Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The hexapeptide angiotensin (ANG) IV, a metabolic product of ANG II, has been reported to play a functional role in the regulation of blood flow in extrapulmonary tissues. Here, we demonstrate that ANG IV-specific (AT4) receptors are present in porcine pulmonary arterial endothelial cells (PAECs) and that the binding of ANG IV to AT4 receptors can be blocked by its antagonist divalinal ANG IV but not by the ANG II-, AT1-, and AT2-receptor blockers [Sar1,Ile8]ANG II, losartan, and PD-123177, respectively. ANG IV significantly increased endothelial cell constitutive nitric oxide synthase (ecNOS) activity (P < 0.05) as well as cellular cGMP content (P < 0. 001). Western blot analysis revealed that ecNOS protein expression was comparable in control and ANG IV-stimulated cells. Divalinal ANG IV but not [Sar1,Ile8]ANG II, losartan, or PD-123177 inhibited the ANG II- and ANG IV-stimulated increases in ecNOS activity and cGMP content in PAECs. Incubation in the presence of N-nitro-L-arginine methyl ester (L-NAME) or methylene blue but not of indomethacin significantly diminished ANG IV-stimulated as well as basal levels of cGMP (P < 0.001). Similarly, in situ studies with precontracted porcine pulmonary arterial rings showed that ANG IV caused an endothelium-dependent relaxation that was blocked by L-NAME or methylene blue. Collectively, these results demonstrate that ANG IV binds to AT4 receptors, activates ecNOS by posttranscriptional modulation, stimulates cGMP accumulation in PAECs, and causes pulmonary arterial vasodilation, suggesting that ANG IV plays a role in the regulation of blood flow in the pulmonary circulation.
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PMID:Angiotensin IV receptor-mediated activation of lung endothelial NOS is associated with vasorelaxation. 984 42

Nitric Oxide (NO) is a gas that diffuses freely through membranes of target cells to activate cGMP formation. NO is synthesised from arginine, by a family of Nitric Oxide Synthase (NOS). In the brain, NO influences synaptic plasticity, apoptosis and development. It has been recently shown that angiotensin II (Ang II) could mediate NO production by its two types of receptors, AT1 and AT2. Since we have shown that Ang II, via the AT2 receptor could induce neurite outgrowth and morphological differentiation of NG108-15 cells, the aim of the study was to investigate if NO could be one of the second messengers involved in the Ang II effect. Using the Griess colorimetric assay, we found that Ang II, by its AT2 receptor, induced nitrite formation from NO. This effect was abolished by the N-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor. We also found that treatment of the cells with S-nitroso-N-acetylpenicillamine (SNAP), an exogenous source of NO, induced the same morphological differentiation. These results demonstrate that the morphological differentiation induced by the AT2 receptor is partly due to an increase in NO production.
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PMID:Nitric oxide, a new second messenger involved in the action of angiotensin II on neuronal differentiation of NG108-15 cells. 988 14

1. Human isolated subcutaneous arteries were studied under isometric conditions in a myograph. 2. Addition of angiotensin II (AII) induced a concentration-dependent increase in tone in isolated arteries. The active metabolite of candesartan (CV 11974), losartan and the active metabolite of losartan, E-3174 antagonized AII-induced tone in a non-competitive manner, but the AT2 selective antagonist, PD123319, was without effect on responses to AII. The effects of candesartan, losartan and E-3174 were analysed using a classical model of non-competitive antagonism and a two-state receptor model. 3. Mechanical removal of the endothelium; pre-incubation with Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME); pre-incubation with indomethacin, a cyclo-oxygenase inhibitor; or pre-incubation with BQ 485, an endothelin antagonist; had no significant effect on contractions induced by AII. 4. Our results suggest AII contracts human isolated resistance arteries by an action on AT1 receptors and does not involve release of endothelial factors. Use of a two-state receptor model successfully described the action of the AT1 antagonists without sacrificing assumptions regarding the competitive nature of binding of these antagonists.
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PMID:Action of AT1 receptor antagonists on angiotensin II-induced tone in human isolated subcutaneous resistance arteries. 1048 19

