiotensin II (Ang II) type-2 (AT2) receptor, thereby decreasing the contractile response to Ang II in the thoracic aorta of the rat. The aim of this study was to use a mouse model to clarify the mechanisms by which the banding elicits upregulation of the aortic AT2 receptor and the subsequent attenuation of Ang II responsiveness. Concomitantly with the elevation in blood pressure and plasma renin concentration after banding, AT2-receptor mRNA levels in the thoracic aorta rapidly increased in mice within 4 days. Upregulation of the AT2 receptor, as well as blood pressure elevation after banding, was abolished by losartan administration. The contractile response to Ang II was depressed in aortic rings of banding mice but not of sham mice, and was restored by either the AT2-receptor antagonist PD123319 or the bradykinin B2-receptor antagonist icatibant. cGMP content in the thoracic aorta of banding mice was 9-fold greater than that of sham mice, and the elevation was reduced to sham levels 1 hour after intravenous injection of PD123319 or icatibant. When aortic rings were incubated with Ang II, cGMP content increased in banding rings but not in sham rings; the pretreatment with PD123319 or icatibant inhibited Ang II-induced cGMP production. These results suggest that aortic banding induces upregulation of the AT2 receptor through increased circulating Ang II via the AT1 receptor, thereby activating a vasodilatory pathway in vessels through the AT2 receptor via the kinin/cGMP system.
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PMID:Stimulation of cyclic GMP production via AT2 and B2 receptors in the pressure-overloaded aorta after banding. 1512 75

Studies on Angiotensin II (Ang II) receptor type AT1 have suggested that interaction between the two highly conserved residues, Tyr292 in the 7th transmembrane domain (TMD) and the Asp74 in the 2nd TMD, is critical for linking the Ang II binding and AT1 receptor-Gq protein coupling. In the Ang II receptor type AT2, the Asp is conserved (Asp90 in 2nd TMD), however, there is no Tyr residue in the 7th TMD and Phe308 occupies the analogous position to Tyr292 of the AT1. Replacing this Phe308 with Ala reduced receptor affinity to peptidic ligands (125)I-Ang II (K(d) = 0.37 nM) and (125)I-CGP42112A (K(d) = 0.56 nM), but retained the ability of the AT2 to reduce cGMP levels in Xenopus oocytes. Thus, the Phe308 of the AT2 does not mimic the role of Tyr292 of the AT1 in the receptor activation upon Ang II binding. We have also shown that the M8 mutant of the AT2 with the 7th TMD similar to that of wild type AT2 can couple to PLC like the AT1 and bind the AT2-specific ligands with high affinity. Since the Ang II is shown to bind to both the AT1 and the AT2 in an identical manner, we propose that the absence of Tyr in the 7th TMD of the AT2 does not prevent the receptor from coupling to Gq-protein, rather may contribute to the freedom of the AT2 to couple to trimeric G-proteins in both G- betagamma dependent and independent manners upon Ang II binding.
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PMID:Role of Phe308 in the seventh transmembrane domain of the AT2 receptor in ligand binding and signaling. 1519 86

We studied renal AT1 and AT2 receptors in male, female, ovariectomized and ovariectomized-estrogen-treated Wistar-Hanover and Wistar-Kyoto rats. AT1 receptors and AT1A receptor mRNA predominated, with no significant differences between males and females. AT2 receptor expression was restricted in female rats to the capsule, the transition zone between outer and inner medulla, the endothelium lining the papilla, and arcuate arteries and veins. There were no AT2 receptors in male rats, while male mice express substantial numbers of estrogen-dependent AT2 receptors. Arcuate arteries and veins expressed AT1B mRNA in males and females, and AT2 mRNA in females only. AT1 receptor and AT2 receptor expression were estrogen-dependent, with increases in AT1 and AT2 receptor expression after estrogen treatment in ovariectomized rats. Estrogen treatment increased prostaglandin E2 (PGE2) and cGMP concentrations in the renal medulla, and eNOS expression in cortical arteries. In rodents, expression of renal Angiotensin II receptor types is estrogen-dependent, with significant species, strain and area differences. Our results support an important role for AT2 receptors in the regulation of renal function and in the protective effects of estrogen in the kidney.
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PMID:Estrogen upregulates renal angiotensin II AT1 and AT2 receptors in the rat. 1554 36

