AJP - Heart AJP citation statistics
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 284: H1985-H1994, 2003. First published February 6, 2003; doi:10.1152/ajpheart.01145.2002
0363-6135/03 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
284/6/H1985    most recent
01145.2002v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (40)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sampaio, W. O.
Right arrow Articles by Santos, R. A. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sampaio, W. O.
Right arrow Articles by Santos, R. A. S.
Vol. 284, Issue 6, H1985-H1994, June 2003

SPECIAL TOPICS
Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting Enzyme Systems
Systemic and regional hemodynamic effects of angiotensin-(1-7) in rats

Walkyria O. Sampaio, Antônio A. S. Nascimento, and Robson A. S. Santos

Department of Physiology and Biophysics, Federal University of Minas Gerais, 31270901 Minas Gerais, Brazil


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

The systemic and regional hemodynamics effects of ANG-(1-7) were examined in urethane-anesthetized rats. The blood flow distribution (kidneys, skin, mesentery, lungs, spleen, brain, muscle, and adrenals), cardiac output, and total peripheral resistance were investigated by using fluorescent microspheres. Blood pressure and heart rate were recorded from the brachial artery. ANG-(1-7) infusion (110 fmol · min-1 · 10 min-1 iv) significantly increased blood flow to the kidney (5.10 ± 1.07 to 8.30 ± 0.97 ml · min-1 · g-1), mesentery (0.73 ± 0.16 to 1.17 ± 0.49 ml · min-1 · g-1), brain (1.32 ± 0.44 to 2.18 ± 0.85 ml · min-1 · g-1), and skin (0.07 ± 0.02 to 0.18 ± 0.07 ml · min-1 · g-1) and the vascular conductance in these organs. ANG-(1-7) also produced a significant increase in cardiac index (30%) and a decrease in total peripheral resistance (2.90 ± 0.55 to 2.15 ± 0.28 mmHg · ml-1 · min · 100 g). Blood flow to the spleen, muscle, lungs, and adrenals, as well as the blood pressure and heart rate, were not altered by the ANG-(1-7) infusion. The selective ANG-(1-7) antagonist A-779 reduced the blood flow in renal, cerebral, mesenteric, and cutaneous beds and blocked the ANG-(1-7)-induced vasodilatation in the kidney, mesentery, and skin, suggesting a significant role of endogenous ANG-(1-7) in these territories. The effects of ANG-(1-7) on the cerebral blood flow, cardiac index, systolic volume, and total peripheral resistance were partially attenuated by A-779. A high dose of ANG-(1-7) (11 pmol · min-1 · 10 min-1) caused an opposite effect of that produced by the low dose. Our results show for the first time that ANG-(1-7) has a previously unsuspected potent effect in the blood flow distribution and systemic hemodynamics.

regional blood flow; fluorescent microspheres


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

ANGIOTENSIN-(1-7), a bioactive component of the renin-angiotensin system, is formed in the circulation and various tissues from ANG I or ANG II through ANG-converting enzyme (ACE)-dependent and independent pathways (11, 48, 51). The recent discovery of the ANG-(1-7)-forming enzyme ACE2 adds a potentially new dimension to the ANG-(1-7) formation and favors the possibility that this peptide acts like a true paracrine hormone (9, 56). Interestingly, although the ACE pathway predominantly metabolizes ANG-(1-7) (11, 51), this peptide inhibits the ACE C-domain (3, 8), and as a result, increased levels of ANG-(1-7) observed during ACE inhibition may have an important participation in the cardiovascular effects produced by this therapy (24, 25, 51).

The actions of ANG-(1-7) are either complementary or distinct from those of ANG II. Actually, the accumulating evidence indicates that ANG-(1-7) exerts mainly a counterregulatory role within the renin-ANG system (11, 46, 48).

