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Biomedical subjects

G Thibault

Publications and source records attributed to G Thibault.

At least 19 recordsLinked to original sources
PubMed2005

Microvascular rarefaction and decreased angiogenesis in rats with fetal programming of hypertension associated with exposure to a low-protein diet in utero.

In hypertension, increased peripheral vascular resistance results from vascular dysfunction with or without structural changes (vessel wall remodeling and/or microvascular rarefaction). Humans with lower birth weight exhibit evidence of vascular dysfunction. The current studies were undertaken to investigate whether in utero programming of hypertension is associated with in vivo altered response and/or abnormal vascular structure. Offspring of Wistar dams fed a normal (CTRL) or low (LP)-protein diet during gestation were studied. Mean arterial blood pressure response to ANG II was significantly increased, and depressor response to sodium nitroprusside (SNP) infusions significantly decreased in male LP adult offspring relative to CTRL. No arterial remodeling was observed in male LP compared with CTRL offspring. Capillary and arteriolar density was significantly decreased in striated muscles from LP offspring at 7 and 28 days of life but was not different in late fetal life [day 21 of gestation (E21)]. Angiogenic potential of aortic rings from LP newborn (day of birth, P0) was significantly decreased. Striated muscle expressions (Western blots) of ANG II AT(1) receptor subtype, endothelial nitric oxide synthase, angiopoietin 1 and 2, Tie 2 receptor, vascular endothelial growth factor and receptor, and platelet-derived growth factor C at E21 and P7 were unaltered by antenatal diet exposure. In conclusion, blood pressure responses to ANG II and SNP are altered, and microvascular structural changes prevail in this model of fetal programming of hypertension. The capillary rarefaction is absent in the fetus and appears in the neonatal period, in association with decreased angiogenic potential. The study suggests that intrauterine protein restriction increases susceptibility to postnatal factors resulting in microvascular rarefaction, which could represent a primary event in the genesis of hypertension.

Animals↗
PubMed2004

Alpha8beta1 integrin is upregulated in myofibroblasts of fibrotic and scarring myocardium.

Integrins mediate cell attachment to the extracellular matrix (ECM) regulating migration, proliferation, and differentiation. We previously reported the presence of alpha8beta1 integrin on cultured cardiac fibroblasts. Extending this information, we localized alpha8beta1 integrin in normal rat myocardial tissue, and investigated its expression pattern in rats chronically infused with angiotensin II (Ang II, 500 ng/kg/min), a well-recognized profibrotic factor. Alpha8beta1-integrin expression was analyzed by binding assay, western blotting, and immunohistochemistry. In normal myocardium, immunohistochemical staining for alpha8 was found in fibroblasts, as well as in the epicardium, endocardium, and valves. Vascular smooth muscle cells (VSMCs) of the media of cardiac arteries also stained positively. After 14-d-Ang II infusion, staining for fibronectin, as well as collagen staining by Sirius red, revealed extensive interstitial and perivascular fibrosis. Increased expression of alpha8 integrin in ventricular smooth muscle (SM) alpha-actin-positive fibroblasts (myofibroblasts) was also recorded. The upregulation of alpha8beta1 integrin was confirmed by binding assay and by western blotting. Microscopic scars, a characteristic of reparative fibrosis, were invaded by matrix proteins and by strongly alpha8- and SM alpha-actin-positive myofibroblasts. The results indicate that, in rat adult myocardium, alpha8beta1 integrin is expressed in fibroblasts and VSMC. In Ang II-infused animals, alpha8beta1-integrin expression was enhanced in the left ventricle and arteries. The coordinate regulation of alpha8beta1 integrin on fibroblasts and ECM proteins raises the possibility that this integrin is implicated in the deposition of matrix components leading to fibrosis.

Angiotensin II↗
PubMed2001

The transmembrane protein of HIV-1 primary isolates modulates cell surface expression of their envelope glycoproteins.

