Abstract 579: Increased Role of COX-derived Prostanoids in Regulating Ang II Induced Uterine Artery Contraction at Early Pregnancy in a Transgenic Model of Preeclampsia

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Victor M Pulgar ◽  
Liliya M Yamaleyeva ◽  
Jasmina Varagic ◽  
Carolynne M McGee ◽  
Michael Bader ◽  
...  
Keyword(s):  
Uterine Artery ◽  
Inhibitory Effect ◽  
Isometric Tension ◽  
Late Gestation ◽  
Female Rat ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Vascular Control ◽  
Human Renin

The balance between vasodilatory and vasoconstrictor prostanoids contributes to vascular control during pregnancy. Alterations in this balance are involved in the development of hypertensive pregnancy. The transgenic female rat containing the human angiotensinogen (hAGN) gene mated with the male transgenic containing human renin (hREN) is a model of preeclampsia (TgA), and shows hypertension and proteinuria at late gestation. We investigated the role COX-derived mediators have on contractility of the uterine artery (UA) in TgA rats before the hypertensive phenotype develops. UA were isolated from transgenic TgA (n=9) and Sprague-Dawley (n=7) control rats at 7 days of gestation. UA were mounted in a wire myograph for determinations of isometric tension (DMT USA, 620M). Responses to acetylcholine (ACh), phenylephrine (Phe) and sodium nitroprusside (SNP) were measured in control conditions and after preincubation with indomethacin (Indo, 10-5M). Data were fitted to a dose response curve, vasodilatation was expressed as percent of pre-constriction and sensitivity as pD2 (pD2= -Log [EC50]). Responses to ACh reached similar maximal relaxations (64±8 vs 75±6%, p>0.05), and an increased contraction in TgA UA at ACh >10μM (p<0.05) was eliminated by Indo. Contraction to Phe was similar in both groups with an inhibitory effect of Indo on TgA UA (p<0.05). Relaxation to SNP was lower in TgA vs SD UA (92±2 vs 74±5%, p<0.05), this difference was abolished by Indo. Thus, inhibition of COX enzymes had a greater effect on TgA UA suggesting an imbalance towards an increased prostanoids-derived constrictor tone in TgA UA. This imbalance appears before the hypertensive phenotype is established.

scholarly journals Functional changes in the uterine artery precede the hypertensive phenotype in a transgenic model of hypertensive pregnancy

2015 ◽  
Vol 309 (9) ◽  
pp. E811-E817 ◽  
Author(s):  
Victor M. Pulgar ◽  
Liliya M. Yamaleyeva ◽  
Jasmina Varagic ◽  
Carolynne McGee ◽  
Michael Bader ◽  
...  
Keyword(s):  
Uterine Artery ◽  
Late Gestation ◽  
Transgenic Rat ◽  
Sprague Dawley ◽  
Early Gestation ◽  
Functional Changes ◽  
Hypertensive Pregnancy ◽  
Human Renin ◽  
Stretch Response

The pregnant female human angiotensinogen (hAGN) transgenic rat mated with the male human renin (hREN) transgenic rat is a model of preeclampsia (TgA) with increased blood pressure, proteinuria, and placenta alterations of edema and necrosis at late gestation. We studied vascular responses and the role of COX-derived prostanoids in the uterine artery (UA) at early gestation in this model. TgA UA showed lower stretch response, similar smooth muscle α-actin content, and lower collagen content compared with Sprague-Dawley (SD) UA. Vasodilation to acetylcholine was similar in SD and TgA UA (64 ± 8 vs. 75 ± 6% of relaxation, P > 0.05), with an acetylcholine-induced contraction in TgA UA that was abolished by preincubation with indomethacin (78 ± 6 vs. 83 ± 11%, P > 0.05). No differences in the contraction to phenylephrine were observed (159 ± 11 vs. 134 ± 12 %KMAX, P > 0.05), although in TgA UA this response was greatly affected by preincubation with indomethacin (179 ± 16 vs. 134 ± 9 %KMAX, P < 0.05, pD2 5.92 ± 0.08 vs. 5.85 ± 0.03, P < 0.05). Endothelium-independent vasodilation was lower in TgA UA (92 ± 2 vs. 74 ± 5% preconstricted tone, P < 0.05), and preincubation with indomethacin restored the response to normal values (90 ± 3 vs. 84 ± 3%). Immunostaining showed similar signals for α-actin, COX-2, and eNOS between groups ( P > 0.05). Plasma thromboxane levels were similar between groups. In summary, TgA UA displays functional alterations at early gestation before the preeclamptic phenotype is established. Inhibition of COX enzymes normalizes some of the functional defects in the TgA UA. An increased role for COX-derived prostanoids in this model of preeclampsia may contribute to the development of a hypertensive pregnancy.

