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Results for “Receptor, Angiotensin, Type 1”

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At least 19 recordsLinked to original sources
PubMed2001

Differential activation of the STAT pathway by angiotensin II via angiotensin type 1 and type 2 receptors in cultured human fetal mesangial cells.

The vasoactive peptide angiotensin II is the principal effector of the renin-angiotensin system. It exerts mitogenic and growth-inhibiting effects in many target tissues, including renal mesangial cells. To investigate mechanisms of angiotensin II signaling in human mesangial cells, we explored the signal transducer and activator of transcription (STAT) pathway as a possible regulator of angiotensin II receptor-specific signaling. We tested whether angiotensin II could induce STAT activation and nuclear translocation of STAT proteins in human mesangial cells by electromobility shift assays and by immunostaining and confocal microscopy. We found that fetal human mesangial cells express STAT1,2,3,5, and 6 and that stimulation of these cells by angiotensin II results in rapid induction of STAT1 and STAT5 DNA-binding activity. This DNA-binding activity was identified as STAT5 for angiotensin receptor type 1 activation and STAT1 for angiotensin receptor type 2-mediated activation, as induction of STAT-DNA binding by angiotensin II could be differentially blocked by the angiotensin receptor type 1 blocker losartan and by angiotensin II receptor type 2 blocker PD 123,319. Angiotensin II also induced STAT1 and STAT5 tyrosine phosphorylation and nuclear translocation of activated STATs in a receptor subtype-specific manner. STAT activation thus appears to provide an important signaling pathway for angiotensin II-induced cellular responses.

Angiotensin II↗
PubMed1997

Enhancement by exogenous and locally generated angiotensin II of purinergic neurotransmission via angiotensin type 1 receptor in the guinea-pig isolated mesenteric artery.

1. Angiotensin II is known to enhance sympathetic neurotransmission in the vasculature by increasing the release of noradrenaline, but little is known about the effect on the co-released transmitter, adenosine 5'-triphosphate (ATP). In the present study we have examined the effect of angiotensin II on the excitatory junction potential (e.j.p.) elicited by repetitive field stimulation in the guinea-pig isolated mesenteric artery, to establish the angiotensin II receptor subtype involved in modulating the release of ATP and the role of the endothelium in converting angiotensin I to angiotensin II. 2. Suramin (300 microM), a P2 purinoceptor antagonist, abolished both the e.j.p.s and depolarizing response to alpha,beta-methylene-ATP, a stable analogue of ATP, without affecting the resting membrane potential and noradrenaline-induced depolarization. 3. Angiotensin II (0.1 microM) affected neither the resting membrane potential nor the amplitude of the first e.j.p., but increased the amplitudes of the subsequent e.j.p.s. This enhancing effect of angiotensin II was abolished by CV-11974 (0.1 microM), an angiotensin II type 1 (AT1) receptor antagonist, but unaffected by PD 123319 (1 microM), an angiotensin II type 2 (AT2) receptor antagonist, or CGP 42112A (1 microM), AT2 receptor ligand. 4. Angiotensin I (0.1 microM) exerted a similar effect on e.j.p.s to that of angiotensin II. CV-11974 (0.1 microM) or temocaprilat (10 microM), an angiotensin converting enzyme (ACE) inhibitor, abolished the effect of angiotensin I. Removal of the endothelium did not alter the action of angiotensin I. 5. The results of the present study indicate that the release of ATP from sympathetic nerves innervating the guinea-pig isolated mesenteric artery, as determined from the magnitude of the e.j.p., can be enhanced by angiotensin II via activation of prejunctional AT1 receptors. Qualitatively similar effects were observed with angiotensin I, which appears to be converted into angiotensin II by a subendothelial process.

Adenosine Triphosphate↗
PubMed2003

Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor.

