(Hypertension. 1998;31:356.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Angiotensin-(1–7) Contributes to the Antihypertensive Effects of Blockade of the Renin-Angiotensin System
From the Hypertension Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina.
Reprint requests to Carlos M. Ferrario, MD, Hypertension Center, The Bowman Gray School of Medicine of Wake Forest University, Medical Center Boulevard, Winston-Salem, NC 27157-1095 E-mail cferrari{at}bgsm.edu
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Abstract |
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Angiotensin-converting enzyme (ACE) inhibition alone or in combination with the angiotensin type-I receptor (AT1) antagonist losartan augments circulating levels of the bioactive peptide angiotensin-(1–7) [Ang-(1–7)]. Hence, we determined whether Ang-(1–7) contributes to the hypotensive effects produced by the combined administration of lisinopril and losartan in spontaneously hypertensive rats by blocking the peptide’s synthesis with either of two structurally different neprilysin inhibitors. Intravenous administration of CGS 24592 (30 mg/kg) to rats in which blood pressure was normalized by 9 days of therapy with lisinopril and losartan elicited an elevation of mean arterial pressure that was sustained throughout the infusion period and for 20 minutes thereafter. The hypertensive response was associated with a 62% reduction in circulating levels of Ang-(1–7) and no change in plasma angiotensin II (Ang II). Intravenous infusion of one other neprilysin inhibitor (SCH 39370, 30 mg/kg) produced an increase in mean blood pressure of a magnitude similar to that found with CGS 24592. Pretreatment with the nonselective antagonist [Sar,1Thr8]-Ang II abolished any additional pressor effects of either neprilysin inhibitor in spontaneously hypertensive rats treated with lisinopril or losartan. However, neither the endothelin A antagonist BQ123 nor the kinin B2 antagonist HOE 140 had an effect on basal blood pressure or altered the pressor or heart rate effects of the neprilysin inhibitors. These data suggest that inhibition of Ang-(1–7) formation in rats exposed to the combined blockade of Ang II production and activity is associated with a reversal of the antihypertensive actions produced by these therapies. Thus, endogenous Ang-(1–7) functions as a vasodilator hormone in this form of genetic hypertension.
Key Words: angiotensin-(1–7) • neprilysin • angiotensin-converting enzyme • lisinopril • losartan • SHR • hypertension
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Introduction |
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Angiotensin-(1–7) [Ang-(1–7)], one of several bioactive end products of the renin-angiotensin system, may function as an antihypertensive hormone1 by virtue of its potent natriuretic and diuretic actions2–4 and vasodepressor effects in the coronary and mesenteric vascular beds.5–7 Moreover, low concentrations of Ang-(1–7) enhance the vasodepressor actions of bradykinin in both intact rats8,9 and isolated canine coronary artery rings.10 The receptor mediating the vascular actions of Ang-(1–7) has been tentatively characterized as a non-angiotensin type-I receptor (AT1)/angiotension type-II receptor (AT2) subtype.11,12
Production of Ang-(1–7) from angiotensin I (Ang I) is determined by the action of tissue endopeptidases;13 neutral endopeptidase 24.11 (EC 3.4.24.11, neprilysin) account for the generation of the peptide in the systemic and renal circulations.14 Whereas the enzymatic pathway involved in the generation of Ang-(1–7) is distinct from that of Ang II, angiotensin converting enzyme (ACE) EC 3.4.15.1 cleaves the heptapeptide into inactive products.10,15 This finding explains the observation in man and animals of a 5- to 25-fold increase in the plasma concentration of Ang-(1–7) during chronic treatment with ACE inhibitors.16–20 Because previous studies suggest that endogenous neutralization of Ang-(1–7) mitigates the antihypertensive actions of the combined administration of lisinopril and losartan,11 we have now explored the effects of acute inhibition of Ang-(1–7) synthesis in spontaneously hypertensive rats (SHRs) after their blood pressure was normalized by these therapies. The physiological consequences of endogenous Ang-(1–7) inhibition were determined by the comparative effect of infusion of two specific inhibitors of neprilysin at a time when circulating levels of Ang-(1–7) were increased significantly by chronic therapy with lisinopril and losartan.11
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Animals
Adult male SHRs (12 weeks of age, 350 g) were purchased from Charles River. Animals had free access to tap water and rat chow (Purina Mills Inc.) providing an intake of 17 mmol sodium/28 mmol potassium per 100 g each day. The rats were housed under a 12-hour light/dark cycle in an AAALAC-approved facility and were treated for 9 days with lisinopril (20 mg/kg/24 hours) and losartan (10 mg/kg/24 hours) administered in the drinking water, as described previously.11 Systolic blood pressure was measured in conscious animals by a tail-cuff method (Narco Bio-Systems).
