bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 520: Fine Mapping of Two Loci Within a Major Albuminuria QTL on Rat Chromosome 6 That Affect Both Albuminuria and Deficient Nephron Development in The Munich Wistar Frömter Rat
Authors: Schulz Angela , Herlan Laura , Schmidbauer Martina , Kreutz Reinhold 
Published: March 2022

We previously confirmed in the Munich Wistar Frömter (MWF) rat a functional role of a major quantitative trait locus (QTL) on rat chromosome (RNO)6 for both albuminuria development and an inherited nephron deficit in the consomic strain MWF-6SHR. We addressed the question whether an inherited nephron deficit is linked to the genetic basis of albuminuria and whether common genetic factors are responsible for both phenotypes in this rat model.
We generated congenic lines to dissect the RNO6-QTL using SHR rats with low albuminuria as a reference strain. Chromosomal fine mapping was performed by breeding of subcongenic lines, comparative genome analysis and physical mapping. The nephron number was determined by determination of the glomerular density in animals at 4 weeks of age; this method was validated by comparison with the absolute nephron numbers as determined by the physical fractionator method in parental strains.

Phenotyping of the congenic lines covering the RNO6-QTL demonstrated that both the albuminuria and the nephron locus were subdivided into at least two different colocalized informative loci. One interval defined by the congenic lines MWF.SHR-(D6Rat1-D6Rat81) and MWF.SHR-(D6Rat1-D6Rat117) covers 2.1 Mb and contains 26 known genes. Exchange of this locus had a strong impact on albuminuria at 8 weeks of age resulting in a decrease from 18.1 to 5.0 mg/24 h (p<0.0001) between the congenic strains and affected also the glomerular density (184 vs. 223 /mm
3
, p=0.0004). The second interval flanked by the congenic lines MWF.SHR-(D6Rat1-D6Rat117) and MWF.SHR-(D6Rat1-D6Mgh4) encompasses 2.8 Mb and contains 49 known genes. This interval influenced also albuminuria (decrease from 5.0 to 1.5 mg/24h, p=0.0001) and glomerular density (223 vs. 243 /mm
3
, p=0.008). These findings support the genetic link between albuminuria and nephron deficit in this model and provide the basis for further functional and comparative genomic analysis to obtain new insights into this association.
Abstract 562: Differential Effects of Renin Inhibitors and Ca2+ Channel Blockers on Blood Pressure and Vascular Function in Caveolin-1 Null Mice
Authors: Pojoga Luminita , Opsasnick Lauren A , Siddiqui Waleed T , Reslan Ossama M , Adler Gail K , Williams Gordon H , Khalil Raouf A 
Published: March 2022

Caveolin-1 (cav-1) is a transmembrane protein identified in plasma membrane caveolae, and a potential modulator of renal and vascular function and insulin sensitivity. We have shown that cav-1 gene variants are associated with insulin resistance (IR) in hypertensive humans, and that cav-1 deficiency in mice leads to increased blood pressure (BP) and IR. To test whether these changes in the cav-1 KO involve renal or vascular abnormalities, we treated WT and cav-1 KO mice for 14 days with placebo, the renin inhibitor aliskiren (50 mg/kg/day), or the Ca
2+
channel blocker amlodipine (6 mg/kg/day) and assessed BP, fasting blood glucose, HOMA-IR, plasma aldosterone (ALDO), and vascular function.

