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PubMed1986

Adenylate cyclase inhibition is not involved in the adrenal steroidogenic response to angiotensin II.

Angiotensin II (AII) receptors in adrenal glomerulosa cells are coupled to adenylate cyclase inhibition. We investigated the importance of cyclase inhibition in adrenal steroidogenesis by treating adrenal glomerulosa cells with the toxin of Bordetella pertussis (20 ng/ml) for 3 and 18 h. This treatment prevented inhibition of forskolin-stimulated adenylate cyclase by AII. However, the aldosterone response to AII was not altered by toxin treatment. These results strongly suggest that adenylate cyclase inhibition is not directly involved in mediating the adrenal actions of AII. In addition, ACTH-induced steroidogenesis also was unaffected by toxin treatment demonstrating that cyclase inhibition is not involved in suppressing steroidogenesis via the cAMP pathway.

Adenylate Cyclase Toxin↗

PubMed1998

Tissue-specific regulation of growth factors and clusterin by angiotensin II.

Angiotensin II (ANG II) has been implicated in the hypertrophic and fibrotic responses of the heart and kidney to systemic hypertension. To determine whether these actions of ANG II are related to tissue-specific stimulation of growth factors, we infused adult Sprague-Dawley rats with ANG II at 50 ng/min (low dose), 100 ng/min (high dose), or vehicle for 1 week. Rats receiving vehicle or low-dose ANG II were normotensive with normal plasma aldosterone concentration, whereas rats receiving high-dose ANG II were hypertensive with increased plasma aldosterone. Tissue fibrosis was quantified morphometrically, and messenger RNA (mRNA) for transforming growth factor-beta1 (TGF-beta1) and prepro-epidermal growth factor (EGF) was measured in liver, heart, and renal glomeruli and tubules. In addition, mRNA was determined for clusterin, a glycoprotein expressed in response to tissue injury. Compared to vehicle, low-dose ANG II increased TGF-beta1 expression in glomeruli, tubules, and heart, but not in liver, and increased EGF expression in renal tubules only. High-dose ANG II decreased clusterin expression in liver only. Fibrosis was induced by low- and high-dose ANG II in kidney and heart, but not in liver. We conclude that ANG II selectively stimulates TGF-beta1 mRNA in the heart and kidney, which may contribute to cardiac and renal interstitial fibrosis resulting from activation of the renin-angiotensin system independent of hypertension. By stimulating cellular proliferation, selective stimulation by ANG II of EGF in renal tubules may amplify the effects of TGF-beta1. Suppression of clusterin expression in the liver of hypertensive rats may represent a specific response to high levels of circulating ANG II or a response to hypertensive injury.

Angiotensin II↗

PubMed1978

Adenosine 3':5'-cyclic monophosphate production and steroidogenesis by isolated rat adrenal glomerulosa cells. Effects of angiotensin II and [Sar 1,Ala 8]angiotensin II.

Angiotensin II effects on cyclic AMP production and steroid output were studied in a sensitive preparation of isolated rat adrenal glomerulosa cells. With increasing concentrations of angiotensin II logarithmic dose-response curves for aldosterone and cyclic AMP production were similar. The minimum effective dose (0.2nm) for stimulation of aldosterone production also significantly (P<0.001) increased cyclic AMP output. For both aldosterone and cyclic AMP production, the peptide hormone concentration eliciting maximal response (0.2mum) and the ED(50) (median effective dose) values (1nm) were the same; this is consistent with cyclic AMP acting as an intracellular mediator for angiotensin II-stimulated aldosterone production by glomerulosa cells. The angiotensin II antagonist [Sar(1),Ala(8)]angiotensin II inhibited angiotensin II-stimulated corticosterone and aldosterone production in these cells. An equimolar concentration of antagonist halved the response to 20nm-angiotensin II, and complete inhibition was observed with 0.2mum-antagonist. In contrast, [Sar(1),Ala(8)]angiotensin II had no effect on maximally stimulated steroidogenesis induced by serotonin and a raised extracellular K(+) concentration. Increasing concentrations of [Sar(1),Ala(8)]angiotensin II alone decreased corticosterone and aldosterone outputs significantly (P<0.05) at concentrations of 20nm and 2nm of antagonist respectively. A significant (P<0.001) decrease in cyclic AMP production occurred with 2mum antagonist and this was comparable with the decrease in aldosterone production. It is concluded that [Sar(1),Ala(8)]angiotensin II can independently affect glomerulosa-cell steroidogenesis, possibly by modulating adenylate cyclase activity.

Adrenal Glands↗

PubMed1983

Is the adrenal angiotensin receptor angiotensin II--or angiotensin III like?