Experimental Protocol
On day 8 of the treatment period, a plastic catheter (PE-50, Clay Adams, Becton Dickinson) was implanted under aseptic conditions into a carotid artery. A second PE-50 catheter was implanted into a jugular vein. The free ends of the catheters were tunneled cephalad and exteriorized at the nape of the neck. The procedures were performed under sterile conditions using inhalation anesthesia with 1% halothane (Ayerst Laboratories Inc.) in 95% O2/5% room air. Measurements of arterial pressure and heart rate were obtained in freely moving conscious rats between 9:00 AM and 12:00 noon the day after the surgery. During the experiments, arterial pressure was recorded continuously using a strain gauge transducer (Uniflow Pressure Transducer, Baxter Healthcare Corp.) connected to the arterial line. The electronic signal was directed to an analog-to-digital converter for beat-by-beat analysis of arterial pressure and heart rate as described in detail elsewhere.11 Calibrated displays of systolic, diastolic, and mean blood pressure and heart rate were imaged using a laser printer.
After a 90-minute recording of baseline hemodynamics, the animals were infused with either of two specific neprilysin inhibitors. Six SHRs received CGS 24592 (IC50=2 nmol/L for neprilysin)21 at a dose of 30 mg/kg, whereas five other SHRs were infused with SCH 39370 (Ki=11 nmol/L) at a dose of 30 mg/kg. A third group of SHRs (n=4) were given corresponding infusions of the vehicles (see Materials section, below). All agents were infused intravenously at a rate of 100 µL/min for 10 minutes. Samples of arterial blood (1 mL) were collected for peptide measurements at the completion of the experiment to ascertain the effect of the drugs or vehicle on the plasma concentrations of Ang II and Ang-(1–7). Blood samples were collected into chilled tubes containing a mixture of peptidase inhibitors and chelating agents as described by us previously.19,22 Plasma samples were stored at -80°C before extraction and assay (see below).
Evaluations of the receptor mechanisms that may contribute to the hemodynamic actions produced by inhibition of neprilysin were determined by administration of receptor antagonists for Ang II, bradykinin, and endothelin-A in separate groups of chronically treated SHR. [Sar,1Thr8]-Ang II (n=5) was infused at a dose of 80 µmol/kg/min for 10 minutes before delivery of either CGS 24592 or SCH 39370. At this dose, [Sar,1Thr8]-Ang II displays no agonist actions in losartan-treated animals.11 The contribution of endothelin and kinin systems to the hemodynamic events associated with inhibition of neprilysin was assessed by acute administration of either the kinin B2 antagonist HOE 140 (0.1 mg/kg, n=3) or the endothelin A antagonist BQ123 (1 mg/kg, n=4). After a 30-minute period, SCH 39370 was infused for 10 minutes to both groups and blood pressure was recorded for an additional 20 minutes. The dose of HOE compound used in these experiments blocks the depressor effects of atrial administration of bradykinin.23,24 Likewise, the dose of BQ123 given to SHRs was shown to prevent the pressor effect of exogenous endothelin.25,26
Assays
Immunoreactive plasma levels of Ang-1–7 and Ang II were measured by radioimmunoassay (RIA) as described by us elsewhere.27,28 Plasma was extracted on C18 Sep-Pak columns (Waters Corporation) activated with acetonitrile, methanol, water, and 0.1% heptafluorobutyric acid (HFBA, Pierce)/water. Plasma was thawed on ice, diluted with 0.1% HFBA and spun in a microcentrifuge at 4°C to remove precipitated material. After sample application, the column was washed with 3 mL of 0.1% HFBA, 20% ACN/0.1% HFBA and the peptides were eluted in 3 mL of 80% ACN/0.1% HFBA. Several aliquots of differing volumes from the eluted fraction were completely evaporated before RIA measurement. Peptide recoveries averaged 75±7% (n=8) using 125I-Ang-(1–7). Plasma values for Ang-(1–7) and Ang II were not corrected for recovery. The minimum detectable levels for the Ang II and Ang-(1–7) assays were 4.0 fmol/tube and 2.2 fmol/tube, respectively.