We have recently shown that the level of cell surface expression of envelope glycoproteins derived from various human immunodeficiency virus type 1 (HIV-1) primary isolates (PI) was lower than those of envelope glycoproteins derived from T-cell laboratory-adapted (TCLA) HIV-1 (D. Brand et al., 2000, Virology 271, 350-362). We investigated this phenomenon by comparing the cell surface expression of chimeric envelope glycoproteins constructed by swapping the gp120 surface and gp41 transmembrane glycoproteins of the TCLA HIV-1MN and the PI HIV-1(133), HIV-1G365, or HIV-1EFRA. We found that each chimeric envelope construct had a cell surface-specific pattern of expression similar to that of the parental envelope glycoproteins corresponding to the gp41. Thus, the difference in cell surface expression observed between TCLA viruses and various PI is probably due to a signal located in gp41. Identification of this signal may be important for the design of PI envelope-derived immunogens and may increase our understanding of the mechanisms by which HIV-1 escapes from the immune system.

Cell Membrane↗
PubMed2001

In vitro decrease of glomerular heparan sulfate by lymphocytes from idiopathic nephrotic syndrome patients.

BACKGROUND: Lymphocytes are involved in the physiopathologic mechanism of idiopathic nephrotic syndrome (INS). We have recently demonstrated that plasma from patients with INS decreases human glomerular epithelial cell (GEC) glycosaminoglycans (GAGs), particularly heparan sulfates (HS) in vitro. In this study we investigate the effect of peripheral blood lymphocytes (PBL) from INS patients on glomerular cell GAG and HS. METHODS: Human GECs were cultured with total peripheral blood mononuclear cells (PBMCs), PBL, and monocytes from patients and controls. The amounts of GAG and HS were assessed using a cationic membrane after metabolic labeling. RESULTS: In coculture with GECs, mononuclear cells from controls decreased total epithelial cell GAG (-30% with PBMC, P < 0.05; -25% with PBL, P < 0.02; -19% with monocytes, P < 0.05). Particularly HSs were decreased (-36% with PBMC, P < 0.05; -27% with PBL, P < 0.02; and -19% with monocytes, P < 0.05). When GECs were in coculture with PBL from INS patients, the decrease in GAG and HS was significantly greater in comparison to control PBL (-10%, P < 0.02; -10%, P < 0.02, respectively, for GAG and HS). Moreover, supernatants of stimulated PBMCs from patients decreased also GAG and HS in comparison with controls (-13%, P < 0.02; -15%, P < 0.02, respectively, for GAG and HS). CONCLUSION: These data provide direct evidence that PBLs from INS patients are able to decrease GEC HS as previously shown with plasma from patients. This might be instrumental in the onset of albuminuria.

Cells, Cultured↗
PubMed2001

Upregulation of alpha(8)beta(1)-integrin in cardiac fibroblast by angiotensin II and transforming growth factor-beta1.

Using a novel pharmacological tool with (125)I-echistatin to detect integrins on the cell, we have observed that cardiac fibroblasts harbor five different RGD-binding integrins: alpha(8)beta(1), alpha(3)beta(1), alpha(5)beta(1), alpha(v)beta(1), and alpha(v)beta(3). Stimulation of cardiac fibroblasts by angiotensin II (ANG II) or transforming growth factor-beta1 (TGF-beta1) resulted in an increase of protein and heightening by 50% of the receptor density of alpha(8)beta(1)-integrin. The effect of ANG II was blocked by an AT(1), but not an AT(2), receptor antagonist, or by an anti-TGF-beta1 antibody. ANG II and TGF-beta1 increased fibronectin secretion, smooth muscle alpha-actin synthesis, and formation of actin stress fibers and enhanced attachment of fibroblasts to a fibronectin matrix. The alpha(8)- and beta(1)-subunits were colocalized by immunocytochemistry with vinculin or beta(3)-integrin at focal adhesion sites. These results indicate that alpha(8)beta(1)-integrin is an abundant integrin on rat cardiac fibroblasts. Its positive modulation by ANG II and TGF-beta1 in a myofibroblast-like phenotype suggests the involvement of alpha(8)beta(1)-integrin in extracellular matrix protein deposition and cardiac fibroblast adhesion.

Angiotensin II↗
PubMed2001

Chronic exposure to beta-hydroxybutyrate impairs insulin action in primary cultures of adult cardiomyocytes.