The blood vessels are an important site for the opposing actions of ANG II and ANG-(1-7). Vascular responses to ANG-(1-7) significantly differ from those induced by ANG II. In blood vessels, ANG-(1-7) acts mainly as a vasodilator and antiproliferative hormone (16, 48, 51). It has been shown to produce relaxation of the aortic rings of Sprague-Dawley (57) and mRen-2 transgenic rats (27), canine (5) and porcine coronary arteries (44), canine middle cerebral artery (15), piglet pial arterioles (36), feline systemic vasculature (42), rabbit renal afferent arterioles (45), and mesenteric microvessels of normotensive and hypertensive rats (10, 41). Furthermore, ANG-(1-7) potentiates the vasodilator effect of bradykinin in several vascular beds, including dog and rat coronary vessels (1, 5) and rat mesenteric arterioles (10, 41). These actions appear to involve increased production of vasodilatory prostanoids and/or nitric oxide (5, 22, 24, 28, 39, 44). One important question that arises from these observations is how this peptide contributes to the regulation of both regional and systemic hemodynamics in vivo. From the contrast between the vasodilatory effects of ANG-(1-7) and its negligible effects on blood pressure (2, 4, 60), we hypothesized that this peptide could influence blood flow distribution and present opposite effects on cardiac output (CO) and total peripheral resistance (TPR). To test this hypothesis, we determined the effects of ANG-(1-7) and of its selective antagonist A-779 on regional blood flow distribution in rats. Moreover, we assessed the effects of these peptides on CO and TPR.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Animals and Surgical Preparation

Male Wistar rats weighing 250-300 g were housed in separate cages and maintained in a temperature-regulated room (25°C) on a 12:12-h light-dark cycle (light on from 6:00 AM to 6:00 PM).

Rats were anesthetized with urethane (1.2 g/kg ip). A tracheotomy was performed to avoid airway obstruction. Body temperature was kept at 36-37°C by a heating pad; temperature was continually monitored with a rectal probe. The left braquial artery was cannulated with polyethylene tubing (PE-10) for recording of blood pressure and heart rate (Biopac System; Santa Barbara, CA). For administration of fluorescent microspheres, the right carotid artery was exposed, and a PE-50 cannula was guided through the common carotid artery into the left ventricle. The positioning of the cannula in the left ventricle was confirmed by blood pressure recording. The right femoral artery was cannulated and connected to a withdrawal pump (Minipuls 3, Gilson; Villiers le Bel, France). The right femoral vein was also cannulated for infusion of vehicle (0.9% NaCl) and peptides. The experimental procedures used in the studies were conducted according to the ethical recommendations approved by our constitutional animal committee.

Determination of Systemic and Regional Hemodynamics

Systemic hemodynamics and regional blood flow were determined using 15-µm fluorescent polystyrene microspheres (FluoSpheres Blood Flow Determination, Molecular Probes; Eugene, OR) as previously reported (17, 20). Briefly, two different colors of fluorescent microspheres were used. The colors of microspheres were selected as previously described to avoid the spillover between the colors (20). To prevent aggregation, the microsphere suspension was vortexed for 1 min, followed by sonication for an additional 20 s. After mixing was completed, 300,000 fluorescent microspheres were infused into the left ventricle over a 10-s period and flushed with 0.3 ml of saline over an additional 10-s period. To calculate the blood flow, arterial blood was withdrawn at a rate of 0.85 ml/min through the right femoral artery. Blood for reference blood sample was withdrawn for 90 s starting 10 s before the microsphere injection. At the end of the experiments, the animals were killed with an overdose of anesthetic, and the tissues (kidneys, brain, mesentery, adrenals, spleen, abdominal skin, gastrocnemius muscle, and lungs) were dissected, weighed, and placed in individual vials. Both tissue and reference blood flow samples were digested by using a solution of 4 M ethanolic KOH and 2% Tween 80 kept in a hot bath (50°C) overnight. At the end of the digestion period the microspheres were recovered by the sedimentation method (59), and the dye was extracted by using 4 ml of the organic solvent ethyl acetate. The fluorescence intensity of the dye was measured using a luminescence spectrofotometer (Spex Fluoromax), and the following parameters were calculated as previously described: cardiac output, stroke volume, TPR, regional blood flow, and regional vascular resistance (17, 20, 59).