Angiotensin II type 1 (AT1) receptor activation as well as proinflammatory cytokines such as interleukin-6 (IL-6) are involved in the development and progression of atherosclerosis. The detailed underlying mechanisms including interactions between inflammatory agonists and the renin-angiotensin system are poorly understood. Stimulation of cultured rat aortic vascular smooth muscle cells (VSMCs) with IL-6 led to upregulation of AT1 receptor mRNA and protein expression, as assessed by Northern and Western blot experiments. Nuclear run-on and transcription blockade experiments showed that IL-6 increases AT1 receptor mRNA de novo synthesis but not mRNA stability. Preincubation of VSMCs with IL-6 resulted in an enhanced angiotensin II-induced production of reactive oxygen species, as assessed by DCF fluorescence laser microscopy. Treatment of C57BL/6J mice with IL-6 for 18 days increased vascular AT1 receptor expression (real-time RT-PCR) and angiotensin II-induced vasoconstriction, enhanced vascular superoxide production (L-012 chemiluminescence, DHE fluorescence), and impaired endothelium-dependent vasodilatation. These effects were completely omitted in AT1 receptor knockout mice (AT1A-/- mice). Upregulation of vascular AT1 receptor expression in vitro and in vivo is decisively involved in IL-6-induced propagation of oxidative stress and endothelial dysfunction. This interaction of the proinflammatory cytokine IL-6 with the renin-angiotensin system may represent an important pathogenetic mechanism in the atherosclerotic process.

Animals↗
PubMed2003

Estrogen regulates adrenal angiotensin type 1 receptors by modulating adrenal angiotensin levels.

Estrogen inhibits adrenal angiotensin type 1 receptor (AT(1)R) binding sites and attenuates the adrenal responsivity to angiotensin II (Ang II). Ang II modulates AT(1)R expression. Here, we determined if estrogen-induced down-regulation of adrenal AT(1)Rs involves modulation of adrenal Ang II. Female rats were ovariectomized (OVX) and injected with 17beta-estradiol benzoate (E(2); 40 micro g/kg) or vehicle for 7 d. Adrenal Ang II was separated from other angiotensin peptides by HPLC and measured by RIA. Scatchard analysis of radioligand binding curves showed that E(2) or captopril (Cap; 0.5 g/liter water) significantly reduced adrenal AT(1)R binding (maximum binding capacity) by 22% and 19%, respectively, compared with OVX (276 +/- 2.09 fmol/mg protein). E(2) and Cap lowered adrenal Ang II levels by 39% and 21%, respectively, compared with OVX (4.10 +/- 0.44 pmol/g). E(2) caused no further reductions in adrenal AT(1)R binding or in Ang II levels in Cap-treated OVX rats. High-dose Ang II infusion (1000 ng/kg.min) increased adrenal Ang II levels by 71% and lowered AT(1)R binding by 18%. Under these infusion conditions, E(2) did not reduce adrenal Ang II or AT(1)R binding. No differences in AT(1)R affinity (dissociation constant) were observed among groups. These data suggest that E(2) regulates the number of adrenal AT(1)R binding sites indirectly by modulating adrenal Ang II.

Adrenal Glands↗
PubMed2002

Angiotensin II increases intracellular calcium concentration in pig endometrial stromal cells through type 1 angiotensin receptors, but does not stimulate phospholipase C activity or prostaglandin F2alpha secretion.

Although the presence of endometrial receptors for angiotensin (Ang) II has been demonstrated, a specific function for AngII in the uterus has not been identified. Cytosolic free Ca2+ concentration [Ca2+]i, phospholipase C (PLC) activity and prostaglandin (PG) F2alpha secretion in response to AngII and oxytocin (OT) were measured in pig endometrial stromal cells collected 16 days after oestrus. Treatment with 100 nM OT or AngII increased (P<0.001) [Ca2+]i in stromal cells similarly (720 +/- 34 v. 690 +/- 33 pM, respectively). Subsequent administration of OT or AngII to the same cells induced smaller [Ca2+]i increases (25% or 35% of the initial responses, respectively) that occurred only if the second exposure to the same agent took place at least 5 min after the first. When administered sequentially, OT and AngII each induced a full response within 1 min of the previous treatment, regardless of which peptide was applied first. Whereas OT increased PLC activity and PGF2alpha secretion in stromal cells (P<0.01), AngII did not increase either PLC activity or PGF2alpha secretion. Type I AngII (AT1) receptors were present on stromal cells, whereas AT2 receptors were absent. Therefore, the effect of AngII in stromal cells was mediated via AT1 receptors. That AngII increased [Ca2+]i in stromal cells, but did not increase PLC or PGF2alpha secretion, indicates that either AngII releases a pool of Ca2+ through a mechanism that is not mediated by PLC and is not involved in PGF2alpha secretion or that a mechanism for PGF2alpha production other than one involving Ca2+ may exist.