Materials
The neprilysin inhibitors SCH 39370 and CGS 24592 were provided by Dr. E. J. Sybertz of Schering Plow Research and Dr. A. J. Trapani of Novartis Corporation. The inhibitors were initially dissolved in NaOH and diluted with phosphate-buffered saline (PBS); the vehicle contained the same volume NaOH and PBS. Merck Research Laboratories provided lisinopril and losartan. The antagonists BQ123, HOE 140, and [Sar,1Thr8]-Ang II were purchased from Bachem Inc.
Statistics
Statistical differences in arterial pressure and heart rate resulting from experimental manipulations were evaluated by repeated-measures ANOVA followed by Scheffés post hoc test. Changes in the plasma concentrations of angiotensin peptides were analyzed by the unpaired t test. All data were presented as the mean±SEM and the criterion for statistical significance were set at a value of P<.05.
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Results |
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Eight days of treatment with the combination of lisinopril and losartan caused a decrease in systolic blood pressure from 180±3 mm Hg to 104±5 mm Hg (P<.05) in SHRs at 12 weeks of age. Intravenous infusion of the potent neprilysin inhibitor CGS 24592 (IC50=2 nmol/L)21 caused a rapid rise in mean arterial blood pressure (from 81±3 mm Hg to 96±4 mm Hg) that peaked at approximately 5 minutes after the start of the infusion (Fig 1). At the peak of the pressor response, mean arterial pressure had risen by 15±3 mm Hg (P<.05), a 20% increase above baseline values. CGS 24592 caused an increase in diastolic pressure by 18±3 mm Hg (from 74±1 mm Hg to 92±2 mm Hg), whereas systolic blood pressure rose by 13±1 mm Hg (from 90±3 mm Hg to 103±4 mm Hg). Arterial pressure remained elevated throughout the 20-minute recording period without a significant change in heart rate (365±15 beats per minute [bpm] and 385±7 bpm before and after CGS 24592 infusion, respectively).
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The effectiveness of CGS 24592 as an inhibitor of Ang-(1–7) formation was evaluated by measurements of plasma angiotensin levels in treated SHRs given either the vehicle or the neprilysin inhibitor. Table 1 shows that CGS 24592 was associated with plasma concentrations of Ang-(1–7) that were 62% below the values determined in vehicle-treated SHRs (P<.01). Plasma Ang II levels were not different (P<.05) in SHRs infused with vehicle and CGS 24592 (Table 1).
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Fig 2 shows the effect of pretreatment of SHRs with [Sar,1Thr8]-Ang II before administration of CGS 24592. Infusion of [Sar,1Thr8]-Ang II elicited a statistically significant increase in mean blood pressure to a peak value of 98±4 mm Hg from pretreatment levels of 83±3 mm Hg (P<.05); however, heart rate did not change (342±6 bpm and 337±5 bpm before and after [Sar,1Thr8]-Ang II infusion, respectively). The subsequent administration of CGS 24592 did not cause an additional elevation in mean arterial pressure but heart rate increased to an average of 366±10 bpm (Fig 2).
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A second structurally different neprilysin inhibitor was used to evaluate the specificity of the hemodynamic response of CGS 24592. The carboxylic ester compound SCH 39370 also displays selective and potent inhibitory properties against neprilysin (Ki=11 nmol/L).29 As shown in the upper panel of Fig 3, treatment with SCH 39370 increased mean arterial blood pressure from 89±6 mm Hg to 110±3 mm Hg (P<.01). The increase in mean blood pressure with SCH 39370 was of a magnitude not different than that obtained with CGS 24592. On the other hand, the pressor response produced by SCH 39370 was associated with significant tachycardia averaging 406±13 bpm versus 381±15 bpm (P<.05).