1. Renal vasoconstriction in response to angiotensin II (ANGII) is known to be modulated by nitric oxide (NO). Since shear stress stimulates the release of a variety of vasoactive compounds from endothelial cells, we studied the impact of shear stress on the haemodynamic effect of ANGII in isolated perfused kidneys of rats under control conditions and during NO synthase inhibition with L-NAME (100 microM). 2. Kidneys were perfused in the presence of cyclo-oxygenase inhibitor (10 microM indomethacin) with Tyrode's solution of relative viscosity zeta=1 (low viscosity perfusate, LVP) or, in order to augment shear stress, with Tyrode's solution containing 7% Ficoll 70 of relative viscosity zeta=2 (high viscosity perfusate, HVP). 3. Vascular conductance was 3.5+/-0.4 fold larger in HVP as compared with LVP kidneys, associated with an augmentation of overall wall shear stress by 37+/-5%. During NO inhibition, vascular conductance was only 2.5+/-0.2 fold elevated in HVP vs LVP kidneys, demonstrating shear stress-induced vasodilatation by NO and non-NO/non-prostanoid compound(s). 4. ANGII (10 - 100 pM) constricted the vasculature in LVP kidneys, but was without effect in HVP kidneys. During NO inhibition, in contrast, ANGII vasoconstriction was potentiated in HVP as compared with LVP kidneys. 5. The potentiation of ANGII vasoconstriction during NO inhibition has been shown to be mediated by endothelium-derived P450 metabolites and to be sensitive to AT2 receptor blockade in our earlier studies. Accordingly, in HVP kidneys, increasing concentrations of the AT2 receptor antagonist PD123319 (5 and 500 nM) gradually abolished the potentiation of ANGII vasoconstriction during NO inhibition, but did not affect vasoconstriction in response to ANGII in LVP kidneys. 6. Our results demonstrate, that augmentation of shear stress by increasing perfusate viscosity induces vasodilatation in the rat kidney, which is partially mediated by NO. Elevated levels of shear stress attenuate renal ANGII vasoconstriction through enhanced NO production and are required for AT2 sensitive potentiation during NO inhibition.
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PMID:Role of shear stress in nitric oxide-dependent modulation of renal angiotensin II vasoconstriction. 1048 26

Angiotensin II (Ang II) is a potent vasopressor peptide that interacts with 2 major receptor isoforms - AT1 and AT2. Although blood pressure is increased in AT2 knockout mice, the underlying mechanisms remain undefined because of the low levels of expression of AT2 in the vasculature. Here we overexpressed AT2 in vascular smooth muscle (VSM) cells in transgenic (TG) mice. Aortic AT1 was not affected by overexpression of AT2. Chronic infusion of Ang II into AT2-TG mice completely abolished the AT1-mediated pressor effect, which was blocked by inhibitors of bradykinin type 2 receptor (icatibant) and nitric oxide (NO) synthase (L-NAME). Aortic explants from TG mice showed greatly increased cGMP production and diminished Ang II-induced vascular constriction. Removal of endothelium or treatment with icatibant and L-NAME abolished these AT2-mediated effects. AT2 blocked the amiloride-sensitive Na(+)/H(+) exchanger, promoting intracellular acidosis in VSM cells and activating kininogenases. The resulting enhancement of aortic kinin formation in TG mice was not affected by removal of endothelium. Our results suggest that AT2 in aortic VSM cells stimulates the production of bradykinin, which stimulates the NO/cGMP system in a paracrine manner to promote vasodilation. Selective stimulation of AT2 in the presence of AT1 antagonists is predicted to have a beneficial clinical effect in controlling blood pressure.
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PMID:Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. 1052 37