Experimental protocol 1. To examine the systemic and regional responses to ANG-(1-7), the peptide was infused at 110 fmol · min-1 · 10 min-1 and 11 pmol · min-1 · 10 min-1 intravenously (n = 5 and n = 3, respectively). In the control group, vehicle (0.9% NaCl) was infused at a 50 µl/min rate. The doses of ANG-(1-7) were selected based on preliminary studies. Immediately after the first injection of microspheres, ANG-(1-7) or vehicle were administrated through the femoral vein for 10 min. The second color of microspheres was injected at the end of the infusion period.

Experimental protocol 2. In separated experiments, systemic and regional responses to infusion of 11 pmol/min of A-779 (n = 5), a selective antagonist of ANG-(1-7), were determined. The first injection of microspheres was made before the A-779 infusion. Subsequently, A-779 was administrated for 10 min through the catheter placed in the femoral vein, and then the second injection of microsphere was made as described above.

Experimental protocol 3. The last series of experiment were performed in ANG-(1-7)-infused rats pretreated with A-799 (n = 4). Immediately after the A-779 infusion (11 pmol/min, during 10 min), the first infusion of microspheres was made. Subsequently, ANG-(1-7) (110 fmol · min-1 · 10 min-1) was infused, and the second infusion of a different color of microspheres was made.

Data Analysis

Data are presented as means ± SE. Statistical comparisons of the means values were done using Student's t-test. Values of P < 0.05 were considered significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Effects of Intravenous Infusion of ANG-(1-7) on Regional Blood Flow and Vascular Resistance

Figures 1 and 2 show the changes in regional blood flow and calculated vascular resistance in rats infused with the low dose of ANG-(1-7) (110 fmol · min-1 · 10 min-1). The blood flow rates in the kidney, brain, mesentery, and skin were substantially increased (30-60%) in ANG-(1-7)-infused rats (Fig. 1A) compared with both vehicle-infused rats (Fig. 1B) and the control period. There were no statistically significant differences in the blood flow rates to the adrenals, lung, spleen, and muscle. There was also a significant reduction in the vascular resistance in renal, cerebral, mesenteric, and cutaneous territories without significant changes of vascular resistance in other organs or tissues (Fig. 2A). In contrast, a higher dose of ANG-(1-7) (11 pmol · min-1 · 10 min-1) significantly reduced blood flow in the kidney, mesentery, and skin with a significant increase in vascular resistance in these organs (Table 1).


View larger version (19K):
[in this window]
[in a new window]
  		Fig. 1.   Effect of intravenous infusion of angiotensin (ANG)-(1-7) on regional blood flow in anesthetized rats. Blood flow (in ml · min-1 · g-1) was measured before (basal) and after 10 min of ANG-(1-7) (A, 110 fmol/min, n = 5) or vehicle (B, 50 µl/min, n = 5) infusion. *P < 0.05 compared with basal values.



View larger version (22K):
[in this window]
[in a new window]
  		Fig. 2.   Effect of intravenous infusion of ANG-(1-7) on vascular resistance in anesthetized rats. Vascular resistance (in mmHg · ml-1 · min · g) was measured before (basal) and after 10 min of ANG-(1-7) (A, 110 fmol/min, n = 5) or vehicle (B, 50 µl/min, n = 5) infusion. *P < 0.05 vs. basal values.