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Infusion of [Sar,1Thr8]-Ang II before administration of SCH 39370 abolished any additional increase in blood pressure produced by the neprilysin inhibitor (Fig 4) but did not block the increase in heart rate (445±15 bpm). Thus, administration of the competitive nonselective Ang II receptor blocker obtunded any further elevation in arterial pressure produced by two structurally different neprilysin inhibitors having equivalent effects on blood pressure but not heart rate.
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The potential contribution of endogenous activation of other vasoactive hormones due to inhibition of the catalytic activity of neprilysin was evaluated by injection of selective receptor antagonists of bradykinin and endothelin-A before the infusion of a neprilysin inhibitor in chronically treated SHRs. Injection of HOE 140 had no effect on the baseline mean arterial blood pressure (79±3 mm Hg and 80±4 mm Hg before and after HOE 140 injection, respectively) and heart rate (376±11 bpm and 380±10 bpm before and after HOE 140 injection, respectively) of treated SHRs. In addition, HOE 140 did not attenuate the changes in mean arterial pressure and heart rate produced by subsequent infusion of SCH 393720 (Fig 5). Similarly, administration of BQ123 did not induce a change in basal mean blood pressure (95±6 mm Hg and 94±7 mm Hg before and after BQ123 injection, respectively) or heart rate (358±24 bpm and 360±22 bpm before and after BQ123 injection, respectively). Blockade of endothelin-A receptors did not attenuate either the increase in mean arterial blood pressure or heart rate produced by subsequent infusion of SCH 39370 (Fig 5). These results suggest that neither bradykinin nor endothelin contribute to the chronic hypotensive actions of lisinopril/losartan treatment or modify the acute blood pressure responses to neprilysin inhibition.
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Discussion |
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The present study showed that acute blockade of Ang-(1–7) formation with two different neprilysin inhibitors reverses the hypotensive effects of combined lisinopril/losartan treatment in SHRs. The hypertensive actions of the neprilysin inhibitor CGS 24592 were associated with a significant reduction in circulating levels of Ang-(1–7) but no changes in plasma Ang II concentrations. The hypertensive effects of both neprilysin inhibitors were not evident in the presence of Ang II receptor blockade with [Sar,1Thr8]-Ang II. The pressor effects of acute neprilysin inhibition in this model of genetic hypertension extend previous findings showing that endogenous neutralization of Ang-(1–7) with a selective monoclonal antibody reversed the antihypertensive effect of the combined treatment with lisinopril and losartan.11 The similarity of the effects obtained by either neutralization of endogenous Ang-(1–7) or inhibition of Ang-(1–7) synthesis in chronically treated SHRs indicates that Ang-(1–7) exerts a depressor function and mediates, in part, the antihypertensive effects associated with combined ACE inhibition and AT1 receptor blockade.
To our knowledge, this is the first study that addresses the acute effects of neprilysin inhibition in lisinopril/losartan-treated animals. This combination therapy normalized the blood pressure of SHRs and markedly elevated plasma levels of Ang-(1–7). High levels of plasma Ang-(1–7) are due to several factors. Inhibition of ACE contributes to the increases in plasma Ang-(1–7) concentration through both increased availability of the Ang I substrate19 and inhibition of Ang-(1–7) metabolism.10,15 An additional, albeit smaller, contribution may originate from the conversion of excess circulating Ang II into Ang-(1–7) as a result of AT1 receptor blockade.30
The two structurally different specific inhibitors of neprilysin caused a partial reversal of the sustained antihypertensive effect of the combined ACE inhibition and AT1 receptor blockade. The hypertensive response was accompanied by a 62% reduction in the circulating levels of Ang-(1–7), a finding that agrees with the previous demonstration that neprilysin is a major enzymatic pathway for the in vivo generation of Ang-(1–7) in both Wistar Kyoto rats and SHR.14 The absence of an additional pressor response to the neprilysin inhibitors by the prior administration of [Sar,1Thr8]-Ang II suggests that the hypertensive response was related to blockade of an angiotensin receptor that may mediate a vasodepressor effect. Thus, the combination of hormone assay measurements and angiotensin receptor blockade suggest that the reversal of the antihypertensive action of the combined therapy is accounted for by the removal of a vasodepressor action of high circulating levels of Ang-(1–7). The similarity of the effects obtained with the neprilysin inhibitors and the administration of a specific monoclonal Ang-(1–7) antibody11 supports this interpretation.