Angiotensin II↗
PubMed1995

Mapping of G protein coupling sites of the angiotensin II type 1 receptor.

Angiotensin II type 1 (AT1) receptors have been identified in a wide variety of tissues, including the kidney, liver, adrenal gland, cardiovascular system, and brain. AT1 receptors also mediate complex signaling mechanisms that elicit a diversity of specific physiological effects. The rat AT1A receptor has seven transmembrane domains and couples with three distinct G proteins: Gq, Gi, and Go. But it is unknown which domains of AT1A couple with and activate each type of G protein. To identify the domains responsible for the activation of various types of G protein, we studied the effect of five different synthetic peptides representing different domains of cytosolic segments of the rat AT1A receptor on the binding of the 35S-labeled stable analogue of GTP, GTP gamma S. Peptides P-3, which is located in the N-terminal region of the putative third intracellular loop of AT1A (residues 216 through 230), and P-5 (residues 306 through 320), corresponding to the N-terminal region of the C-terminal tail, were found to activate purified Gi1, Gi2, and Go proteins. These results indicate that not only the third cytosolic loop but also the C-terminal cytosolic domain of AT1A is important for Gi1, Gi2, and Go protein coupling and activation.

Amino Acid Sequence↗
PubMed2001

Coronary hemodynamic and ventricular responses to angiotensin type 1 receptor inhibition in SHR: interaction with angiotensin type 2 receptors.

This study was designed to determine the effects of angiotensin II type 1 (AT(1)) receptor inhibition on coronary hemodynamics and ventricular mass and hydroxyproline content and the additive effects of angiotensin II type 2 (AT(2)) receptor inhibition in spontaneously hypertensive rats (SHR). The selective AT(1) receptor antagonist candesartan (10 mg/kg per day) was administered alone or in combination with the AT(2) receptor antagonist PD 123319 (50 mg/kg per day) for 12 weeks. Control SHR received placebo for the same period. Left and right ventricular coronary blood flow, blood flow reserve, and minimal coronary vascular resistance were determined by using radiomicrospheres in male 35-week-old rats. Mean arterial pressure; total peripheral resistance; left and right ventricular, renal, and aortic weights; and hydroxyproline concentration were also determined. Candesartan reduced mean arterial pressure and left ventricular, renal, and aortic masses, as well as hydroxyproline concentration and minimal coronary vascular resistance of both ventricles. PD 123319 partially prevented the hypotensive effect of AT(1) receptor inhibition and reversed the effect on myocardial hydroxyproline concentration. These data suggest that AT(2) receptors contribute to the hypotensive and antifibrotic effects but not the coronary hemodynamic improvement or reduced left ventricular mass of AT(1) receptor inhibition in these adult SHR.

Angiotensin Receptor Antagonists↗
PubMed2001

Effects of angiotensin-converting enzyme inhibitor and angiotensin type 1 receptor antagonist in deoxycorticosterone acetate-salt hypertensive mice lacking Ren-2 gene.