Type 1 and type 2 diabetic patients often show elevated plasma ketone body concentrations. Because ketone bodies compete with other energetic substrates and reduce their utilization, they could participate in the development of insulin resistance in the heart. We have examined the effect of elevated levels of ketone bodies on insulin action in primary cultures of adult cardiomyocytes. Cardiomyocytes were cultured with the ketone body beta-hydroxybutyrate (beta-OHB) for 4 or 16 h, and insulin-stimulated glucose uptake was evaluated. Although short-term exposure to ketone bodies was not associated with any change in insulin action, our data demonstrated that preincubation with beta-OHB for 16 h markedly reduced insulin-stimulated glucose uptake in cardiomyocytes. This effect is concentration dependent and persists for at least 6 h after the removal of beta-OHB from the media. Ketone bodies also decreased the stimulatory effect of phorbol 12-myristate 13-acetate and pervanadate on glucose uptake. This diminution could not be explained by a change in either GLUT-1 or GLUT-4 protein content in cardiomyocytes. Chronic exposure to beta-OHB was associated with impaired protein kinase B activation in response to insulin and pervanadate. These results indicate that prolonged exposure to ketone bodies altered insulin action in cardiomyocytes and suggest that this substrate could play a role in the development of insulin resistance in the heart.

3-Hydroxybutyric Acid↗
PubMed2001

Comparative specificity of platelet alpha(IIb)beta(3) integrin antagonists.

Several platelet alpha(IIb)beta(3) integrin antagonists have been designed as preventive agents against the formation of arterial thrombi. Although the potency of these compounds in inhibiting platelet aggregation is in the nanomolar range, their specificity on other integrins that can bind ligands through an arginine-glycine-aspartic acid (RGD) motif is far from being well established. For instance, some cyclic RGD peptides can also interact with alpha(v)beta(3) integrin. We used a novel pharmacological assay, based on SDS-stable interaction between (125)I-echistatin and RGD-dependent integrins, to evaluate the specificity of several RGD compounds on integrins present on rat cardiac fibroblasts and human skin fibroblasts. None of the RGD peptidomimetics tested (L-734,217, lamifiban, Ro 44-3888, SR 121566A, BIBU-52, XV459) could interact with either alpha(v)beta(3) and alpha(8)beta(1) on rat fibroblasts or with alpha(v)beta(3) and alpha(v)beta(1) on human fibroblasts. Cyclic RGD peptides showed some potency (3-80 microM) on rat and human integrins with an alpha(v) subunit. We also compared the potency of these compounds on platelets. All RGD compounds demonstrated IC(50) between 0.6 and 530 nM on basal human platelets. Activation of the receptor with thrombin resulted in a 2- to 60-fold increase in potency, with L-734,217 and BIBU-52 showing the largest difference. On basal and thrombin-activated rat platelets, only eptifibatide, DMP728, and XJ735 could displace (125)I-echistatin (IC(50) approximately 0.1-1.5 microM). These results indicate that RGD peptidomimetics have a specificity limited to alpha(IIb)beta(3) integrin, whereas cyclic RGD peptides can also interact with other RGD-dependent integrins, particularly those of the alpha(v) subunit family.

Animals↗
PubMed2000

Antigenic properties of recombinant envelope glycoproteins derived from T-cell-line-adapted isolates or primary human immunodeficiency virus isolates and their relationship to immunogenicity.

The native envelope glycoproteins of primary HIV-1 virions have weaker antigenicity than do T-cell laboratory-adapted (TCLA) viruses. These antigenic properties require further evaluation if recombinant envelope glycoproteins are produced as part of a vaccine strategy. In this study, we compared the antigenicity of recombinant envelope glycoproteins derived from three primary isolates (PI) (HIV-1(BX08), HIV-1(CHA), and HIV-1(133)) and two TCLA viruses (HIV-1(HXB2) and HIV-1(MN)) produced using the Semliki Forest virus (SFV) system. This analysis was performed by radioimmunoprecipitation assays and flow cytometry. The results suggest that the SFV produces envelope glycoproteins with features in common with the envelopes found in naturally occurring virions. In particular, the PI envelopes had weak heterogeneous antigenic properties. However, the cytometric analysis also showed that there was less envelope glycoprotein on the cell surface for the PI envelopes than for those of TCLA viruses, suggesting differences in their intracellular trafficking. The immunogenic properties of the various envelope glycoproteins were evaluated in mice using recombinant SFV particles as vaccine vectors. The PI envelopes were less immunogenic than the TCLA envelopes, probably due to both their low antigenicity and cell surface expression level. Thus, it may be difficult to design an effective vaccine based on native recombinant PI envelopes.