As suggested by us previously,11 the combination of lisinopril and losartan augments the vasodilator actions of Ang-(1–7) such that inhibition of peptide synthesis translates into a partial reversal of the antihypertensive effects of the drug regimen. Whether chronic inhibition of neprilysin will be associated with a sustained inhibition of Ang-(1–7) formation and reduced effectiveness of the antihypertensive regimen was not determined in these experiments. The demonstration that acute neprilysin inhibition elevates blood pressure does provide a model to investigate the effects of long-term inhibition. However, alternate pathways exist for the generation of Ang-(1–7), which may complicate the results of chronic neprilysin inhibition.13 Nevertheless, in the acute setting of these experiments, our data show that the vasodepressor actions of Ang-(1–7) contributed to the maintenance of the antihypertensive action of a chronic therapy resulting from the combination of ACE inhibition and AT1 receptor blockade.
The involvement of other vasoactive autocoids whose metabolism is dependent on the catalytic activity of neprilysin is unlikely. Blockade of endothelin and kinin receptors did not prevent the hemodynamic response produced by inhibition of neprilysin. Moreover, the effects of [Sar,1Thr8]-Ang II suggests that the vasodepressor actions of Ang-(1–7) are mediated by an angiotensin receptor. Our data exclude AT1 receptors because SHRs were chronically treated with losartan. It is also unlikely that high Ang-(1–7) concentrations (
200 pmol/L) may stimulate AT1 receptors because the peptide exhibits such a low affinity for the vascular receptor (IC50>1µmol/L).31 Treatment with the AT2 antagonist PD 123319 did not block the pressor actions of [Sar,1Thr8]-Ang II,11 whereas we also showed32 that Ang-(1–7) exhibits very low affinity (IC50>5 µmol/L) for Ang II binding at the AT2 receptor. Our studies33 and those of others34 suggest that Ang-(1–7) interacts with a non-AT1/AT2 receptor that is sensitive to the [Sar,1Thr8]-Ang II antagonist.
The increases in blood pressure resulting from the two neprilysin inhibitors were blocked by [Sar,1Thr8]-Ang II; however, the antagonist did not attenuate the increase in heart rate. Preliminary studies indicated that the ß1-adrenergic antagonist metoprolol blocked the increase in heart rate but not the pressor response to SCH 39370 (unpublished observations). Additional studies will be required to assess the specificity of the cardiac rate response produced by inhibition of the neprilysin.
Neprilysin inhibitors have been used as antihypertensive agents with equivocal results.35 In addition, mixed ACE and neprilysin inhibitors are currently being evaluated for antihypertensive properties.36 Our findings point to the potential pitfalls of this therapeutic approach, especially in conditions in which AT1 receptor function may be impaired or blocked. In view of the wide use of ACE inhibitors and AT1 blockers, the data obtained in these experiments suggest a need for a further understanding of the mechanisms that contribute to the antihypertensive actions of these agents.
In conclusion, the results from the present study reinforce the concept that not only do different hormonal systems contribute to the regulation of blood pressure, but peptide products within a single system such as Ang II and Ang-(1–7) exhibit counter-regulatory actions.37 The vasodepressor actions of Ang-(1–7) in this model of hypertension reveal the complex role that neprilysin has in the generation and metabolism of vasoactive hormones.
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Acknowledgments |
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Studies were supported by Grants HL-56973 and HL-51952 from the National Heart, Lung, and Blood Institute of the National Institutes of Health.
Received September 18, 1997; first decision October 16, 1997; accepted October 31, 1997.