                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Effect of a high dose of ANG-(1-7) on blood flow in anesthetized rats

Effects of Intravenous Infusion of ANG-(1-7) on Systemic Hemodynamics

Figure 3 shows the CO, stroke volume, and TPR responses to ANG-(1-7) infusion. ANG-(1-7) at 110 fmol · min-1 · 10 min-1 significantly increased CO by 30% (from 30.8 ± 4.4 to 39.4 ± 4.5 ml · min-1 · 100 g-1 P < 0.05) and stroke volume from 0.25 ± 0.04 to 0.32 ± 0.05 ml/beat. ANG-(1-7) infusion also resulted in a significant reduction in TPR from 2.9 ± 0.5 to 2.15 to 0.3 mmHg · ml-1 · min · 100 g. Vehicle-infused rats did not show significant changes in these parameters. Mean arterial pressure and heart rate did not change in neither vehicle-infused nor ANG-(1-7)-infused rats (baseline values: 96 ± 4 mmHg, 337 ± 26 beats/min, and 87 ± 4 mmHg, 326 ± 35 beats/min in vehicle, and ANG-(1-7)-infused rats, respectively). Contrasting with these effects, ANG-(1-7) at 11 pmol · min-1 · 10 min-1 produced a significant reduction in CO and stroke volume. The TPR significantly increased from 2.9 ± 0.3 to 3.3 ± 0.4 mmHg · ml-1 · min · 100 g (Table 2).


View larger version (16K):
[in this window]
[in a new window]
  		Fig. 3.   Effect of intravenous infusion of ANG-(1-7) on systemic hemodynamics in anesthetized rats. Cardiac index (in ml · min-1 · 100 g-1), stroke volume (in ml/beat), and total peripheral resistance (TPR, in mmHg · ml-1 · min · 100 g) were measured before and with 10 min of ANG-(1-7) (110 fmol/min, n = 5) or vehicle (saline, 50 µl/min, n = 5) infusion. *P < 0.05 vs. basal values.


                              
View this table:
[in this window]
[in a new window]
  		Table 2.   Effect of high dose of ANG-(1-7) on systemic hemodynamics in anesthetized rats

Regional Effects of Intravenous Infusion of ANG-(1-7) Selective Antagonist A-779

Figures 4A and 5A show the individual changes in regional blood flow and calculated vascular resistance in A-779-infused rats. A-779 at 11 pmol · min-1 · 10 min-1 caused a significant reduction of blood flow in the kidneys, brain, mesentery, and skin, in which A-779 produced a significant augmentation of vascular resistance. There were no statistically significant differences in these parameters in the adrenals, lung, spleen, and muscle. After treatment with A-779, the vasodilatation induced by ANG-(1-7) at 110 fmol · min-1 · 10 min-1 was completely abolished in the kidney, mesentery, and skin. A-779 reduced but did not prevent, the ANG-(1-7)-induced decrease in TPR in the brain (Fig. 5B). In addition, an unexpected increase in adrenal blood flow was observed (Fig. 4B). In other vascular territories, neither the blood flow rate nor vascular resistance were altered.


View larger version (19K):
[in this window]
[in a new window]
  		Fig. 4.   Effect of intravenous infusion of A-779 on basal and ANG-(1-7)-induced changes in regional blood flow of anesthetized rats. Regional blood flow (in ml · min-1 · g-1) was measured before and with 10 min infusion of A-779 (11 pmol · min-1 · 10 min-1) (A) and during A-779 infusion (11 pmol · min-1 · 10 min-1) followed by A-779 combined with ANG-(1-7) (110 fmol · min · 10 min-1, n = 5) (B). *P < 0.05 vs. basal values (A) or A-779 infusion (B).



View larger version (22K):
[in this window]
[in a new window]
  		Fig. 5.   Effect of intravenous infusion of A-779 on basal and ANG-(1-7)-induced changes in vascular resistance of anesthetized rats. Vascular resistance (in mmHg · ml-1 · min · g) was calculated based on mean arterial pressure and blood flow measured before and with 10 min infusion of A-779 (11 pmol · min-1 · 10 min-1) (A) and during A-779 infusion (11 pmol · min-1 · 10 min-1), followed by A-779 combined with ANG-(1-7) (110 fmol · min-1 · 10 min-1, n = 5) (B). *P < 0.05 vs. basal values (A) or A-779 infusion (B).