POSSIBLE ROLE OF 5α-ANDROSTANE-3α,17β-DIOL IN THE CONTROL OF FOLLICLE-STIMULATING HORMONE SECRETION IN THE IMMATURE FEMALE RAT

1982 ◽  
Vol 92 (1) ◽  
pp. 37-42 ◽  
Author(s):  
H. M. A. MEIJS-ROELOFS ◽  
P. KRAMER ◽  
L. GRIBLING-HEGGE
Keyword(s):  
Inhibitory Action ◽  
Combined Treatment ◽  
Hormone Secretion ◽  
Inhibitory Effect ◽  
Ovariectomized Rats ◽  
Female Rat ◽  
Immature Rat ◽  
Rat Strain ◽  
Intact Rats

A possible role of 5α-androstane-3α,17β-diol (3α-androstanediol) in the control of FSH secretion was studied at various ages in ovariectomized rats. In the rat strain used, vaginal opening, coincident with first ovulation, generally occurs between 37 and 42 days of age. If 3α-androstanediol alone was given as an ovarian substitute, an inhibitory effect on FSH release was evident with all three doses tested (50, 100, 300 μg/100 g body wt) between 13 and 30 days of age; at 33–35 days of age only the 300 μg dose caused some inhibition of FSH release. Results were more complex if 3α-androstanediol was given in combined treatment with oestradiol and progesterone. Given with progesterone, 3α-androstanediol showed a synergistic inhibitory action on FSH release between 20 and 30 days of age. However, when 3α-androstanediol was combined with oestradiol a clear decrease in effect, as compared to the effect of oestradiol alone, was found between 20 and 30 days of age. Also the effect of combined oestradiol and progesterone treatment was greater than the effect of combined treatment with oestradiol, progesterone and 3α-androstanediol. At all ages after day 20 none of the steroid combinations tested was capable of maintaining FSH levels in ovariectomized rats similar to those in intact rats. It is concluded that 3α-androstanediol might play a role in the control of FSH secretion in the immature rat, but after day 20 the potentially inhibitory action of 3α-androstanediol on FSH secretion is limited in the presence of oestradiol.

Angiotensin II-mediated biphasic regulation of proximal tubular Na+/H+ exchanger 3 is impaired during oxidative stress

2011 ◽  
Vol 301 (2) ◽  
pp. F364-F370 ◽  
Author(s):  
Anees Ahmad Banday ◽  
Mustafa F. Lokhandwala
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Tap Water ◽  
Buthionine Sulfoximine ◽  
Inhibitory Effect ◽  
Ang Ii ◽  
Sprague Dawley ◽  
High Concentration ◽  
Nitric Oxide Signaling ◽  
Proximal Tubular