Cav-1 KO mice, as compared with WT, showed increased BP (131±7 vs. 110±2 mm Hg), blood glucose (112±4 vs. 83±4 mg/dl), HOMA-IR (1.9±1.1 vs. 1.1±0.4), lower plasma ALDO (97±10 vs. 131±42 ng/dl), and altered vascular reactivity--reduced Phe-induced vasoconstriction (0.6±0.2 vs. 1.1±0.2g), enhanced acetylcholine (ACh)-induced relaxation (65±11 vs 23±7%), and enhanced relaxation in response to exogenous NO. Endothelium removal, NOS inhibition, or guanylate cyclase inhibition abolished ACh-induced relaxation, suggesting changes in endothelium-dependent NO-cGMP pathway in cav-1 KO mice. In cav-1 KO mice aliskiren significantly reduced BP to 113±4 mm Hg, ALDO levels by 40%, and HOMA-IR to 0.9±0.1, but had no significant effects on blood glucose, Phe-induced vasoconstriction, ACh- or exogenous NO-induced vasorelaxation. In contrast, amlodipine reduced BP to 117±4 mmHg (this effect did not reach significance), had no effect on ALDO levels, and showed a trend for increased IR. Importantly, amlodipine enhanced the sensitivity to Phe in both WT and cav-1 KO, and reduced the ACh-induced relaxation in cav-1 KO mice to 47±11%.
Thus aliskiren treatment in cav-1 KO mice reduced BP possibly through suppression of RAAS and improved insulin sensitivity, but did not affect vascular function. In contrast, amlodipine treatment showed small changes in BP and IR but had adverse effects on vascular reactivity in cav-1 KO mice, raising the concern that it could have similar adverse effects on vascular function in hypertensive individuals that carry the cav-1 minor allele gene variants.
Abstract 630: Blood Pressure and Kidney Function in PRCP deficient Mice
Authors: Maier Christoph , Wysocki Jan , Ye Minghao , Haber Philipp K , Schmaier Alvin H , Batlle Daniel 
Published: March 2022

Changes in the enzymes involved in Ang II degradation may influence disease conditions such as hypertension and kidney disease. The enzyme prolylcarboxypeptidase (PRCP) catalyzes the conversion of Ang II to Ang(1-7) and its deficiency results in a phenotype characterized by a prothrombotic state, hypertension, and impaired wound healing. Here, we investigated kidney function and blood pressure in young mice, 10-16 weeks of age, with a subtotal PRCP deficiency (PRCP genetrap, PRCPgt).
Enzyme activity based on a synthetic fluorogenic peptide was used to measure PRCP activity. The activity of recombinant PRCP was strongly pH-dependent with an optimum in the acidic range (pH 5). In keeping with this, recombinant PRCP degraded Ang II at pH 5, but not at pH 7.4 in-vitro. PRCP activity was detected in serum and in kidney of WT mice whereas PRCPgt/gt mice displayed highly diminished serum PRCP activity (about 5% of the WT).
Kidney function was assessed by urinary protein/creatinine ratio and GFR. At 10 weeks of age, neither female nor male PRCPgt/gt animals showed elevations in urinary protein/creatinine-ratio (female PRCPgt/gt 19.9±1.4 vs. WT 23.5±1.9 and male PRCPgt/gt 32.4±3.5 vs. WT 34.8±1.8). At 16 weeks of age, the GFR (measured by clearance of FITC-Inulin) was not different (female PRCPgt/gt 4.10±0.32 vs. WT 4.33±0.29 and male PRCPgt/gt 4.41±0.50 vs. WT 4.28±0.31 ul/min/g). Systolic blood pressure was significantly elevated in PRCPgt/gt animals as compared to the respective WT controls (female PRCPgt/gt 147.8±3.4 vs. WT 117.3±7.1 mmHg, male 138.1±8.4 vs. 120.5±3.6 mmHg, p<0.05).
PRCP deficient mice have normal GFR but elevated basal blood pressure. Whether PRCP deficiency causes hypertension as a result of impaired Ang II degradation or other mechanisms needs to be determined.
Abstract 65: Soluble Angiotensin Converting Enzyme 2 as an Additional Source of Blood Pressure Regulation within the Kidney
Authors: Ortiz Melo David I , Mattocks Natalie K , Xu Katherine , Griffiths Robert , Gurley Susan B 
Published: March 2022