Although accumulating lines of evidence indicate the proangiogenic role of angiotensin II (Ang II), little is known about the molecular mechanisms associated with such an effect. This study aimed to identify molecular events involved in Ang II-induced angiogenesis in the Matrigel model in mice. C57Bl/6 female mice received a subcutaneous injection of either Matrigel or Matrigel with Ang II (10(-7) M) alone, with Ang II and an AT1 receptor antagonist (candesartan, 10(-6) M), or with Ang II and AT2 receptor antagonist (PD123319, 10(-6) M). After 14 days, angiogenesis was assessed in the Matrigel-plug by histological evaluation and cellular counting. Ang II increased by 1.9-fold the number of cells within the Matrigel (p < 0.01 versus control). Immunohistological analysis revealed the presence of macrophages, endothelial and smooth muscle cells, and the development of vascular-like structure. Such an angiogenic effect was associated with an increase in vascular endothelial growth factor (VEGF) (1.5-fold, p < 0.01), endothelial nitric oxide (eNOS) (1.7-fold, p < 0.01), and cyclooxygenase-2 (1.4-fold, p < 0.05) protein levels measured by Western blotting. Conversely, Ang II treatment did not affect MMP-9 and MMP-2 activity, assessed by zymography. Blockade of AT1 receptor completely prevented the Ang II-induced angiogenesis and protein regulations, whereas that of AT2 was ineffective. Administration of VEGF neutralizing antibody (2.5 microg ip twice a week) and cyclooxygenase-2 selective inhibitor (nimesulide, 30 mg/L) also hampered Ang II proangiogenic effect. In addition, Ang II-induced cell ingrowth was impaired by treatment with nitric oxide synthase inhibitor (L-NAME, 10 mg/kg/day) and in eNOS-deficient mice. Therefore, in an in vivo model, Ang II induced angiogenesis through AT1 receptor, which involved activation of VEGF/eNOS-related pathway and of the inflammatory process.
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PMID:Angiotensin II angiogenic effect in vivo involves vascular endothelial growth factor- and inflammation-related pathways. 1206 85

We have previously demonstrated that stimulation of the angiotensin (Ang) II type 2 receptor in vascular smooth muscle cells caused bradykinin production by activating kininogenase in transgenic mice. The aim of this study was to determine whether overexpression of AT2 receptors in cardiomyocytes attenuates Ang II-induced cardiomyocyte hypertrophy or interstitial fibrosis through a kinin/nitric oxide (NO)-dependent mechanism in mice. Ang II (1.4 mg/kg per day) or vehicle was subcutaneously infused into transgenic mice and wild-type mice for 14 days. The amount of cardiac AT2 receptor relative to AT1 receptor in transgenic mice was 22% to 37%. Ang II caused similar elevations in systolic blood pressure (by approximately 45 mm Hg) in transgenic mice and wild-type mice. Myocyte hypertrophy assessed by an increase in myocyte cross-sectional area, left ventricular mass, and atrial natriuretic peptide mRNA levels were similar in transgenic and wild-type mice. Ang II induced prominent perivascular fibrosis of the intramuscular coronary arteries, the extent of which was significantly less in transgenic mice than in wild-type mice. Inhibition of perivascular fibrosis in transgenic mice was abolished by cotreatment with HOE140, a bradykinin B2 receptor antagonist, or L-NAME, an inhibitor of NO synthase. Cardiac kininogenase activity was markedly increased (approximately 2.6-fold, P<0.001) after Ang II infusion in transgenic mice but not in wild-type mice. Immunohistochemistry indicated that both bradykinin B2 receptors and endothelial NO synthase were expressed in the vascular endothelium, whereas only B2 receptors were present in fibroblasts. These results suggest that stimulation of AT2 receptors present in cardiomyocytes attenuates perivascular fibrosis by a kinin/NO-dependent mechanism. However, the effect on the development of cardiomyocyte hypertrophy was not detected in this experimental setting.
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PMID:Cardiac angiotensin II type 2 receptor activates the kinin/NO system and inhibits fibrosis. 1251 37

To examine the possible role of the bradykinin-NO system in the action of ACE inhibitors, we studied the effects of imidapril, an ACE inhibitor, on inflammatory vascular injury by using AT1a-receptor-deficient (AT1aKO) mice. A polyethylene cuff was placed around the femoral artery of AT1aKO mice and wild-type (WT; C57BL/6J) mice. Neointimal area in cross sections of the artery was measured 14 days after cuff placement. A low dose of imidapril (1 mg/kg per day), which did not affect blood pressure, was administered by gavage. Expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha was detected by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR) 7 days after the operation. Neointimal formation, vascular smooth muscle cell proliferation, and expression of MCP-1 and TNF-alpha were attenuated in the injured artery in AT1aKO mice compared with those in WT mice. Imidapril inhibited neointimal formation, DNA synthesis of vascular smooth muscle cells, and expression of MCP-1 and TNF-alpha in AT1aKO mice as well as in WT mice. In addition, imidapril increased tissue cGMP content after cuff placement. These inhibitory effects of imidapril were significantly reduced or abolished by a bradykinin receptor antagonist, Hoechst 140, or an NO synthase inhibitor, L-NAME, both in WT and AT1aKO mice. Treatment with imidapril did not change AT2 receptor and ACE expression detected by RT-PCR in the injured artery. These results indicate that not only blockade of angiotensin II production but also activation of the bradykinin-NO system plays an important role in the beneficial effects of imidapril on vascular remodeling.
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PMID:Important role of nitric oxide in the effect of angiotensin-converting enzyme inhibitor imidapril on vascular injury. 1296 79