Angiotensin (ANG) II via AT1 receptors (AT1Rs) maintains sodium homeostasis by regulating renal sodium transporters including Na+/H+ exchanger 3 (NHE3) in a biphasic manner. Low-ANG II concentration stimulates whereas high concentrations inhibit NHE3 activity. Oxidative stress has been shown to upregulate AT1R function that could modulate the ANG II-mediated NHE3 regulation. This study was designed to identify the signaling pathways responsible for ANG II-mediated biphasic regulation of proximal tubular NHE3 and the effect of oxidative stress on this phenomenon. Male Sprague-Dawley rats were chronically treated with a pro-oxidant l-buthionine sulfoximine (BSO) with and without an antioxidant tempol in tap water for 3 wk. BSO-treated rats exhibited oxidative stress and high blood pressure. At low concentration (1 pM) ANG II increased NHE3 activity in proximal tubules from all animals. However, in BSO-treated rats, the stimulation was more robust and was normalized by tempol treatment. ANG II (1 pM)-mediated NHE3 activation was abolished by AT1R blocker, intracellular Ca2+ chelator, and inhibitors of phospholipase C (PLC) and Ca2+-dependent calmodulin (CaM) but it was insensitive to Giα and protein kinase C inhibitors or AT2R antagonist. A high concentration of ANG II (1 μM) inhibited NHE3 activity in control and tempol-treated rats. However, in BSO-treated rats, ANG II (1 μM) continued to induce NHE3 stimulation. Tempol restored the inhibitory effect of ANG II (1 μM) in BSO-treated rats. The inhibitory effect of ANG II (1 μM) involved AT1R-dependent, cGMP-dependent protein kinase (PKG) activation and was independent of AT2 receptor and nitric oxide signaling. We conclude that ANG II stimulates NHE3 via AT1R-PLC-CaM pathway and inhibits NHE3 by AT1R-PKG activation. Oxidative stress impaired ANG II-mediated NHE3 biphasic response in that stimulation was observed at both high- and low-ANG II concentration.

Changes in Vsmc Phenotypes in Ang Ii-Dependent Hypertension of TGR (mREN2) 27 (Tgr) Transgenic Rats

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 688-688
Author(s):  
Gian Paolo P Rossi ◽  
Saverio Sartore ◽  
Stefania Colonna ◽  
Alfredo Sacchetto ◽  
Damiano Rizzoni ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Iliac Artery ◽  
Structural Changes ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Selective Antagonist ◽  
Heavy Chains ◽  
Group I ◽  
Group B

57 Arterial hypertension is associated with vascular smooth muscle cells (VSMC) phenotypic differentiation, but the role of Ang II and ET-1 is still unclear. Thus, we investigated the changes of VSMC phenotypes in Ang II-dependent hypertension and the role of ET-1 and its A receptor (ET A ). Four-week old heterozygote male TGR rats (n=24) were body weight (BW)- and blood pressure (BP)-matched and randomly allocated to receive orally a placebo (Group P), the mixed ET A /ET B antagonist Bosentan (100 mg/Kg, Group B) the Ang II AT-1 specific receptor antagonist Irbesartan (50 mg/Kg BW, Group I) or the ET A selective antagonist BMS-182874 (52 mg/Kg BW, Group BMS). After 4-wk of treatments, during which BW and BP were measured weekly, animals were euthanized; the iliac artery and mesenteric arterioles were collected. In the latter the structural changes were assessed with a myograph. Immunohistochemistry with a panel of different antibodies specific for ET-1, ET A , smooth muscle (SM) myosin, SM actin, SM 22, myosin heavy chains Apla 22 and fibronectin EIIIA was carried out. The fetal, neonatal and adult aorta from normotensive Sprague-Dawley rats were studied as control. Compared to all other groups, Group I rats showed significantly (p<0.001) lower systolic BP (161±8 mmHg, vs 269±23 Group P; vs 254±21 Group BMS), LV weight (2.28±0.15 mg/g BW vs 3.71±0.26, 3.38±0.27 and 3.96±0.51), and normalized media thickness of the mesenteric arterioles (22.3±0.6 μm vs 25.3±0.5, 25.5±0.7 and 24.1±1.5). Hypertension, LVH and medial arterioles hypertrophy in group P TGR were paralleled by a shift of VSMC toward a fetal phenotype in the iliac artery, despite no change in the expression of both irET-1 and ET A . The VSMC phenotypic shift was prevented by both irbesartan and Bosentan, but not by the ET A -selective antagonist BM 182874. Thus, Ang II-dependent hypertension of TGR is associated with both vascular hypertrophy and a shift of VSMC toward a fetal phenotype, which occurs through AT-1- and ET B - but not ET A -mediated mechanisms.