Angiotensin Converting Enzyme 2 (ACE2) is a transmembrane carboxypeptidase that degrades angiotensin II (AngII) to Ang(1-7). This membrane-bound enzyme can be cleaved by metalloproteinases such as ADAM17, releasing the catalytically active ectodomain to generate soluble ACE2. The objective of this study is to determine if soluble ACE2, acting locally in the kidney, could modulate the blood pressure (BP) response to AngII infusion.
In order to isolate the actions of ACE2 in the kidney from systemic tissues, we utilized kidney cross-transplantation. We studied male (129/SvEv x C57BL/6)F1 ACE2 knockout (KO) and wild-type (WT) mice. Kidney transplants were performed to generate 4 experimental groups: 1) WT, 2) kidney ACE2KO, 3) systemic ACE2KO, and 4) total ACE2KO. Mean arterial BPs (MAP) were measured with radiotelemetry at baseline and during a 2-week infusion of AngII (1ug/kg/min). Enzymatic activity was determined using an ACE2-specific quenched fluorescent substrate assay.
Total ACE2KO mice had an enhanced hypertensive response to AngII compared to WT mice (152±6 vs.144±7 mmHg; p=0.03), consistent with our previous findings of enhanced susceptibility to AngII hypertension in mice globally deficient in ACE2. The presence of ACE2 in either the kidney or systemic tissues restored MAPs to levels similar to the WT group (kidney ACE2KO 140±7mmHg, systemic ACE2 KO 140±5 mmHg, p<0.01 vs. total KO). Serum ACE2 activity levels were decreased in systemic KO mice (40±35 RFU/ul/hr) but unaffected in kidney KO mice, compared to WT (153±25 vs. 126±26 RFU/ul/hr, respectively). However, despite genetic deletion from all kidney cells, kidney ACE2KO mice had similar urinary ACE2 activity compared to systemic ACE2KO (76±32 and 108±52 RFU/ul/hr, p=NS). Urinary ACE2 activity in WT mice was highest, 217±36 RFU/ul/hr, compared to total KO which was undetectable (p<0.001).
Our studies demonstrate that restoration of ACE2 in either the kidney or systemic tissues is sufficient to abrogate the exaggerated hypertensive response to chronic AngII infusion. Soluble ACE2 delivered to the kidney may be an additional source of ACE2 to act within the kidney since the cells produce no ACE2 locally in kidney KO mice. Our studies highlight a possible role of soluble ACE2 in BP regulation.
Abstract 204: Non-dipper Pattern Is Associated With Urinary Metanephrines In Patients With Refractory Hypertension
Authors: Dudenbostel Tanja , Acelajado Maria C , Li Peng , Oparil Suzanne , Calhoun David A 
Published: March 2022

Refractory hypertension (HTN) is an extreme phenotype of treatment-resistant HTN and is defined as blood pressure (BP) ≥140/90 mm Hg on ≥5 antihypertensive drug classes including a diuretic and mineralocorticoid antagonist.
Observational data indicate that African Americans, males, body mass index, kidney function, and diabetes are associated with refractory HTN. Available BP data of refractory HTN are based on clinic or in-home evaluations. Less is known about ambulatory blood pressure (ABP) levels, circadian patterns and pathophysiologic mechanisms.

Aim:
Prospective study of ABP levels, nocturnal BP fall, and urinary (U-) 24-hour metanephrines as index of sympathetic activity.

Methods:
Over a 2 year period, 44 subjects were prospectively enrolled (15 subjects with refractory HTN matched with 29 controlled resistant hypertensive subjects who served as comparator group). All subjects underwent 24-ABP monitoring (ABPM) and U-24-hour metanephrines testing.

Results:
Subjects with refractory HTN were on more antihypertensive drugs (6±1 vs 4.1±1.1, p≤ 0.05) and had significantly higher 24-hour systolic BP(SBP) (174±20.2 vs 139.8±16.3 mm Hg, p=0.0017), higher 24-hour diastolic BP (DBP) (94.7±19.8 vs 75.7±11.8 mm Hg, p=0.006), higher daytime SBP (178.1±97.4 vs 141±15.7 mm Hg, p=0.0046), higher daytime DBP (97.4±19.8 vs 77.2±11.4 mm Hg, p=0.007), higher nighttime SBP (165.2±19.2 vs 133.5±19.8 mm Hg, p=0.0002), and higher nighttime DBP (87.7±16.5 vs 70.2±15.1 mm Hg, p=0.007). Analysis of circadian patterns revealed significant increase in non-dipper pattern, defined as nocturnal BP fall of 0-10%, in subjects with refractory HTN (53.3 % (8 of 15) vs 14.3 % (3 of 28), p=0.0267). Biochemical analysis of U-24-hr fractionated metanephrines revealed significantly higher levels in refractory compared to controlled resistant HTN indicative of higher sympathetic activity (U-24-h total metanephrines (592.2 ±246.9 vs 409.3±167.0 μg, p=0.021, and U-24-h total normetanephrines 464.4 ±250.2 vs 309.8±147.6 μg, p=0.039).