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References |
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 J. C. Sullivan Sex and the renin-angiotensin system: inequality between the sexes in response to RAS stimulation and inhibition Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2008; 294(4): R1220 - R1226. [Abstract] [Full Text] [PDF]
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 A. Pignone, A. D. Rosso, K B. Brosnihan, F. Perfetto, R. Livi, G. Fiori, S. Guiducci, M. Cinelli, V. Rogai, A. Tempestini, et al. Reduced circulating levels of angiotensin-(1 7) in systemic sclerosis: a new pathway in the dysregulation of endothelial-dependent vascular tone control Ann Rheum Dis, October 1, 2007; 66(10): 1305 - 1310. [Abstract] [Full Text] [PDF]
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J. F. Giani, M. M. Gironacci, M. C. Munoz, C. Pena, D. Turyn, and F. P. Dominici Angiotensin-(1 7) stimulates the phosphorylation of JAK2, IRS-1 and Akt in rat heart in vivo: role of the AT1 and Mas receptors Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1154 - H1163. [Abstract] [Full Text] [PDF]
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S. J. Miller, L. E. Norton, M. P. Murphy, M. C. Dalsing, and J. L. Unthank The role of the renin-angiotensin system and oxidative stress in spontaneously hypertensive rat mesenteric collateral growth impairment Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2523 - H2531. [Abstract] [Full Text] [PDF]
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 S. Keidar, M. Kaplan, and A. Gamliel-Lazarovich ACE2 of the heart: From angiotensin I to angiotensin (1-7) Cardiovasc Res, February 1, 2007; 73(3): 463 - 469. [Abstract] [Full Text] [PDF]
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 E. O'Brien, J. Barton, J. Nussberger, D. Mulcahy, C. Jensen, P. Dicker, and A. Stanton Aliskiren Reduces Blood Pressure and Suppresses Plasma Renin Activity in Combination With a Thiazide Diuretic, an Angiotensin-Converting Enzyme Inhibitor, or an Angiotensin Receptor Blocker Hypertension, February 1, 2007; 49(2): 276 - 284. [Abstract] [Full Text] [PDF]
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I. F. Benter, M. H. M. Yousif, C. Cojocel, M. Al-Maghrebi, and D. I. Diz Angiotensin-(1-7) prevents diabetes-induced cardiovascular dysfunction Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H666 - H672. [Abstract] [Full Text] [PDF]
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 C. Schindler, K. B. Brosnihan, C. M. Ferrario, P. Bramlage, U. Maywald, R. Koch, R. Oertel, and W. Kirch Comparison of Inhibitory Effects of Irbesartan and Atorvastatin Treatment on the Renin Angiotensin System (RAS) in Veins: A Randomized Double-Blind Crossover Trial in Healthy Subjects J. Clin. Pharmacol., January 1, 2007; 47(1): 112 - 120. [Abstract] [Full Text] [PDF]
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 H. A. Shaltout, B. M. Westwood, D. B. Averill, C. M. Ferrario, J. P. Figueroa, D. I. Diz, J. C. Rose, and M. C. Chappell Angiotensin metabolism in renal proximal tubules, urine, and serum of sheep: evidence for ACE2-dependent processing of angiotensin II Am J Physiol Renal Physiol, January 1, 2007; 292(1): F82 - F91. [Abstract] [Full Text] [PDF]
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J. A. Jessup, P. E. Gallagher, D. B. Averill, K. B. Brosnihan, E. A. Tallant, M. C. Chappell, and C. M. Ferrario Effect of angiotensin II blockade on a new congenic model of hypertension derived from transgenic Ren-2 rats Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2166 - H2172. [Abstract] [Full Text] [PDF]
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 M. Paul, A. Poyan Mehr, and R. Kreutz Physiology of local Renin-Angiotensin systems. Physiol Rev, July 1, 2006; 86(3): 747 - 803. [Abstract] [Full Text] [PDF]