It has been suggested that low concentrations of angiotensin II cause vasoconstriction, whereas high concentrations evoke vasodilation. Thus, this work aimed to characterize functionally the mechanisms underlying angiotensin II-induced relaxation, at high concentration, in isolated rat aortic rings. Vascular reactivity experiments, using standard muscle bath procedures, showed that angiotensin II (1-30 microM) concentration-dependently induces relaxation of phenylephrine-precontracted rings with intact or denuded endothelium. The relaxation was not altered in the presence of ethylenediamine tetraacetic acid (EDTA), a nonselective inhibitor of metalloprotease. The selective antagonist of AT2 receptors, PD123319, inhibited angiotensin II-induced relaxation. Conversely, losartan or A-779, selective AT1 and Ang1-7 receptor antagonists, respectively, did not alter the relaxation induced by angiotensin II. HOE-140, a selective antagonist of the bradykinin B2 receptor, and amiloride, a Na+/H+ exchanger inhibitor, abolished angiotensin II-induced relaxation. Administration of exogenous bradykinin on precontracted tissues produced concentration-dependent relaxation, which was also inhibited by HOE-140. Preincubation of denuded-rings with NG-nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), indomethacin, or tetraethylammonium (TEA) reduced angiotensin II-induced relaxation. The combination of L-NAME, indomethacin, and TEA completely abolished the relaxation induced by angiotensin II. 4-Aminopyridine (4-AP) as well as charybdotoxin reduced angiotensin II-induced relaxation. On the other hand, neither apamin nor glibenclamide altered the relaxation induced by angiotensin II. The major new finding of this work is that it demonstrated functionally the existence of AT2 receptors located on smooth muscle of rat aortic rings that mediated vasorelaxation via stimulation of B2 receptors by bradykinin, which in turns results in the activation of the NO-cGMP pathway, vasodilator cyclooxygenase product(s), and voltage-dependent and Ca+-activated large-conductance K+ channels.
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PMID:Mechanisms underlying the endothelium-independent relaxation induced by angiotensin II in rat aorta. 1565 62

To evaluate the role of vascular angiotensin II (Ang II) type 2 (AT2) receptor in renovascular hypertension, we investigated expressions of AT2 receptor and endothelial nitric oxide synthase (eNOS) in thoracic aortas of mice with 2-kidney, 1-clip (2K1C) hypertension. The mRNA levels of AT2 receptor in aortas, but not those of AT1 and bradykinin B2 receptors, increased 14 days but not 42 days after clipping. The contractile response to Ang II (>0.1 micromol/L) was attenuated in aortic rings excised 14 days after clipping and was restored to that of rings from sham mice by antagonists of AT2 receptor (PD123319) and B2 receptor (icatibant). The aortic levels of total eNOS, phosphorylated eNOS at Ser1177 (p-eNOS), total Akt, and phosphorylated Akt at Ser473 (p-Akt) were increased in 2K1C mice on day 14, whereas only eNOS levels were increased on day 42. The aortic cGMP levels were 20-fold greater in 2K1C mice on day 14 compared with sham mice. Administration of nicardipine for 4 days before the excision of aortas 14 days after clipping not only reduced blood pressure but also decreased the aortic levels of eNOS, p-eNOS, Akt, p-Akt, and cGMP to sham levels, whereas the administration of PD123319 or icatibant to 2K1C mice decreased p-eNOS and cGMP to sham levels without affecting blood pressure and the levels of eNOS, Akt and p-Akt. These results suggest that vascular NO production is enhanced by increased eNOS phosphorylation via the activation of AT2 receptors in the course of 2K1C hypertension.
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PMID:Angiotensin type 2 receptor-mediated phosphorylation of eNOS in the aortas of mice with 2-kidney, 1-clip hypertension. 1583 34

Angiotensin II elicits pial artery dilation by activating angiotensin AT1 and angiotensin AT2 receptors. This study determined if vasodilatation in response to angiotensin AT2 receptor activation is due to stimulated release of nitric oxide (NO) in newborn pigs equipped with a closed cranial window. Angiotensin II (10(-8), 10(-6) M) elicited pial artery dilatation that was unchanged by the NO synthase inhibitor N omega-Nitro-L-Arginine (L-NNA) (10(-6) M) (12+/-3 and 18+/-2 versus 12+/-3 and 21+/-4%). Angiotensin II was not associated with changes in artificial cerebrospinal fluid (CSF) cGMP concentration, an indicator of NO release. Similar data were obtained for the angiotensin AT1 receptor agonist L 162,313. In contrast, the angiotensin AT2 receptor agonist CGP 42112A (10(-8), 10(-6) M) induced vasodilatation that was blocked by L-NNA (9+/-2 and 18+/-3 versus 1+/-1 and 1+/-1%). CGP 42112A dilatation was associated with elevated artificial CSF cGMP concentration (757+/-18, 1590+/-89, and 2101+/-116 fmol/ml) and such stimulated release was blocked by L-NNA. These data indicate that stimulated NO release contributes to angiotensin AT2 but not angiotensin AT1 induced vasodilatation. These data suggest that angiotensin II primarily elicits dilatation via angiotensin AT1 receptor activation.
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PMID:Nitric oxide contributes to AT2 but not AT1 angiotensin II receptor-mediated vasodilatation of porcine pial arteries and arterioles. 1625 81