Systemic Effects of Intravenous Infusion of ANG-(1-7) Selective Antagonist A-779

As shown in Fig. 6, the stroke volume was slightly but significantly lower in A-779-infused rats compared with the control period. No significant differences were observed in CO and TPR. The increase in CO and stroke volume induced by ANG-(1-7) at 110 fmol · min-1 · 10 min-1 was not abolished in the presence of A-779. A-779 also did not prevent the reduction in TPR induced by ANG-(1-7). Mean arterial pressure and heart rate did not change during the infusion of A-779 alone or during the infusion of A-779 combined with ANG-(1-7) (baseline values: 84 ± 8 mmHg, 384 ± 25 beats/min, and 82 ± 3 mmHg, 333 ± 63 beats/min in A-779 and ANG-(1-7) + A-779-infused rats, respectively).


View larger version (15K):
[in this window]
[in a new window]
  		Fig. 6.   Effect of intravenous infusion of A-779 on basal and ANG-(1-7)-induced changes in systemic hemodynamics of anesthetized rats. Cardiac index (in ml · min-1 · 100 g-1), stroke volume (in ml/beat), and TPR (in mmHg · ml · min-1 · 100 g-1) were measured before and after 10-min infusion of A-779 (11 pmol · min-1 · 10 min-1) and during A-779 infusion (11 pmol · min-1 · 10 min-1), followed by A-779 combined with ANG-(1-7) (110 fmol · min-1 · 10 min-1, n = 5). *P < 0.05 vs. basal values or A-779 infusion.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Several studies have demonstrated that the blood vessels are an important site for the formation and actions of ANG-(1-7) (47, 48, 51, 55). Our results indicate that ANG-(1-7) has a previously unsuspected effective and important role in the control of blood flow distribution.

Infusion of ANG-(1-7) at a very low rate (110 fmol/min) produced marked changes on regional blood flow, increasing vascular conductance in the mesenteric, cerebral, cutaneous, and renal territories. The CO was increased by 30%, which can be explained, at least in part, by the decrease in TPR (~26%). The potent and selective effect of ANG-(1-7) in several territories confirms and extends previous observations (17, 31, 35, 36, 41, 45).

ANG-(1-7) increased mesentery blood flow. Accordingly, Oliveira et al. (41) demonstrated that ANG-(1-7) causes both vasodilatation and bradykinin potentiation in mesenteric arterioles, which were blocked by A-779, Nomega -nitro-L-arginine methyl ester, and indomethacin, suggesting an important participation of local prostanoids and nitric oxide in the ANG-(1-7) action. The same group showed that ANG-(1-7) potentiates the bradykinin vasodilatory effect in mesenteric arterioles of spontaneously hypertensive rats via release of prostanoids and [EDHF] (10).

Our data suggest that the renal vasculature is very sensitive to the influence of ANG-(1-7). The kidney, where ANG-(1-7) can be locally formed, is an important target for the actions of this peptide (23, 48, 51, 54). The influence of ANG-(1-7) in this organ is complex apparently depending on the hydroelectrolytic status, the renal nervous activity, and the level of activity of the renin-ANG system (54). It has been described that intrarenal infusion of ANG-(1-7) produces diuretic and natriuretic effects on isolated and intact kidneys of Wistar and Sprague-Dawley rats (23, 54). A small but significant increase in glomerular filtration rate was also seen after ANG-(1-7) infusion in isolated kidneys, suggesting a vasodilatory effect of this peptide (23, 35). Recently, it was demonstrated that ANG-(1-7) has a receptor-mediated vasodilator effect on the rabbit afferent arteriole, probably due to nitric oxide production (45). Our results confirm these observations and suggest that ANG-(1-7) can importantly modulate renal blood flow.