In order to determine whether the adrenal receptor is primarily directed at angiotensin II (AII) or angiotensin III (AIII) the following in vitro experiments were performed examining aldosterone responsiveness in isolated glomerulosa cells. 1) Cells exposed to increasing doses (2.4 X 10(-10)M - 2.4 X 10(-6)M) of AII or AIII were found to be significantly more responsive to AII (AII's ED50 was 6.3 X 10(-10) M vs AIII's 4.6 X 10(-9)M P less than 0.001). 2) Octapeptide analogues (Sar1 Ala8 and Asn1 Ala8), while demonstrating different inhibitory potencies relative to each other, were equally effective in blocking AII vs AIII stimulation. 3) The heptapeptide analogues (des1 Ala8 and des1 Ile8) however, inhibited AIII stimulation preferentially (P less than 0.01). 4) The 8 alanine octapeptide analogues were better inhibitors of both AII and AIII stimulation than the 8 alanine heptapeptide analogue. 5) HPLC analysis indicated that AII and AIII were being degraded at the same rate during the incubation procedure. These results, taken together, strongly suggest that the angiotensin adrenal receptor is an AII receptor.

1-Sarcosine-8-Isoleucine Angiotensin II↗

PubMed1988

Functional angiotensin receptor on cultured bovine chromaffin cells: secretory response to angiotensin II and angiotensin III.

The adrenal medulla responds in vivo to exogenous angiotensin II by secreting catecholamines. We previously reported that an angiotensin receptor is present on cultured bovine chromaffin cells and mediates secretion of adrenal catecholamines. The present report examines whether the bovine chromaffin cell receptor responds to angiotensin III. We show in this report that angiotensin III is nearly equiactive with angiotensin II as a secretagogue in these cultured cells.

Angiotensin II↗

PubMed1996

Angiotensin II receptors and angiotensin II stimulation of ciliary activity in human fallopian tube.

Using an antibody (6313/G2) directed against a specific sequence in the extracellular domain of the type 1 angiotensin II receptor (AT1), we demonstrated the presence of angiotensin II (AII) receptors in human fallopian tube. Immunoperoxidase staining for AT1 receptor showed positive staining in the epithelium of the tubal mucosa. The intensity of staining varied depending upon the hormonal status at the time of salpingectomy, being strongest in the proliferative phase of the ovarian cycle and weakest after menopause. Ligand binding assay confirmed that the AII receptor concentration was highest in the mucosa of fallopian tubes from premenopausal women. Mucosa from the ampullary segment had higher concentrations of AII receptor than the fimbrial and isthmic segments in both premenopausal and postmenopausal women. Displacement studies using specific AII receptor subtype antagonists showed that approximately 60% of the total activity could be displaced by CGP42112B (type 2 specific) and 40% by losartan (AT1 specific). Immunoblotting confirmed that the antibody detected a protein of approximately 60 kDa. Functional studies showed that AII had a stimulatory action on tubal ciliary beat frequency, but had no significant effect on myosalpingseal activity. This effect was achieved at nanomolar concentrations of AII; further increases in the AII concentration were without additional effect. The stimulatory effect of AII was inhibited by the specific AT1 antagonist losartan, whereas the type 2 antagonist, CGP42112B, had no effect. The data demonstrate that AII may play an important role in ovum transport and fertility.

Angiotensin II↗

PubMed1990

Discrimination of two angiotensin II receptor subtypes with a selective agonist analogue of angiotensin II, p-aminophenylalanine6 angiotensin II.

Angiotensin II receptor binding sites in rat liver and PC12 cells differ in their affinities for a nonpeptidic antagonist, DuP 753, and p-aminophenylalanine6 angiotensin II. In liver, which primarily contains the sulfhydryl reducing agent-inhibited type of angiotensin II receptor, which we refer to as the AII alpha subtype, DuP 753 displays an IC50 of 55 nM, while p-aminophenylalanine6 angiotensin II displays an IC50 of 8-9 microM. In PC12 cells, which primarily contain the angiotensin II receptor type whose binding affinity is enhanced by sulfhydryl reducing agents (AII beta), DuP 753 displays an IC50 in excess of 100 microM, while p-aminophenylalanine6 angiotensin II displays an IC50 of 12 nM. p-Aminophenylalanine6 angiotensin II binding affinity in liver is decreased in the presence of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) suggesting that this analogue is an agonist.

Adrenal Gland Neoplasms↗

PubMed1994

Effects of central angiotensin II and angiotensin III on baroreflex regulation.