We previously reported that inhibition of angiotensin-converting enzyme (ACE) prevented the hypertension and left ventricular hypertrophy induced by deoxycorticosterone acetate-salt (DOCA-salt) in 129/SvEvTac mice, which have 2 renin genes (Ren-1 and Ren-2). In the present study, we induced hypertension by uninephrectomy and DOCA-salt in mice having only the Ren-1 gene (C57BL/6J) and investigated the effect of an ACE inhibitor (ramipril, 4 mg. kg(-)(1). d(-)(1)) and an angiotensin type 1 (AT(1)) receptor antagonist (L-158809, 4 mg. kg(-)(1). d(-)(1)) on the development of hypertension, cardiac hypertrophy, and renal injury. After 4 weeks of treatment, systolic blood pressure in DOCA-salt mice was significantly increased (128+/-2 mm Hg) compared with controls (109+/-2 mm Hg) (P:<0.001), while plasma renin concentration was decreased by 97% (P:<0.001). DOCA-salt also induced left ventricular and renal hypertrophy and renal damage as manifested by proteinuria. Collagen content in the left ventricle and kidney was significantly higher in DOCA-salt mice (P:<0.001). Urinary albumin (P:<0.05) and proliferating cell nucleic antigen-positive cells in the tubules and interstitium of the renal cortex (P:<0.001) were significantly increased in the DOCA-salt group. Neither the ACE inhibitor nor the AT(1) antagonist had any antihypertensive effect; however, they partially prevented cardiac hypertrophy and completely inhibited left ventricular collagen deposition. In the kidney, both the ACE inhibitor and AT(1) antagonist partially reduced the increase in collagen but had no effect on hypertrophy. They also significantly prevented the effect of DOCA-salt on urinary albumin and proliferating cell nucleic antigen expression in the kidney. Despite the lack of an antihypertensive effect, both ACE inhibitor and AT(1) antagonist prevented cardiac remodeling and renal damage. Our results indicate that ACE inhibitors and AT(1) antagonists exert beneficial effects on the heart and kidney in DOCA-salt hypertensive mice independently of their effects on blood pressure.

Angiotensin Receptor Antagonists↗
PubMedDate not supplied

Importance of the angiotensin type 1 receptor in angiotensin II-induced bronchoconstriction and bronchial hyperresponsiveness in the guinea pig.

Although angiotensin II (Ang II) causes bronchoconstriction and bronchial hyperresponsiveness to methacholine in mildly asthmatic patients, the responsible mechanisms for these reactions are unclear. The authors examined the effect of intravenous infusion of Ang II on airway constriction in guinea pigs. Furthermore, the effects of subthreshold concentrations of Ang II on bronchial responsiveness to methacholine were investigated. Airway opening pressure (Pao), an index of bronchoconstriction, increased dose dependently after intravenous infusion of 3 and 10 nmol/kg Ang II (72.2 and 236.5 increase above the baseline value, respectively). In another set of experiments, animals received a methacholine inhalation challenge under a constant intravenous infusion of a subthreshold dose of Ang II (2 nmol/kg/min). The Ang II infusion elicited bronchial hyperresponsiveness to methacholine. The provocative concentration of methacholine, which produced a 200% increase above the baseline Pao (PC200), decreased from 306.9 to 156.1 micrograms/mL upon Ang II infusion. Pretreatment with TCV-116, a type 1 Ang II (AT1) receptor antagonist, but not PD123319, a type 2 Ang II (AT2) receptor antagonist, dose dependently prevented both the Ang II-induced bronchoconstriction and bronchial hyperresponsiveness to methacholine. The authors conclude that Ang II caused bronchoconstriction and induced bronchial hyperresponsiveness to methacholine via the AT1 receptors and that this effect did not involve the release of other bronchoactive mediators.

Angiotensin II↗
PubMed2002

Dilatation of cerebral parenchymal vessels mediated by angiotensin type 1 receptor in cats.

We report the effects of angiotensin II (ANG-II), as well as angiotensin II type 1 (AT1) and type 2 receptor antagonists (CV-11974 and PD-123319, respectively) on the cerebral parenchymal microvessels in cats using the photoelectric method. ANG-II continuously and dose-dependently increased the cerebral blood volume (CBV) for 15 min. Maximum CBV increases were +0.36+or-0.11 vol% for 0.01 nmol/kg (P<0.05), +0.51+or-0.24 vol% for 0.1 nmol/kg (P<0.05), +1.87+or-0.55 vol% for 1 nmol/kg (P<0.05), and +2.14+or-0.77 vol% for 10 nmol/kg (P<0.05). Systemic arterial blood pressure increased at only 1 min following ANG-II infusion (1 and 10 nmol/kg). CV-11974 and PD-123319 per se did not change the resting CBV. CV-11974 completely inhibited the vasodilatory action of ANG-II, however, PD-123319 did not block it. We conclude that ANG-II directly dilates the parenchymal vessels through the AT1 receptor without increasing systemic blood pressure, and that intrinsic ANG-II may not be associated with maintenance of resting vascular tone.