Angiotensin II AT2 receptors act as a functional antagonist for the AT1 receptors in various tissues. We previously reported that activation of the renal AT2 receptors promotes natriuresis and diuresis; however, the mechanism is not known. The present study was designed to investigate whether activation of AT2 receptors affects the activity of Na+-K+-ATPase (NKA), an active tubular sodium transporter, in the proximal tubules isolated from Sprague-Dawley rats. The AT2 receptor agonist CGP-42112 (10(-10)-10(-7) M) produced a dose-dependent inhibition of NKA activity (9-38%); the inhibition was attenuated by the presence of the AT2 receptor antagonist PD-123319 (1 microM), suggesting the involvement of the AT2 receptors. The AT1 receptor antagonist losartan (1 microM) did not affect the CGP-42112 (100 nM)-induced inhibition of NKA activity. The presence of guanylyl cyclase inhibitor ODQ (10 microM) and the nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 100 microM) abolished the CGP-42112 (100 nM)-induced NKA inhibition. ANG II (100 nM), in the presence of losartan, significantly inhibited NKA activity; the inhibition was attenuated by PD-123319. CGP-42112 also, in a dose-dependent manner, stimulated NO production (approximately 0-230%) and cGMP accumulation (approximately 25-100%). The CGP-42112 (100 nM)-induced NO and cGMP increases were abolished by the AT2 receptor antagonist PD-123319, ODQ, and L-NAME. The data suggest that the activation of the AT2 receptor via stimulation of the NO/cGMP pathway causes inhibition of NKA activity in the proximal tubules. This phenomenon provides a plausible mechanism responsible for the AT2 receptor-mediated natriuresis-diuresis in rodents.
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PMID:Angiotensin II AT2 receptors inhibit proximal tubular Na+-K+-ATPase activity via a NO/cGMP-dependent pathway. 1638 Apr 64

It has been suggested that low concentrations of angiotensin II cause vasoconstriction whereas high concentrations evoke vasodilation. Thus, this work aimed to functionally characterize the mechanisms underlying the relaxation induced by angiotensin II at high concentrations in isolated rat carotid rings. Experiments using standard muscle bath procedures showed that angiotensin II (0.01-3 microM) concentration dependently induces relaxation of phenylephrine-pre-contracted rings. No differences between intact or denuded endothelium were found. The angiotensin II-induced relaxation was strongly inhibited by saralasin, the non-selective antagonist of angiotensin II receptors but not by the selective antagonists of AT1 and AT2 receptors, losartan and PD123319, respectively. However, A-779, a selective angiotensin-(1-7) receptor antagonist, reduced the relaxation induced by angiotensin II. Administration of exogenous angiotensin-(1-7) on pre-contracted tissues produced concentration-dependent relaxation, which was also inhibited by A-779. HOE-140, the selective antagonist of the bradykinin in B2 receptor did not produce any significant effect on angiotensin II-induced relaxation. Pre-incubation of denuded-rings with N G-nitro-L-arginine methyl ester (L-NAME) or 1H-[1,2,4] Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced angiotensin II-induced relaxation. On the other hand, neither indomethacin nor tetraethylammonium (TEA) produced any significant effect. The major new finding of this work is that high concentrations of angiotensin II induce relaxation of the rat carotid via activation of the NO-cGMP pathway through a mechanism that seems to be partially dependent on activation of angiotensin-(1-7) receptors.
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PMID:Analysis of the mechanisms underlying the vasorelaxant action of angiotensin II in the isolated rat carotid. 1638 63

The molecular mechanisms involved in the Ang-(1-7) [angiotensin-(1-7)] effect on sodium renal excretion remain to be determined. In a previous study, we showed that Ang-(1-7) has a biphasic effect on the proximal tubule Na+-ATPase activity, with the stimulatory effect mediated by the AT1 receptor. In the present study, we investigated the molecular mechanisms involved in the inhibition of the Na+-ATPase by Ang-(1-7). All experiments were carried out in the presence of 0.1 nM losartan to block the AT1 receptor-mediated stimulation. In this condition, Ang-(1-7) at 0.1 nM inhibited the Na+-ATPase activity of the proximal tubule by 54%. This effect was reversed by 10 nM PD123319, a specific antagonist of the AT2 receptor, and by 1 muM GDP[beta-S] (guanosine 5'-[beta-thio]diphosphate), an inhibitor of G protein. Ang-(1-7) at 0.1 M induced [35S]GTP[S] (guanosine 5'-[gamma-[35S]thio]triphosphate) binding and 1 mug/ml pertussis toxin, an inhibitor of G(i/o) protein, reversed the Ang-(1-7) effect. Furthermore, it was observed that the inhibitory effect of Ang-(1-7) on the Na+-ATPase activity was completely reversed by 0.1 microM LY83583, an inhibitor of guanylate cyclase, and by 2 muM KT5823, a PKG (protein kinase G) inhibitor, and was mimicked by 10 nM d-cGMP (dibutyryl cGMP). Ang-(1-7) increased the PKG activity by 152% and this effect was abolished by 10 nM PD123319 and 0.1 microM LY83583. Taken together, these data indicate that Ang-(1-7) inhibits the proximal tubule Na+-ATPase by interaction with the AT2 receptor that subsequently activates the G(i/o) protein/cGMP/PKG pathway.
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PMID:Involvement of the Gi/o/cGMP/PKG pathway in the AT2-mediated inhibition of outer cortex proximal tubule Na+-ATPase by Ang-(1-7). 1639 Mar 32

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