Involvement of AT2 receptors at NRVL in tonic baroreflex suppression by endogenous angiotensins

1997 ◽  
Vol 272 (5) ◽  
pp. H2204-H2210 ◽  
Author(s):  
K. S. Lin ◽  
J. Y. Chan ◽  
S. H. Chan
Keyword(s):  
Suppressive Effect ◽  
Angiotensin Receptors ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Inhibitory Modulation ◽  
Sprague Dawley Rats ◽  
Peptide Antagonist ◽  
Endogenous Activity ◽  
At2 Receptors

We evaluated the role of endogenous angiotensin II and III (ANG II and ANG III) at the rostral nucleus reticularis ventrolateralis (NRVL) in the modulation of baroreceptor reflex (BRR) response and the subtype of angiotensin receptors involved in this process. Adult male Sprague-Dawley rats anesthetized and maintained with pentobarbital sodium were used. Exogenous application of ANG II or ANG III (10, 20, or 40 pmol) by bilateral microinjection into the NRVL significantly suppressed the BRR response to transient hypertension induced by phenylephrine (5 micrograms/kg i.v.). The suppressive effect of ANG II (20 pmol) was reversed by an equimolar dose (1.6 nmol) of its peptide antagonist, [Sar1, Ile8]ANG II, and the nonpeptide antagonists for AT1 and AT2 receptors, losartan and PD-123319, respectively. On the other hand, the inhibitory action of ANG III (20 pmol) was blunted by its peptide antagonist. [Ile7]ANG III or PD-123319, but not by losartan. Blocking the endogenous activity of the angiotensins by microinjection into the bilateral NRVL of [Sar1, Ile8]ANG II, [Ile7]ANG III, or PD-123319 elicited an appreciable enhancement of the BRR response, whereas losartan produced minimal effect. These results suggest that, under physiological conditions, both endogenous ANG II and ANG III may exert a tonic inhibitory modulation on the BRR response by acting selectively on the AT2 receptors at the NRVL.

scholarly journals Activation of angiotensin II type 2 receptor suppresses TNF-α-induced ICAM-1 via NF-кB: possible role of ACE2

2015 ◽  
Vol 309 (5) ◽  
pp. H827-H834 ◽  
Author(s):  
Liping Zhu ◽  
Oscar A. Carretero ◽  
Jiang Xu ◽  
Pamela Harding ◽  
Nithya Ramadurai ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Ang Ii ◽  
Human Coronary Artery ◽  
Activity Inhibition ◽  
Tnf Α ◽  
System Activation ◽  
Interfering Rna ◽  
Stimulation Of

ANG II type 2 receptor (AT2) and ANG I-converting enzyme 2 (ACE2) are important components of the renin-ANG system. Activation of AT2 and ACE2 reportedly counteracts proinflammatory effects of ANG II. However, the possible interaction between AT2 and ACE2 has never been established. We hypothesized that activation of AT2 increases ACE2 activity, thereby preventing TNF-α-stimulated ICAM-1 expression via inhibition of NF-κB signaling. Human coronary artery endothelial cells were pretreated with AT2 antagonist PD123319 (PD) or ACE2 inhibitor DX600 and then stimulated with TNF-α in the presence or absence of AT2 agonist CGP42112 (CGP). We found that AT2 agonist CGP increased both ACE2 protein expression and activity. This effect was blunted by AT2 antagonist PD. ICAM-1 expression was very low in untreated cells but greatly increased by TNF-α. Activation of AT2 with agonist CGP or with ANG II under concomitant AT1 antagonist reduced TNF-α-induced ICAM-1 expression, which was reversed by AT2 antagonist PD or ACE2 inhibitor DX600 or knockdown of ACE2 with small interfering RNA. AT2 activation also suppressed TNF-α-stimulated phosphorylation of inhibitory κB (p-IκB) and NF-κB activity. Inhibition of ACE2 reversed the inhibitory effect of AT2 on TNF-α-stimulated p-IκB and NF-κB activity. Our findings suggest that stimulation of AT2 reduces TNF-α-stimulated ICAM-1 expression, which is partly through ACE2-mediated inhibition of NF-κB signaling.