Adaptation, Physiological↗
PubMed2000

Downregulation of endothelial nitric oxide synthase in rat aorta after prolonged hypoxia in vivo.

The goal of this study was to determine whether hypoxia alters expression of endothelial nitric oxide synthase (eNOS) in the systemic circulation. Rats breathed either air or 10% oxygen for 12 hours, 48 hours, or 7 days. Thoracic aortas were excised and either mounted in organ bath myographs or frozen in liquid nitrogen for later extraction of protein and RNA. eNOS protein (Western blotting) was decreased (20% of normoxic control) after 12 hours, 48 hours, and 7 days of hypoxia. eNOS mRNA (ribonuclease protection assay) was similarly reduced. Acetylcholine (10(-4) mol/L) reversed phenylephrine (10(-5) mol/L) preconstriction by 53.3+/-5.6% in aortic rings from normoxic rats and 26.1+/-4.8% in rings from rats exposed to hypoxia for 48 hours (P<0.05), with comparable impairment of relaxation by the calcium ionophore A23187 (10(-5) mol/L). Responses to diethylamine nitric oxide and 8-bromo-cGMP were unaffected. Aortic cGMP levels after incubation with acetylcholine (10(-6) mol/L) averaged 14.0+/-1.8 fmol/mg in rings from normoxic rats compared with 8.7+/-1.0 fmol/mg in rings from hypoxic rats (P<0. 05). Similarly, nitrate concentration (by capillary electrophoresis) in the media in which the rings were incubated was reduced in the hypoxic group (5.6+/-0.23 micromol/L for hypoxic rats and 7.8+/-0.7 micromol/L for normoxic rats). Impaired endothelial NO release may handicap the vascular responses that defend vital organ function during hypoxia.

Animals↗
PubMed2000

Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling.

Angiotensin II (AII) is a major determinant of arterial pressure and volume homeostasis, mainly because of its vascular action via the AII type 1 receptor (AT1R). AII has also been implicated in the development of cardiac hypertrophy because angiotensin I-converting enzyme inhibitors and AT1R antagonists prevent or regress ventricular hypertrophy in animal models and in human. However, because these treatments impede the action of AII at cardiac as well as vascular levels, and reduce blood pressure, it has been difficult to determine whether AII action on the heart is direct or a consequence of pressure-overload. To determine whether AII can induce cardiac hypertrophy directly via myocardial AT1R in the absence of vascular changes, transgenic mice overexpressing the human AT1R under the control of the mouse alpha-myosin heavy chain promoter were generated. Cardiomyocyte-specific overexpression of AT1R induced, in basal conditions, morphologic changes of myocytes and nonmyocytes that mimic those observed during the development of cardiac hypertrophy in human and in other mammals. These mice displayed significant cardiac hypertrophy and remodeling with increased expression of ventricular atrial natriuretic factor and interstitial collagen deposition and died prematurely of heart failure. Neither the systolic blood pressure nor the heart rate were changed. The data demonstrate a direct myocardial role for AII in the development of cardiac hypertrophy and failure and provide a useful model to elucidate the mechanisms of action of AII in the pathogenesis of cardiac diseases.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed2000

Altered cardiac endothelin receptors and protein kinase C in deoxycorticosterone-salt hypertensive rats.

The aim of the present study was to assess the status of ET-1 receptor subtypes (ET(A)and ET(B)) in ventricular myocytes and fibroblasts and to determine the role of PKC-dependent pathways in ET-1-stimulated cardiac cells in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Systolic blood pressure and relative heart to body weight were significantly increased in DOCA-salt rats. In unilaterally nephrectomized (Uni-Nx) control rats, more than 90% of cardiomyocyte ET receptors were of the ET(A)subtype, whereas in fibroblasts ET(A)and ET(B)receptors were present in a 1:3 ratio. In DOCA-salt rats, the density of the ET(A)receptor subtype was reduced by 31% in cardiomyocytes and in cardiac fibroblasts only ET(B)receptor density was decreased by 29%. Affinity was unchanged. The relative expression of immunoreactive PKC alpha, gamma and epsilon was significantly increased, whereas PKC delta was not altered in cardiac extracts of DOCA-salt rats. In cardiac fibroblasts from DOCA-salt rats PKC delta was significantly increased and PKC epsilon was not translocated after ET-1 stimulation. The hearts of DOCA-salt hypertensive rats are thus characterized by: (1) decreased density of cardiomyocyte ET(A)receptors and fibroblast ET(B)receptors; (2) cell-specific enhanced expression of some PKC isoenzymes (alpha, gamma, delta and epsilon); and (3) unresponsiveness of PKC epsilon to translocate in the presence of ET-1. Together with alterations of ET-1-induced Ca(2+)handling in cardiac myocytes and fibroblasts, which we previously reported, results from the present study indicate a marked modification of the cardiac ET-1 system of DOCA-salt hypertensive rats.