Angiotensin II↗
PubMed2002

Residues 293 and 294 are ligand contact points of the human angiotensin type 1 receptor.

The human angiotensin II type 1 receptor (hAT(1)) was photolabeled with a high-affinity radiolabeled photoreactive analogue of AngII, (125)I-[Sar(1), Val(5), p-Benzoyl-L-phenylalanine(8)]AngII ((125)I-[Sar(1),Bpa(8)]AngII). Chemical cleavage with CNBr produced a 7 kDa fragment (285-334) of the C-terminal portion of the hAT(1). Manual Edman radiosequencing of photolabeled, per-acetylated, and CNBr-fragmented receptor showed that ligand incorporation occurred through Phe(293) and Asn(294) within the seventh transmembrane domain of the hAT(1). Receptor mutants with Met introduced at the presumed contact residues, F293M and N294M, were photolabeled and then digested with CNBr. SDS-PAGE analysis of those digested mutant receptors confirmed the contact positions 293 and 294 through ligand release induced by CNBr digestion. Additional receptor mutants with Met residues introduced into the N- and C-terminal proximity of those residues 293 and 294 of the hAT(1) produced, upon photolabeling and CNBr digestion, fragmentation patterns compatible only with the above contact residues. These data indicate that the C-terminal residue of AngII interacts with residues 293 and 294 of the seventh transmembrane domain of the human AT(1) receptor. Taking into account a second receptor-ligand contact at the second extracellular loop and residue 3 of AngII (Boucard, A. A., Wilkes, B. C., Laporte, S. A., Escher, E., Guillemette, G., and Leduc, R. (2000) Biochemistry 39, 9662-70) the Ang II molecule must adopt an extended structure in the AngII binding pocket.

Amino Acid Substitution↗
PubMed2003

Arresting angiotensin type 1 receptors.

The type 1 angiotensin (AT(1)) receptor mediates the homeostatic and pathological actions of the peptide hormone, angiotensin II. With regard to the processes that activate and deactivate seven-transmembrane-spanning, G-protein-coupled receptors (GPCRs), AT(1) receptors are among the most widely studied, serving as prototypes for GPCRs that bind and respond to peptide hormones. Arrestins are proteins that bind to activated and phosphorylated GPCRs, terminating initial signals emanating from these receptors, in addition to mediating receptor internalization. New aspects of arrestin function continue to emerge, such as their capacity to act as scaffolds to recruit regulatory and signaling molecules to increase the repertoire of receptor responses. Here, we examine the evidence that arrestins contribute to the signaling, deactivation and trafficking of AT(1) receptors.

Animals↗
PubMed1999

Significance of angiotensin type 1 receptor blockade: why are angiotensin II receptor blockers different?

The angiotensin II receptor blockers (ARBs) are safe and effective agents in the treatment of hypertension, and they have potential in treating other cardiovascular disorders such as heart failure. These drugs share a common mechanism of action: They selectively block the angiotensin type 1 (AT1) receptor. A new ARB, candesartan cilexetil is a prodrug that is converted completely into the active metabolite candesartan during gastrointestinal absorption, whereas losartan is converted partially by hepatic metabolism into the more active compound EXP 3174. Valsartan and irbesartan are active in their own right. These ARBs differ pharmacologically in terms of their affinity for the AT1 receptor, the mechanism by which they block the receptor, and the duration of their receptor-blocking activity. In radioligand-binding studies, candesartan had a slightly higher affinity for the AT1 receptor than the other ARBs. In the rabbit aorta, candesartan blocked angiotensin II-induced contractions in an insurmountable manner, whereas losartan blocked the contractions competitively, and EXP 3174, valsortan and irbesartan blocked the contractions in a manner intermediate between competitive and insurmountable antagonism. The insurmountable antagonism exhibited by candesartan likely reflects its long-lasting blockade of the AT1 receptor due to a slow dissociation rate. This suggests that candesartan will exhibit a longer duration of action than would be predicted simply from its pharmacokinetic elimination half-life. Comparative clinical trials with several ARBs are needed to define the clinical significance of these pharmacologic differences.