Chronic hypoxia alters effects of endothelin and angiotensin on K+ currents in pulmonary arterial myocytes

1999 ◽  
Vol 277 (3) ◽  
pp. L431-L439 ◽  
Author(s):  
Larissa A. Shimoda ◽  
J. T. Sylvester ◽  
James S. K. Sham
Keyword(s):  
Smooth Muscle ◽  
Chronic Hypoxia ◽  
Inhibitory Effect ◽  
Resting Membrane Potential ◽  
Ang Ii ◽  
Voltage Gated ◽  
Pulmonary Arterial ◽  
Arterial Smooth Muscle Cells ◽  
K Currents

We tested the hypothesis that chronic hypoxia alters the regulation of K+ channels in intrapulmonary arterial smooth muscle cells (PASMCs). Charybdotoxin-insensitive, 4-aminopyridine-sensitive voltage-gated K+(KV,CI) and Ca2+-activated K+(KCa) currents were measured in freshly isolated PASMCs from rats exposed to 21 or 10% O2 for 17–21 days. In chronically hypoxic PASMCs, KV,CIcurrent was reduced and KCacurrent was enhanced. 4-Aminopyridine (10 mM) depolarized both normoxic and chronically hypoxic PASMCs, whereas charybdotoxin (100 nM) had no effect in either group. The inhibitory effect of endothelin (ET)-1 (10−7 M) on KV,CI current was significantly reduced in PASMCs from chronically hypoxic rats, whereas inhibition by angiotensin (ANG) II (10−7M) was enhanced. Neither ET-1 nor ANG II altered KCa current in normoxic PASMCs; however, both stimulated KCacurrent at positive potentials in chronically hypoxic PASMCs. These results suggest that although modulation of KV,CI and KCa channels by ET-1 and ANG II is altered by chronic hypoxia, the role of these channels in the regulation of resting membrane potential was not changed.

scholarly journals Early Gestational Exposure to Inhaled Ozone Impairs Maternal Uterine Artery and Cardiac Function

2020 ◽  
Author(s):  
Marcus Garcia ◽  
Raul Salazar ◽  
Thomas Wilson ◽  
Selita Lucas ◽  
Guy Herbert ◽  
...  
Keyword(s):  
Uterine Artery ◽  
Gestational Hypertension ◽  
Resistance Index ◽  
Cardiovascular Effects ◽  
Late Gestation ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Transcriptional Changes ◽  
Adverse Pregnancy ◽  
Underlying Mechanisms

Abstract Exposure to air pollutants such as ozone (O3) is associated with adverse pregnancy outcomes, including higher incidence of gestational hypertension, preeclampsia, and peripartum cardiomyopathy; however, the underlying mechanisms of this association remain unclear. We hypothesized that O3 exposures during early placental formation would lead to more adverse cardiovascular effects at term for exposed dams, as compared with late-term exposures. Pregnant Sprague Dawley rats were exposed (4 h) to either filtered air (FA) or O3 (0.3 or 1.0 ppm) at either gestational day (GD)10 or GD20, with longitudinal functional assessments and molecular endpoints conducted at term. Exposure at GD10 led to placental transcriptional changes at term that were consistent with markers in human preeclampsia, including reduced mmp10 and increased cd36, fzd1, and col1a1. O3 exposure, at both early and late gestation, induced a significant increase in maternal circulating soluble FMS-like tyrosine kinase-1 (sFlt-1), a known driver of preeclampsia. Otherwise, exposure to 0.3 ppm O3 at GD10 led to several late-stage cardiovascular outcomes in dams that were not evident in GD20-exposed dams, including elevated uterine artery resistance index and reduced cardiac output and stroke volume. GD10 O3 exposure proteomic profile in maternal hearts characterized by a reduction in proteins with essential roles in metabolism and mitochondrial function, whereas phosphoproteomic changes were consistent with pathways involved in cardiomyopathic responses. Thus, the developing placenta is an indirect target of inhaled O3 and systemic maternal cardiovascular abnormalities may be induced by O3 exposure at a specific window of gestation.