Animals↗
PubMed2000

Sodium dodecyl sulfate-stable complexes of echistatin and RGD-dependent integrins: a novel approach to study integrins.

This study shows that disintegrins, echistatin as a model, can be used as a radiolabeled probe to simultaneously detect the presence of individual RGD-dependent integrins on cardiac fibroblasts. Binding of (125)I-echistatin to fibroblasts was proportional to cell number, time dependent, reversible, saturable, specific, and membrane bound. SDS-polyacrylamide gel electrophoresis and autoradiograms revealed that (125)I-echistatin was associated with three radioactive protein bands of 180, 210, and 220 kDa that were identified by RGD affinity chromatography, immunoblotting, and immunoneutralization as alpha(v)beta(3), alpha(3)beta(1)/alpha(5)beta(1)/alpha(v)beta(1), and alpha(8)beta(1) heterodimeric integrins, respectively. These results suggest that echistatin binds to RGD-dependent integrins, forming SDS-stable complexes in the absence of chemical cross-linkers, reducing conditions and heating. As assessed by radioligand-binding filtration, disintegrins displayed binding characteristics with an IC(50) ranging from 0.044 to 1.1 nM, but with slope factors lower than 1, indicating the presence of several binding sites. Resolved by SDS-polyacrylamide gel electrophoresis to reveal echistatin-integrin complexes, disintegrins and RGD peptides displayed different binding affinities to individual RGD-dependent integrins present on cardiac fibroblasts. Elegantin and flavostatin demonstrated the highest affinity toward integrins, whereas flavoridin and acPenRGDC had a greater specificity toward alpha(v)beta(3)-integrin. In summary, echistatin forms SDS-stable complexes with RGD-dependent integrins. This model offers a novel way to visualize RGD-dependent integrins, to investigate their activation state, and to determine the integrin specificity of RGD peptides.

Animals↗
PubMed1999

Resistance artery mechanics, structure, and extracellular components in spontaneously hypertensive rats : effects of angiotensin receptor antagonism and converting enzyme inhibition.

BACKGROUND: Altered vascular mechanics resulting from changes in collagen and integrins may influence resistance artery structure and function and, therefore, peripheral resistance and blood pressure in spontaneously hypertensive rats (SHR). METHODS AND RESULTS: Effects of age, angiotensin-converting enzyme inhibition (fosinopril, 10 to 30 mg/kg per day), and AT(1)-receptor antagonism (irbesartan, 50 mg/kg per day) on vascular structure, mechanics, and composition were assessed in SHR. Systolic blood pressure was elevated in young SHR (130+/-2 mm Hg) compared with Wistar-Kyoto (WKY) rats (106+/-2 mm Hg). In adult SHR, the rise in systolic blood pressure (44+/-3 mm Hg) was blunted by fosinopril (18+/-1 mm Hg) and irbesartan (9+/-3 mm Hg). Lumen diameter of mesenteric resistance arteries was smaller and media/lumen ratio was greater in young and adult SHR versus WKY rats. Growth index was 24% in untreated adult SHR versus WKY rats; these values were -35% for fosinopril-treated and -29% for irbesartan-treated SHR versus untreated SHR. Isobaric wall stiffness was normal despite increased stiffness of wall components in adult SHR vessels. Irbesartan partially prevented stiffening of wall components in SHR. The collagen/elastin ratio was greater in adult SHR vessels (6.5+/-1.3) than in WKY (3.2+/-0.4) vessels. Expression of alpha(v)beta(3) and alpha(5)beta(1) integrins was increased in SHR aged 20 versus 6 weeks. Expression of alpha(5)beta(1) integrins was lower in young SHR, and alpha(v)beta(3) integrins were overexpressed in adult SHR versus WKY rats. Irbesartan and fosinopril attenuated differences in the collagen/elastin ratio and integrin expression. CONCLUSIONS: Wall components of mesenteric resistance arteries stiffen with age in SHR. Interrupting the renin-angiotensin system has normalizing effects on integrin expression and composition, stiffness, and growth of the arterial wall.