These findings suggest that increased sympathetic activity may play a role in treatment failure and may promote blunted nocturnal BP fall in refractory hypertension.
Abstract 226: Adherence to Aspirin Therapy for Primary Prevention of Coronary Artery Disease and Cerebrovascular Accidents
Authors: Imran Tasnim F , Samra Mandeep , Hasan Zachariah I , Thiruvarudsothy Srikanth , Kim Stephanie , Feurdean Mirela , Tentler Aleksey 
Published: March 2022

Cardiovascular disease is the leading cause of death in the United States. One simple, overlooked, and easily available therapy can reduce this risk: aspirin. Low dose aspirin reduces the risk of first time myocardial infarction (MI) in men and ischemic stroke (CVA) in women. The American Heart Association recommends anti-platelet therapy for those with an ASCVD (atherosclerotic cardiovascular disease) risk score> 7.5%. The aim of our study was to determine adherence to guidelines regarding aspirin therapy for primary prevention of myocardial infarction and stroke in our resident clinic. A retrospective chart review of randomized patients with risk factors for CAD and CVA seen at Ambulatory Center in Newark, NJ, between 5/1/12 and 10/29/13 was conducted. Those with contraindications to aspirin therapy were excluded.
Over 400 charts were reviewed; 281 met inclusion criteria. Per chart review, only 30% (84/281) of all at-risk patients were taking aspirin. When assessing various risk factors, 44.9% (35/78) of males ages 45-79; 24% (28/116) of females ages 55-79 (95% Confidence Interval [CI] = +-5.9%); 35.7% (51/143) of those with 10-year ASCVD risk score greater than 7.5% (95% CI = +-7.9%); 36.1% (39/108) of diabetic patients (95% CI 95% = +-9.2%); 32.8% (66/201) of those on anti-hypertensive medication (95% CI = +- 6.5%) and 29.3% (36/123) of those with a smoking history were taking aspirin (95% CI = +-8.2%). Of note, the number of women taking aspirin was statistically low as compared to men across all risk factors except for ASCVD score (p<0.01). This study revealed poor adherence to guidelines with regards to use of aspirin for primary prevention of cardiovascular disease and stroke in our resident clinic. In particular, adherence to aspirin therapy for women was strikingly low. However, our estimate may be somewhat low due to improper documentation of over the counter medications. We are implementing interventions to increase awareness of aspirin use such as educational campaigns for patients, mini-lectures for ambulatory resident cohorts, automated EMR reminders and adding aspirin therapy to health maintenance smart texts to achieve our goal of 100% compliance.
Abstract 290: Upregulation Of Regulatory T Cells Improves Fetal Development In Preeclamptic Rat Model But Has No Influence On Hypertension And Proteinuria.
Authors: Przybyl Lukasz , Ibrahim Tarek , Haase Nadine , Golic Michaela , Hünig Thomas , Müller Dominik N , LaMarca Babette , Herse Florian , Dechend Ralf 
Published: March 2022

Preeclampsia is characterized by hypertension, proteinuria and often associated with intrauterine growth retardation. There is a growing body of evidence that immunological dysregulation, involving T-cells, is implicated in causing preeclampsia. Proper recognition of paternal antigens by regulatory T cells is essential for successful outcome of pregnancy.
The aim of the study was to evaluate the effect of upregulating regulatory T cells in an established transgenic rat model for preeclampsia. Application of CD28-superagonistic antibody has been shown to effectively upregulate regulatory T cells. In the first protocol (treatment arm) we applied 1mg of CD28-superagonist or control antibody on day 11 and 15 of pregnancy. In the second protocol (prevention arm) the superagonist or control antibody was applied on day 1, 5 and 9 to improve placentation with an upregulation of regulatory T cells at implantation site.
Superagonist increased regulatory T cells in circulation and placenta from 1.6 ± 0.2% of CD4-positive T cells to 18.9 ± 4.8% and from 2.61 ± 0.96% to 23.27 ± 7.64%, respectively. Blood pressure (152.1 ± 5.8 mmHg vs 155.1 ± 3.6 mmHg, measured by telemetry on day 16) and albuminuria (30.6 ± 15.1 mg/d vs 14.6 ± 5.5 mg/d) were similar in the superagonist or sham treated preeclamptic group for both protocols. Rats treated with CD28-superagonist, showed higher pup weight (2.66 ± 0.03 g vs 2.37 ± 0.05 g) in preventive protocol and (3.04 ± 0.04 g vs 2.54 ± 0.1 g) in the treatment protocol. Intrauterine growth restriction, calculated by brain to liver weight ratio, was also decreased by superagonist in both protocols (0.88 ± 0.03 vs 1.07 ± 0.03 for prevention strategy and 0.72 ± 0.02 vs 1.05 ± 0.07 for therapeutic protocol respectively). Induction of regulatory T cells in circulation and uteroplacental unit early and late in an established preeclamptic rat model had no influence on hypertension and proteinuria. However, it improved the fetal outcome by ameliorating intrauterine growth retardation substantially.
Abstract 322: Protective effects of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) on renal damage in Dahl Salt-Sensitive Rats
Authors: Worou Morel E , D’Ambrosio Martin , Liao Tang-Dong , Nakagawa Pablo , Rhaleb Nour-Eddine , Carretero Oscar A 
Published: March 2022