Angiotensin-(1–7) stimulates the phosphorylation of JAK2, IRS-1 and Akt in rat heart in vivo: role of the AT1 and Mas receptors

2007 ◽  
Vol 293 (2) ◽  
pp. H1154-H1163 ◽  
Author(s):  
Jorge F. Giani ◽  
Mariela M. Gironacci ◽  
Marina C. Muñoz ◽  
Clara Peña ◽  
Daniel Turyn ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Rat Heart ◽  
Inhibitory Effect ◽  
Janus Kinase ◽  
Ang Ii ◽  
Signaling Crosstalk ◽  
Akt Phosphorylation ◽  
Jak2 Inhibitor

Angiotensin (ANG) II exerts a negative modulation on insulin signal transduction that might be involved in the pathogenesis of hypertension and insulin resistance. ANG-(1–7), an endogenous heptapeptide hormone formed by cleavage of ANG I and ANG II, counteracts many actions of ANG II. In the current study, we have explored the role of ANG-(1–7) in the signaling crosstalk that exists between ANG II and insulin. We demonstrated that ANG-(1–7) stimulates the phosphorylation of Janus kinase 2 (JAK2) and insulin receptor substrate (IRS)-1 in rat heart in vivo. This stimulating effect was blocked by administration of the selective ANG type 1 (AT1) receptor blocker losartan. In contrast to ANG II, ANG-(1–7) stimulated cardiac Akt phosphorylation, and this stimulation was blunted in presence of the receptor Mas antagonist A-779 or the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. The specific JAK2 inhibitor AG-490 blocked ANG-(1–7)-induced JAK2 and IRS-1 phosphorylation but had no effect on ANG-(1–7)-induced phosphorylation of Akt, indicating that activation of cardiac Akt by ANG-(1–7) appears not to involve the recruitment of JAK2 but proceeds through the receptor Mas and involves PI3K. Acute in vivo insulin-induced cardiac Akt phosphorylation was inhibited by ANG II. Interestingly, coadministration of insulin with an equimolar mixture of ANG II and ANG-(1–7) reverted this inhibitory effect. On the basis of our present results, we postulate that ANG-(1–7) could be a positive physiological contributor to the actions of insulin in heart and that the balance between ANG II and ANG-(1–7) could be relevant for the association among insulin resistance, hypertension, and cardiovascular disease.

Abstract MP04: Cardiac ACE2/Angiotensin-(1-7) in Rats Expressing Human Angiotensinogen Gene

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Jasmina Varagic ◽  
Jessica VonCannon ◽  
Sarfaraz Ahmad ◽  
Michael Bader ◽  
Carlos M Ferrario
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Tissue ◽  
Male Rats ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Transgenic Rats ◽  
Sd Rats ◽  
Agt Gene ◽  
Tissue Angiotensin

When compared to Sprague Dawley (SD) control rats, transgenic rats expressing the human angiotensinogen (AGT) gene [TGR(hAGT)L1623] exhibit hypertension associated with cardiac hypertrophy and higher cardiac tissue angiotensin (Ang) II. Whether the hypertension and cardiac hypertrophy in these rats expressing the human AGT are related to a non-canonical pathway for Ang II formation or suppression of the counter regulatory mechanism mediated by ACE2 and Ang-(1-7) has not been established. Consequently, cardiac peptides were determined by RIA in 9 [TGR(hAGT)L1623] and 11 SD male rats (17 weeks of age). ACE2 activities in homogenized heart tissues were determined by HPLC. Cardiac Ang II content was four times higher (37.05 ± 5.04 vs. 9.62 ± 0.93 fmol/mg protein; p <0.0001) while the Ang-(1-7) level increased only 1.3 times (18.02 ± 1.62 vs 13.37 ± 1.74 fmol/mg protein; p=0.06) in TGR(hAGT)L1623 rats when compared with SD rats. Although, the Ang II/Ang-(1-7) ratio was higher in transgenic rats harboring the human AGT gene (2.10 ± 0.27 vs 0.90 ± 0.19; p <0.005), ACE2 activities between these two strains of animals were not different (12.21 ± 0.76 vs. 10.80 ± 0.91 fmol/min/mg; p >0.05). Since human AGT protein is not cleaved by rat renin, our data continues to support the view that hypertension and cardiac hypertrophy in this transgenic strain are induced by activation of a non-renin mechanism rather than a primary suppression of the compensatory Ang II degrading pathway mediated by ACE2. Further studies are necessary to determine the role of enzymes affecting Ang-(1-7) metabolism in the observed inadequate balance between Ang II and Ang-(1-7).

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