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 A. Reyes-Engel, L. Morcillo, F. J. Aranda, M. Ruiz, M. J. Gaitan, A. Mayor-Olea, P. Aranda, and C. M. Ferrario Influence of Gender and Genetic Variability on Plasma Angiotensin Peptides Journal of Renin-Angiotensin-Aldosterone System, June 1, 2006; 7(2): 92 - 97. [Abstract] [PDF]
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T. L. Reudelhuber A Place in Our Hearts for the Lowly Angiotensin 1-7 Peptide? Hypertension, May 1, 2006; 47(5): 811 - 815. [Full Text] [PDF]
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I. F. Benter, M. H. M. Yousif, J. T. Anim, C. Cojocel, and D. I. Diz Angiotensin-(1-7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H684 - H691. [Abstract] [Full Text] [PDF]
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 P. E. Gallagher, M. C. Chappell, C. M. Ferrario, and E. A. Tallant Distinct roles for ANG II and ANG-(1-7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes Am J Physiol Cell Physiol, February 1, 2006; 290(2): C420 - C426. [Abstract] [Full Text] [PDF]
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C. M. Ferrario, A. J. Trask, and J. A. Jessup Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2281 - H2290. [Abstract] [Full Text] [PDF]
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K. B. Brosnihan, L. A.A. Neves, and M. C. Chappell Does the Angiotensin-Converting Enzyme (ACE)/ACE2 Balance Contribute to the Fate of Angiotensin Peptides in Programmed Hypertension? Hypertension, November 1, 2005; 46(5): 1097 - 1099. [Full Text] [PDF]
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E. A. Tallant, C. M. Ferrario, and P. E. Gallagher Angiotensin-(1-7) inhibits growth of cardiac myocytes through activation of the mas receptor Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1560 - H1566. [Abstract] [Full Text] [PDF]
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C. H. de Castro, R. A. Souza dos Santos, A. J. Ferreira, M. Bader, N. Alenina, and A. Pinto de Almeida Evidence for a Functional Interaction of the Angiotensin-(1-7) Receptor Mas With AT1 and AT2 Receptors in the Mouse Heart Hypertension, October 1, 2005; 46(4): 937 - 942. [Abstract] [Full Text] [PDF]
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M. J Huentelman, J. L Grobe, J. Vazquez, J. M Stewart, A. P Mecca, M. J Katovich, C. M Ferrario, and M. K Raizada Protection from angiotensin II-induced cardiac hypertrophy and fibrosis by systemic lentiviral delivery of ACE2 in rats Exp Physiol, September 1, 2005; 90(5): 783 - 790. [Abstract] [Full Text] [PDF]
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A. Sakima, D. B. Averill, P. E. Gallagher, S. O. Kasper, E. N. Tommasi, C. M. Ferrario, and D. I. Diz Impaired Heart Rate Baroreflex in Older Rats: Role of Endogenous Angiotensin-(1-7) at the Nucleus Tractus Solitarii Hypertension, August 1, 2005; 46(2): 333 - 340. [Abstract] [Full Text] [PDF]
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 C. M. Ferrario, J. Jessup, M. C. Chappell, D. B. Averill, K. B. Brosnihan, E. A. Tallant, D. I. Diz, and P. E. Gallagher Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2 Circulation, May 24, 2005; 111(20): 2605 - 2610. [Abstract] [Full Text] [PDF]
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M. J. Katovich, J. L. Grobe, M. Huentelman, and M. K. Raizada Angiotensin-converting enzyme 2 as a novel target for gene therapy for hypertension Exp Physiol, May 1, 2005; 90(3): 299 - 305. [Abstract] [Full Text] [PDF]
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J. Stegbauer, V. Oberhauser, O. Vonend, and L. C. Rump Angiotensin-(1-7) modulates vascular resistance and sympathetic neurotransmission in kidneys of spontaneously hypertensive rats Cardiovasc Res, February 1, 2004; 61(2): 352 - 359. [Abstract] [Full Text] [PDF]
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J. P Collister and M. D Hendel Subfornical organ lesion attenuates chronic hypotensive effects of losartan in salt-replete rats Journal of Renin-Angiotensin-Aldosterone System, December 1, 2003; 4(4): 207 - 212. [Abstract] [PDF]