Angiotensin Receptor Antagonists↗
PubMed1999

Trophoblast cell line resistance to NK lysis mainly involves an HLA class I-independent mechanism.

The lack of classical HLA molecules on trophoblast prevents allorecognition by maternal T lymphocytes, but poses the problem of susceptibility to NK lysis. Expression of the nonclassical class I molecule, HLA-G, on cytotrophoblast may provide the protective effect. However, the class I-negative syncytiotrophoblast escapes NK lysis by maternal PBL. In addition, while HLA-G-expressing transfectants of LCL.721.221 cells are protected from lymphokine-activated killer lysis, extravillous cytotrophoblast cells and HLA-G-expressing choriocarcinoma cells (CC) are not. The aim of this work was therefore to clarify the role of HLA class I expression on trophoblast cell resistance to NK lysis and on their susceptibility to lymphokine-activated killer lysis. Our results showed that both JAR (HLA class I-negative) and JEG-3 (HLA-G- and HLA-Cw4-positive) cells were resistant to NK lysis by PBL and were equally lysed by IL-2-stimulated PBL isolated from a given donor. In agreement, down-regulating HLA class I expression on JEG-3 cells by acid treatment, masking these molecules or the putative HLA-G (or HLA-E) receptor CD94/NKG2 and the CD158a/p58.1 NKR with mAbs, and inducing self class I molecule expression on JAR cells did not affect NK or LAK lysis of CC. These results demonstrate that the resistance of CC to NK lysis mainly involves an HLA class I-independent mechanism(s). In addition, we show that the expression of a classical class I target molecule (HLA-B7) on JAR cells is insufficient to induce lysis by allospecific polyclonal CTL.

Antigens, CD↗
PubMed1999

Angiotensin inhibition and atrial natriuretic peptide release after acute volume expansion in rats with aortocaval shunt.

OBJECTIVE: In heart failure atrial natriuretic peptide (ANP) release in response to volume expansion is impaired while the renin-angiotensin system is activated. This study was designed to test the hypothesis that ANP release in heart failure is dependent on an activated angiotensin system. METHODS: We studied the ANP and renin-angiotensin systems in a rat model of shunt-induced high-output heart failure, in which we rapidly increased circulating fluid volume with a 5 ml, hyperoncotic infusion, and evaluated the effects of acute inhibition of the angiotensin converting enzyme as well as of the blockade of the angiotensin II type 1 receptors on the ANP release and on renal excretory function. RESULTS: ANP and angiotensin II plasma concentrations prior to volume expansion were elevated (p < 0.05) in rats with aortocaval shunt compared to controls. The diuretic response to acute volume expansion (18.5 +/- 1.5 vs. 48.2 +/- 2.4 microliters/min, p < 0.001) was markedly blunted. ANP release was attenuated in rats with aortocaval shunt, as was the increase of its second messenger cGMP in plasma and urine. The blunted increase in ANP plasma levels was not due to depleted cardiac stores as cardiac ANP content, as well as ANP synthesis, were increased (p < 0.05). Acute inhibition of the angiotensin converting enzyme as well as blockade of the angiotensin II type 1 receptors restored ANP release in response to volume expansion (p < 0.01). Moreover, acute inhibition of the renin-angiotensin system completely normalized the diuretic response. CONCLUSIONS: Our data suggest that the ANP system is impaired in rats with aortocaval shunt. The activation of the angiotensin system contributes to the impairment of the ANP system. Acute inhibition of the angiotensin II system significantly improved the ability of the ANP system to respond to acute volume expansion. Our findings indicate a hitherto fore unappreciated interaction between both systems and suggest additional mechanisms for the beneficial effects of angiotensin converting enzyme inhibition or angiotensin II type 1 receptor antagonists in heart failure.

Angiotensin II↗