In the present study the cardiovascular effects of intracerebroventricularly (i.c.v.) applied angiotensin II (AN II) and angiotensin III (AN III) were analysed in conscious Wistar rats. The baroreceptor heart reflex (BHR) was elicited by intravenous bolus injection of both phenylephrine (1 microgram) and sodium nitroprusside (5 micrograms) before and after i.c.v. administration (1.5 and 15 min) of the peptides. Administration of 20 ng and 200 ng AN II produced a short increase in inter-beat interval (IBI) and a long-lasting increase in mean blood pressure (MBP), inclusive of a drinking response. Only after the high dose of 200 ng AN II we found a continuous impairment in the BHR for reflex bradycardia. Inversely, the small doses of both 100 pg AN II and 100 pg AN III were without effects on IBI and MBP; they induced an enhancement in BHR for the reflex bradycardia and after 100 pg AN II it was also found for the reflex tachycardia. Pretreatment with 20 nmol amastatin (AM), a specified aminopeptidase A inhibitor, followed by 100 pg An II suppressed the enhancement in BHR. AM alone was without effects in this respect. These findings suggest that: 1) the influence of central angiotensin on the BHR could be dose-dependent in the opposite way and 2) AN III seems to be the active form and involved in the central blood pressure regulatory mechanism.

Angiotensin II↗

PubMed1992

Effects of angiotensin II and angiotensin III on airway epithelial short-circuit current: involvement of pertussis toxin-sensitive G protein.

The effects of angiotensin II (AII) and angiotensin III (AIII) on bioelectric properties of canine cultured tracheal epithelium were investigated. Both peptides increased the short-circuit current (Isc), an effect that was accompanied by the release of prostaglandin (PG) E2 and was abolished by indomethacin and diphenylamine-2-carboxylate but not by amiloride. The AII action was not altered by amastatin. The increases in Isc induced by AII and AIII were inhibited by pertussis toxin, whereas cholera toxin had no effect. Thus, both peptides may selectively stimulate airway epithelial Cl- secretion through the activation of pertussis toxin-sensitive regulatory G protein and the subsequent generation of PGE2.

Angiotensin II↗

PubMed1991

Comparative effects of angiotensin II and angiotensin III in rabbit adrenal and aortic tissues.

The addition of angiotensin II (AII) and angiotensin III (AIII) to isolated tissue baths produced the same maximal contractile response of rabbit aortic strips. AIII was about 10 times less potent, the slope of its concentration-response curve was less steep and its rate of onset slower than that of AII. The responses of both AII and AIII were inhibited with equal potency by the surmountable AII antagonist Phe4, Tyr8-AII and its unsurmountable analog Sar1, Leu8-AII but the kinetic patterns of inhibition by both were less well defined with the agonist AIII than with AII. The addition of AIII to tissues which had exhibited a maximal response to AII did not increase the level of contraction, in contrast to the case when norepinephrine was added to tissues contracted by AII. Both AII and AIII displaced [125I]AII binding from rabbit adrenal membranes; AIII was 6 times less potent than AII but displayed competitive kinetics as an inhibitor of [125I]AII binding. In further studies two binding sites for [125I]AII were identified in adrenal membranes, having KD values of 2.0 +/- 0.2 and 19.6 +/- 2.3 nM, respectively. Each site was inhibited by both AII and AIII and the ratio of the apparent Ki values for the two hormones was not significantly different. The Hill coefficient for the high affinity site was, however, lower for AIII than AII. We interpret our data to suggest that AII and AIII act on the same receptors. AIII apparently binds less efficiently than does AII in both rabbit adrenal membranes and rabbit aortic strips.

Adrenal Glands↗

PubMed1994

Integrin-mediated collagen gel contraction by cardiac fibroblasts. Effects of angiotensin II.

Angiotensin II (Ang II), a vasoactive octapeptide, has been implicated in cardiac growth and the development of hypertrophy and fibrosis secondary in hypertensive disease. These consequences of Ang II imply an effect on the function and morphology of cardiac interstitial cells (fibroblasts). The present investigation was designed to (1) determine whether neonatal heart fibroblasts (NHFs) possess functional Ang II receptors on their plasma membrane and (2) examine the effects of Ang II on NHFs in vitro using three- and two-dimensional (3D and 2D, respectively) cultures. Several analytic techniques were used to test the specific questions of the present study. Since cardiac fibroblast phenotype can be influenced by culture conditions, both 2D and 3D cultures were used in the present investigations. Reverse-transcriptase polymerase chain reaction and radioligand binding analysis were used to test for the presence of Ang II receptors on NHFs. Both revealed that NHFs in 2D culture possess Ang II receptor mRNA and Ang II receptors. When isolated NHFs were cultured in 3D collagen gels and treated with Ang II, gel contraction was stimulated by NHFs. This effect was attenuated by the specific Ang II receptor antagonist [Sar1,Ala8]Ang II. Ang II-stimulated gel contraction was completely inhibited by extracellular matrix receptor (beta 1-integrin) antibodies (P < .05), supporting previous studies indicating that collagen gel contraction is mediated via the integrins. Immunofluorescent staining was used to test the localization of cell-surface integrins. A more intense staining pattern for beta 1-integrin in Ang II-treated versus control cells was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Developmental regulation of ACE gene expression by endogenous kinins and angiotensin II.