Angiotensin II signals via at least two receptors termed AT1 and AT2. The function of the AT1 receptor is well defined, while that of the AT2 receptor is still shrouded in uncertainty. AT2 gene-deficient (-/-) mice have been helpful in unravelling the function of the AT2 receptor. We have studied AT2-/- and AT2+/+ mice with classical physiological techniques developed for the rat. We found that although AT2-/- mice have normal glomerular filtration rate, the pressure-natriuresis relationship in these mice, compared with AT2+/+ mice, is shifted rightward. Moreover, medullary blood flow fails to increase with increased perfusion pressure while the AT1 receptor expression in the kidneys is increased. We used telemetry and found that AT2-/- mice have about 10 mmHg higher blood pressures than AT2+/+ mice and that their circadian rhythm is disturbed. Moreover, their baroreflexes, as measured by spectral analyses, differs from AT2+/+ controls. The cardiac function of AT2-/- mice is remarkably preserved and the differences are subtle. However, if the mice are given l-NAME hypertension, they exhibit an end-systolic pressure-volume relationship that reveals decreased contractility and probable increased vascular stiffness. Furthermore, the hearts of AT2-/- mice hypertrophy more in response to l-NAME than those of AT2+/+ mice and perivascular fibrosis is increased. DOCA-salt treatment also shows a more rightward pressure-natriuresis relationship in AT2-/- compared with AT2+/+ mice. The renal iNOS expression is increased with DOCA-salt treatment. Our findings support the notion that the AT2 receptor signals antiproliferative and antifibrotic effects and that its presence results in lower blood pressures and lesser responses to secondary forms of hypertension. Technical advances that have allowed us to adapt methods for the rat to the much smaller mouse have facilitated our studies.
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PMID:Insights into angiotensin II receptor function through AT2 receptor knockout mice. 1528 62

The rabbit carotid artery, injured by silicone collar, presents a perivascular inflammatory response and alterations in vascular responsiveness. Considering that angiotensin II (Ang II) plays an important role in cardiovascular physiology and pathology and that cardiovascular disease increases in postmenopausal women, the aim of this study was to investigate whether the Ang II contractile response in ovariectomized rat carotid artery is modified after a vascular injury by silicone collar. The positioning of the silicone collar around the common carotid artery for 14 days leads to an increased cross-sectional area of adventitial layer with inflammatory cells and an extensive angiogenesis. The Ang II-induced contraction was significantly decreased in collared arteries when compared with contralateral arteries. The reduction in the constrictor effect of Ang II in collared arteries was not modified by the presence of indomethacin (a non-selective inhibitor of cyclooxygenase) or PD 123,319 (a selective antagonist of the Ang II AT2 receptor). Moreover, while endothelium removal induced an increase in the Ang II responsiveness of both arteries (collared and contralateral), the Emax induced by Ang II was still lower in collared arteries. However, the "in vitro" pretreatment of the arteries with an inhibitor of nitric oxide synthase enzyme (L-NAME) significantly enhanced the maximal contractions response to Ang II only in injured arteries. Furthermore, the expression of iNOS (inducible nitric oxide synthase) was observed in the adventitial layer of collared arteries, indicating that the NO formed in the adventitial layer has an important role in injured arteries. Moreover, our data show impairment of extracellular calcium mobilization, mediated by Ang II, in the collared artery, although the intracellular calcium mobilization was not modified by the injury. In conclusion, the increased production of NO and a decrease in the calcium influx displayed by Ang II in the collared artery appears to counteract and reduce the biologic effect of Ang II.
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PMID:Mechanisms of impaired vascular response to ANG II in perivascular injured carotid arteries of ovariectomized rat. 1547 39


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