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J. P Collister and M. D Hendel The role of Ang (1-7) in mediating the chronic hypotensive effects of losartan in normal rats Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 176 - 179. [Abstract] [PDF]
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 R. M. Carey and H. M. Siragy Newly Recognized Components of the Renin-Angiotensin System: Potential Roles in Cardiovascular and Renal Regulation Endocr. Rev., June 1, 2003; 24(3): 261 - 271. [Abstract] [Full Text] [PDF]
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J. P. Collister and M. D. Hendel Role of the Subfornical Organ in the Chronic Hypotensive Response to Losartan in Normal Rats Hypertension, March 1, 2003; 41(3): 576 - 582. [Abstract] [Full Text] [PDF]
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S. Nakamura, D. B. Averill, M. C. Chappell, D. I. Diz, K. B. Brosnihan, and C. M. Ferrario Angiotensin receptors contribute to blood pressure homeostasis in salt-depleted SHR Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R164 - R173. [Abstract] [Full Text] [PDF]
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I. Kucharewicz, R. Pawlak, T. Matys, D. Pawlak, and W. Buczko Antithrombotic Effect of Captopril and Losartan Is Mediated by Angiotensin-(1-7) Hypertension, November 1, 2002; 40(5): 774 - 779. [Abstract] [Full Text] [PDF]
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 J. A. Schriefer, E. P. Broudy, and A. H. Hassen Inhibitors of Bradykinin-Inactivating Enzymes Decrease Myocardial Ischemia/Reperfusion Injury following 3 and 7 Days of Reperfusion J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 970 - 975. [Abstract] [Full Text]
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M. A. Clark, D. I. Diz, and E. A. Tallant Angiotensin-(1-7) Downregulates the Angiotensin II Type 1 Receptor in Vascular Smooth Muscle Cells Hypertension, April 1, 2001; 37(4): 1141 - 1146. [Abstract] [Full Text] [PDF]
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L. Fernandes, Z. B. Fortes, D. Nigro, R. C. A. Tostes, R. A. S. Santos, and M. H. Catelli de Carvalho Potentiation of Bradykinin by Angiotensin-(1-7) on Arterioles of Spontaneously Hypertensive Rats Studied In Vivo Hypertension, February 1, 2001; 37(2): 703 - 709. [Abstract] [Full Text] [PDF]
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 R. M. Touyz and E. L. Schiffrin Signal Transduction Mechanisms Mediating the Physiological and Pathophysiological Actions of Angiotensin II in Vascular Smooth Muscle Cells Pharmacol. Rev., December 1, 2000; 52(4): 639 - 672. [Abstract] [Full Text] [PDF]
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A. J. Allred, D. I. Diz, C. M. Ferrario, and M. C. Chappell Pathways for angiotensin-(1---7) metabolism in pulmonary and renal tissues Am J Physiol Renal Physiol, November 1, 2000; 279(5): F841 - F850. [Abstract] [Full Text] [PDF]
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M. C. Chappell, M. N. Gomez, N. T. Pirro, and C. M. Ferrario Release of Angiotensin-(1-7) From the Rat Hindlimb : Influence of Angiotensin-Converting Enzyme Inhibition Hypertension, January 1, 2000; 35(1): 348 - 352. [Abstract] [Full Text] [PDF]
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R. E. Widdop, D. B. Sampey, and B. Jarrott Cardiovascular Effects of Angiotensin-(1-7) in Conscious Spontaneously Hypertensive Rats Hypertension, October 1, 1999; 34(4): 964 - 968. [Abstract] [Full Text] [PDF]
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A. P. Davie and J. J. V. McMurray Effect of Angiotensin-(1-7) and Bradykinin in Patients With Heart Failure Treated With an ACE Inhibitor Hypertension, September 1, 1999; 34(3): 457 - 460. [Abstract] [Full Text] [PDF]
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K. Yamada, S. N. Iyer, M. C. Chappell, D. Ganten, and C. M. Ferrario Converting Enzyme Determines Plasma Clearance of Angiotensin-(1–7) Hypertension, September 1, 1998; 32(3): 496 - 502. [Abstract] [Full Text] [PDF]
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