Angiotensin Receptor Antagonists↗
PubMedDate not supplied

Restoration of erectile capacity in normotensive aged rats by modulation of angiotensin receptor type 1.

We investigated the effects of systemic modulation of angiotensin 2 on the erectile dysfunction of aged rats. Young and aged (18 months old) male Sprague-Dawley rats were either treated with daily administration of losartan (angiotensin type 1 receptor antagonist, 30 mg/kg/d PO) or the drug vehicle (control) for 4 weeks (n=6 in each group). We monitored the intracavernosal pressure (ICP) after administration of apomorphine (100 microg/kg), and we measured the degree of lipid peroxidation of corpus cavernosum and the cavernosal protein expression by an immunoblot technique. Compared to the control young rats, the control aged rats showed significant impairment of erectile function; however, losartan treatment effectively restored the erectile function of aged rat to a level similar to that of young rats. Despite the systemic pressure-lowering effect of the drug, the peak ICP was not significantly reduced; rather, the ICP/systemic arterial pressure (SAP) was increased by the losartan treatment. Measurement of lipid peroxidation revealed the fact that the drug was effective in diminishing oxidative stress. While the losartan treatment significantly enhanced the expression of endothelial nitric oxide synthase (eNOS), it had no effect on the expression of transforming growth factor (TGF)-beta1. The results obtained indicated that alteration of the renin-angiotensin system might be implicated in the erectile dysfunction of elderly males, and modulation of this system may be of great therapeutic value.

Aging↗
PubMed2006

Differential roles of Angiotensinogen and Angiotensin Receptor type 1 polymorphisms in breast cancer risk.

While angiotensinogen (AGT) seems to have anti proliferative properties, angiotensin II (ATII) is a potent growth factor and it mediates its actions through the angiotensin type 1 receptor (AGTR1). In the AGT gene, the M235T polymorphism has been associated with the variation in angiotensinogen levels and in the AGTR1 gene; the C573T variant is associated with different pathologies. We aimed to evaluate the relationship of these two variants and the risk of breast cancer. These polymorphisms were genotyped in 3787 women participating the Rotterdam Study. We performed a logistic regression and a disease free survival analysis by genotype. The logistic regression yielded an odds ratio of 1.4 (95% CI: 1.1-1.9) for the MM genotype carriers versus the T allele carriers. The breast cancer free survival by AGT genotype was significantly reduced in MM genotype carriers compared to non-carriers (hazard ratio (HR) = 1.5; 95% CI: 1.1-2.2). We did not find any association of the AGTR1 polymorphism and breast cancer risk or disease free survival. Our results suggest that AGT plays a role in breast cancer risk in postmenopausal women, whereas the role of AGTR1 needs further studying.

Aged↗
PubMed2004

Angiotensin receptor type 1 forms a complex with the transient outward potassium channel Kv4.3 and regulates its gating properties and intracellular localization.

We report a novel signal transduction complex of the angiotensin receptor type 1. In this complex the angiotensin receptor type 1 associates with the potassium channel alpha-subunit Kv4.3 and regulates its intracellular distribution and gating properties. Co-localization of Kv4.3 with angiotensin receptor type 1 and fluorescent resonance energy transfer between those two proteins labeled with cyan and yellow-green variants of green fluorescent protein revealed that Kv4.3 and angiotensin receptor type I are located in close proximity to each other in the cell. The angiotensin receptor type 1 also co-immunoprecipitates with Kv4.3 from canine ventricle or when co-expressed with Kv4.3 and its beta-subunit KChIP2 in human embryonic kidney 293 cells. Treatment of the cells with angiotensin II results in the internalization of Kv4.3 in a complex with the angiotensin receptor type 1. When stimulated with angiotensin II, angiotensin receptors type 1 modulate gating properties of the remaining Kv4.3 channels on the cell surface by shifting their activation voltage threshold to more positive values. We hypothesize that the angiotensin receptor type 1 provides its internalization molecular scaffold to Kv4.3 and in this way regulates the cell surface representation of the ion channel.

Angiotensin II↗