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide hydrolyzed by angiotensin-converting enzyme. We previously reported that Ac-SDKP protects the kidney from inflammation, fibrosis, and dysfunction caused by hypertension. Salt-sensitivity is highly prevalent in African-Americans and elderly patients, and is associated with a high rate of hypertensive renal disease.
The effect of Ac-SDKP on Salt-Sensitive (SS) hypertension is unknown; here, we hypothesized that Ac-SDKP prevents renal fibrosis, glomerulosclerosis and albuminuria in Dahl SS rats on high salt diet without affecting blood pressure.

Dahl SS rats and their consomic control, SS-13BN were fed either 0.23% NaCl (low salt, LS) or 4% NaCl (high salt, HS) diet and infused with Ac-SDKP (800 μg/kg/day, subcutaneously
via
osmotic minipump) or vehicle (0.01 N acetic acid) for 6 weeks. Animals were divided into following groups: LS+vehicle, HS+vehicle, and HS+Ac-SDKP.

High salt increased systolic blood pressure (SBP) in SS rats (HS+vehicle 186±5 vs. LS+vehicle 141±3 mmHg), but not in SS-13BN (HS+vehicle 140±3 vs. LS+vehicle 140±2 mmHg). Ac-SDKP did not affect SBP. In both SS and SS-13BN, HS induced renal and cardiac hypertrophy, which were not prevented by Ac-SDKP. However, in SS rats, Ac-SDKP prevented HS-induced renal interstitial fibrosis (HS+vehicle 12±0.5 vs. HS+Ac-SDKP 7±1 % of renal interstitial area) and glomeruloslerosis (HS+vehicle 18±1 vs. HS+Ac-SDKP 9±1 % of glomerular tuft area). Compared to LS, HS increased albuminuria in both strains, from 13±1 to 94±10 mg/24h in SS and from 7±1 to 44±8 mg/24h in SS-13BN. HS also decreased nephrin protein expression in both strains. Interestingly, in SS-13BN, Ac-SDKP attenuated albuminuria (24±3.18 mg/24h) and partially attenuated the decrease in nephrin expression, but in SS, Ac-SDKP had no effect on either albuminuria (126±34 mg/24h) or nephrin expression.
In summary, Ac-SDKP prevents renal fibrosis, glomerulosclerosis but not albuminuria in Dahl SS rats on high salt diet. On the other hand, the consomic controls fed high salt developed albuminuria and decreased nephrin, and these effects were prevented by Ac-SDKP.
Abstract 402: Surgical Treatment Of Aldosterone Producing Adenoma Could Change Renovascular Hemodynamics –Decrement Of Resistive Index Evaluated By Renal Doppler Sonography–
Authors: Iwakura Yoshitsugu , Morimoto Ryo , Kudo Masataka , Ono Yoshikiyo , Ito Sadayoshi , Satoh Fumitoshi 
Published: March 2022