Angiotensin converting enzyme (ACE, i.e., kininase II), a key regulator of kinins and angiotensin II (ANG II) generation, is developmentally regulated and its expression is induced at a specific time point (day 15) of postnatal kidney development. The present study tested the hypothesis that endogenous kinins and ANG II regulate the developmental expression of the renal ACE gene. In the first protocol, newborn rats received the kallikrein inhibitor, aprotinin (100,000 KIU.kg-1.day-1 sc), or the kinin B2 receptor antagonist, HOE-140 (600 micrograms.kg-1.day-1 sc), or 0.9% saline, from birth until postnatal days 5, 15, or 20. Aprotinin prevented the postnatal rise in renal kallikrein activity without affecting blood pressure in either developing or adult rats. Chronic kallikrein blockade significantly attenuated the postnatal induction of both serum ACE activity (-11% vs. controls) and kidney ACE activity and mRNA (-50% vs. controls). In addition, aprotinin attenuated the postnatal rise of ACE activity in the developing lungs. Kidney renin mRNA and ANG II contents were not altered by aprotinin. HOE-140 also attenuated the postnatal rise in kidney ACE mRNA (-25%) and activity (-40%) without affecting blood pressure. Infusion of aprotinin or HOE-140 via osmotic minipumps for 7 days in adult rats was not associated with any changes in renal or pulmonary ACE.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1971

Specific antagonists for the myotropic action of angiotensin II and angiotensin I on the isolated rat colon.

Substitutions of 8 phenylalanine with L-alanine and D-phenylalanine abolish the myotropic action of the angiotensin II (AT(II)) analogues and confer inhibitory properties on the molecule. [8-L-Ala]-AT(II) and [8-D-Phe]-AT(II) antagonize specifically the myotropic action of AT(II) and angiotensin I (AT(I)) on the rat colon, while the action of other myotropic agents (acetylcholine, 5 hydroxytryptamine) is not modified.

Amino Acids↗

PubMed2004

Mutagenesis of the AT1 receptor reveals different binding modes of angiotensin II and [Sar1]-angiotensin II.

Homology modeling of the structure of the AT1 receptor, based on the high resolution rhodopsin crystal structure, indicated that it is unlikely that the binding of AngII to AT1 involves simultaneously all the receptor's residues reported in the literature to participate in this process. Site-directed mutagenesis using Ala substitution of charged residues Lys20, Arg23, Glu91 and Arg93 was performed to evaluate the participation of their side-chains in ligand binding and in triggering the cell's response. A comparative analysis by competition binding and functional assays using angiotensin II and the analog [Sar1]-angiotensin II suggests an important role for Arg23 of AT1 receptor in binding of the natural agonist. It is discussed whether some receptor's residues participate directly in the binding with AngII or whether they are part of a regulatory site.

Amino Acid Substitution↗

PubMed1994

Human leukocytes contain angiotensin I, angiotensin II and angiotensin metabolites.

Angiotensin I (ANG I) and angiotensin II (ANG II) were measured radioimmunologically in human leukocytes extracted with a mixture of acetone, 1N HCl and water (40:1:10 vol). The analytical recoveries of 125I-ANG I and 125I-ANG II, which were added prior to extraction, were 92.00 +/- 3.10 and 99.19 +/- 0.91% (mean +/- SEM; n = 12). The concentration of ANG I- and ANG II-like material in leukocytes from healthy volunteers was 32.04 +/- 3.64 and 13.05 +/- 1.26 fmol/mg protein (n = 24). The immunoreactive material could be characterized on HPLC as Ile5-ANG I, Ile5-ANG II and angiotensin metabolites such as Ile4-ANG III, Ile3-ANG II hexapeptide, Ile2-ANG II pentapeptide and Ile1-ANG II tetrapeptide. From the ANG I-immunoreactive material determined in the extracts, 26% could be characterized on HPLC as Ile5-ANG I. The ANG II-immunoreactive material present in the extracts could be separated on HPLC into 44% Ile5-ANG II, 14% Ile4-ANG III, 7% Ile3-ANG II hexapeptide, 4% Ile2-ANG II pentapeptide and 8% Ile1-ANG II tetrapeptide. Patients with a history of anaphylactic reactions to bee or wasp venom showed significantly reduced ANG II concentrations in their leukocytes as compared to controls (6.76 +/- 0.76 fmol ANG II/mg protein, n = 22, vs. 13.05 +/- 1.26 fmol ANG II/mg protein, n = 24; p < 0.05). A significant correlation between the severity of clinical symptoms and the ANG II levels was found for grade I and II reactions (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1998