Patients with untreated primary aldosteronism (PA) often show albuminuria, which is a predictor for the decrement of their eGFR after specific treatment. Although the appropriate treatment of PA patients results in reducing albuminuria, the mechanism is still unclear. We planned a prospective study to investigate the effects of aldosterone on renal hemodynamics. Renal Doppler sonography (RDS) is recognized as non-invasive device to evaluate renal hemodynamics. Renal resistive index (RI), which is calculated by peak-systolic (PSV) and end-diastolic (EDV) flow velocities (RI = (PSV - EDV) / PSV) measured by RDS, has been reported as a surrogate marker for renal function and tissue injury.
Ninety four patients with aldosterone producing adenoma (APA) were participated; all of those fulfilled diagnostic criteria of PA and underwent adrenalectomy based on results of adrenal venous sampling. RDS was performed at baseline and followed at 1 and 12 months after adrenalectomy. Ninety one patients with essential hypertension were participated in this study as a control. All sonographic parameters were obtained at bilateral renal arteries including main tract, portal, segmental and interlobular parts and expressed as mean. Aldosterone, blood pressure (BP), albuminuria and estimated glomerular filtration rate (eGFR) were followed throughout the study period. Chronic kidney disease (CKD) was defined as eGFR<60 ml/min/1.73m2 or albuminuria≧30 mg/g creatinine.
Initial RI in the patients with untreated APA at all compartment arteries were significantly higher than those in control subjects (0.70 v.s 0.67 at main tract, 0.67 v.s 0.64 at portal part, 0.64 v.s 0.60 at segmental part and 0.63 v.s 0.60 at interlobular part). With significant decrease in aldosterone (from 28.7 to 8.8ng/dl), albuminuria and eGFR significantly declined after adrenalectomy. RI also immediately showed significant declines to 0.67 at main tract, to 0.63 at portal part, to 0.61 at segmental part and to 0.60 at interlobular part, respectively, at 1 month and remained stable through the follow-up period. Furthermore, RI significantly decreased in the APA patients with or without CKD.
Surgical treatment of APA could change renovascular hemodynamics according to the decrease of aldosterone.
Abstract 407: Aminopeptidase A (APA)/Ang(2-10) and APA/AngIII are the Dominant Axes in the Metabolism of Angiotensin Peptides in Mice Plasma
Authors: Wysocki Jan , Haque Syed K , Ye Minghao , Batlle Daniel 
Published: March 2022

ACE2 is considered an important enzyme in the degradation of Angiotensin (Ang) I (1-10) and especially of Ang II (1-8), as demonstrated by the rapid dissipation of this peptide when recombinant ACE2 is infused but the steady state level of ACE2 in plasma is low. We examined levels of multiple Ang peptides in plasma under steady state conditions in WT and ACE2KO mice on C57BL genetic background (n=4 and 5, respectively). Liquid chromatography mass-spectrometry-based approach which enables concurrent evaluation of ten different angiotensins at physiologic levels (pg/mL) was used for multiple peptide quantification.
The levels of angiotensin peptides in WT mice were highest for Ang I (1-10) (1295±313 pg/mL), Ang (2-10) (657±173 pg/mL) and Ang III (2-8) (1047±178 pg/mL). In contrast, plasma levels of Ang II (1-8), the main effector peptide of the RAS, and Ang (1-7), the product of cleavage of Ang II by ACE2, were very low (7.8±2 and 3.5±0 pg/mL, respectively). In ACE2 KO mice, Ang II and Ang (1-7) levels were not significantly different from WT. Activity of Aminopeptidase A, an enzyme that converts Ang (1-10) to Ang (2-10) and cleaves Ang II (1-8) to Ang III (2-8), was significantly increased in ACE2KO (n=11) as compared to WT (n=17) (149±11 vs. 94±9 RFU/ul/hr, respectively, p<0.001). This finding along with increased ratio of Ang (2-10)/Ang(1-8) (175±31 vs. 84±4, p<0.01, respectively) suggests increased formation of Ang (2-10) from Ang (1-10) in ACE2KO mice by APA over the formation of Ang II (1-8) from Ang (1-10).
These results show that plasma Ang II and Ang (1-7) levels in WT and ACE2KO mice are low relative to the high levels of Ang (2-10) and Ang III (2-8). ACE2 deficiency does not result in plasma Ang II accumulation or reduced Ang (1-7) levels and is associated with an increase in serum APA activity. We conclude that in mice plasma the APA/Ang(2-10) and APA/AngIII pathways, and not ACE2/Ang(1-7), are dominant in the metabolism of Ang I and Ang II under steady state conditions.