Presence of angiotensin II and expression of angiotensin II type-2 receptor in human fallopian tube.

OBJECTIVE: To determine the presence of angiotensin II and angiotensin II type-2 receptor subtype messenger RNA (mRNA) in human fallopian tube. DESIGN: Frozen fallopian tubes were used for all studies. SETTING: Procedures were performed at the Institute of Maternal and Child Research, School of Medicine, University of Chile and San Borja-Arriarán Clinical Hospital, National Health Service, Santiago, Chile. PATIENT(S): Eight patients (30-38 years) undergoing surgical sterilization or hysterectomy for benign gynecologic conditions. INTERVENTION(S): Surgery was scheduled in the proliferative or secretory stage of the menstrual cycle. MAIN OUTCOME MEASURE(S): Localization of angiotensin II by immunofluorescence studies, expression of angiotensin II type-2 receptor mRNA, and concentrations of angiotensin II receptor subtypes and binding characteristics. RESULT(S): Angiotensin II was immunolocalized mainly in blood vessel endothelium and, to a lesser extent, in stromal cells. Both binding and angiotensin II type-2 receptor mRNA were detected at high levels. No differences were seen in receptor concentration, dissociation constants or median inhibitory concentration in fallopian tubes ipsilateral or contralateral to the corpus luteum. CONCLUSION(S): Angiotensin II and angiotensin II receptor are present in human fallopian tube. Angiotensin II type-2 receptor was the main receptor subtype. These results suggest that the renin-angiotensin system may play a regulatory role in functions of the fallopian tube.

Adult↗

PubMed1990

Angiotensin II and angiotensin converting enzyme binding in human adrenal gland and pheochromocytomas.

Binding sites for angiotensin II (Ang II) and angiotensin converting enzyme (ACE) were studied by autoradiography in human, rat and bovine adrenals and human pheochromocytomas. In human and rat adrenals, binding sites for both Ang II and ACE were found in the medulla and zona glomerulosa. In bovine adrenals, ACE binding sites were not detectable, while Ang II binding was higher in the zona glomerulosa, lower in the rest of the cortex and undetectable in the medulla. In pheochromocytomas, ACE binding was homogeneously distributed, but no Ang II binding was detected. These results suggest that circulating and/or locally formed Ang II could regulate adrenomedullary and zona glomerulosa functions in man, and show that chromaffin cells in tumors retain ACE binding sites but lose Ang II binding sites. Thus, there are alterations in the regulation of the renin-angiotensin system in chromaffin tumors.

Adrenal Gland Neoplasms↗

PubMed1980

Regulation of receptor binding interactions of 125I-angiotensin II and 125I-[sarcosine1,leucine8]angiotensin II, an angiotensin antagonist, by sodium ion.

Angiotensin receptor binding interactions of the angiotensin agonist, 125I-angiotensin II (125I-AII), and antagonist, 125I-[sarcosine1,leucine8]angiotensin II (125I[Sar1,Leu8]AII), are differentially affected by sodium ion concentration. 125I-AII binding to calf cerebellar cortex or adrenal cortex is increased 25 or 2.5 fold respectively when sodium ion concentration is increased from 10 to 150 mM. In brain membranes increasing sodium concentration accelerates the association and slows the dissociation of 125I-AII. 125I[Sar1,Leu8]AII binding to these tissues is much less sensitive to changes in sodium ion concentration. In rabbit uterine homogenates, neither 125I-AII nor 125I[Sar1,Leu8]AII binding is significantly altered by changes in sodium ion concentration. The sodium elicited increase in 125I-AII binding to calf cerebellum is correlated with cationic size and is not an ionic strength effect. The effect of sodium on potencies of angiotensin analogues in competing for 125I[Sar1,Leu8]AII binding does not correlate with agonist or antagonist properties, but is largest for peptides with aspartic acid at position one in the peptide structure.

Adrenal Cortex↗