In agreement with previous studies, we have found that ANG-(1-7) also produced vasodilatation in the brain. Meng and Busija (36) demonstrated a vasodilatory effect in piglet pial arterioles. However, the potency of ANG-(1-7) to produce vasodilatation in piglet pial arterioles (10-7-10-4 M) was low compared with the effectiveness of ANG-(1-7) in our study. Feterik et al. (15) found that ANG-(1-7) produces relaxation of canine middle cerebral arteries by release of nitric oxide from endothelial cells. This effect appears to be dependent on activation of local production of kinins, a mechanism not investigated in our study.

In the skin, ANG-(1-7) also produced a potent vasodilatory effect. These data are consistent with the recent observations from Machado et al. (31) showing that ANG-(1-7) acts as vasodilator in a mice model of sponge-induced neovascularization as well as in normal cutaneous vascular beds. The absence of significant alterations on the spleen, muscle, and lung indicates the ANG-(1-7) selectivity and suggests the involvement of tissue-specific signaling mechanisms in its effects. Among the possibilities, these heterogeneous actions may reflect a differential distribution and expression of its receptors along the vascular tree.

Another interesting observation with the low dose of ANG-(1-7) was the significant decrease in TPR, which may have contributed for the increase in stroke volume leading to an increase in CO. The opposite changes in TPR and CO could explain the absence of substantial changes in blood pressure during ANG-(1-7) administration described previously (2, 4, 60). The increased CO could be explained by an increase in venous return, which in turn can be consequence of the reduced TPR resulting from the vasodilatation in several territories, including mesenteric, cerebral, renal, and cutaneous vascular beds. However, a direct inotropic effect of ANG-(1-7) cannot be excluded. Recent studies (12, 14, 30), for example, have suggested that this peptide may exert a cardioprotective action. In isolated hearts, ANG-(1-7) produced a significant reduction in postischemic reperfusion arrhythmias and systolic dysfunction, which was blocked by A-779 (13). In a cardiac failure model in rats, ANG-(1-7) contributed to cardiac and endothelial function preservation (30). The underlying mechanisms of these actions involve, at least partially, prostanoids, nitric oxide, and bradykinin release. The possibility of a direct influence of ANG-(1-7) in heart contractility is further strengthened by the recent observation that knockout mice for ACE2, which form ANG-(1-7) directly from ANG II, presented a severe cardiac dysfunction (7).

The ANG-(1-7) antagonist A-779 blocked its vasodilatatory action in the kidney, skin, and mesentery. These results are in agreement with the evidence for the existence of a specific receptor for ANG-(1-7) in the vascular system (49, 55). Binding studies in bovine aortic endothelial cells demonstrated that the specific 125I-labeled ANG-(1-7) binding was inhibited by both [Sar1, Ile8]ANG II and A-779 (55). A similar result was obtained in rat and mice kidney slices (32, 50). In contrast, AT1 and AT2 receptor antagonists did not displace the ANG-(1-7) binding (55). Studies carried out in our laboratory have demonstrated that the Mas protoncogene, a G protein-coupled receptor (37) mediates or is an essential element of the ANG-(1-7) actions in mice kidneys and aortas (52). Whether this receptor is involved in the ANG-(1-7) actions in the brain, skin, and mesenteric microvessels remains to be demonstrated.

A-779 did not completely block the ANG-(1-7)-induced vasodilatation in the cerebral territory. This observation suggests that another receptor or signaling mechanism could also mediate the ANG-(1-7) action in brain blood vessels. One possibility could be the potentiation of endogenous bradykinin by ANG-(1-7). The interactions between ANG-(1-7) and kinins in the vasculature seem to involve both B2 receptor resensitization and receptor-mediated potentiation of endogenous bradykinin (29, 34). Intracellularly, this interaction may elicit release of nitric oxide, prostanoids, and possibly [EDHF] (1, 8, 10, 22, 23, 28, 43). Another possibility could be binding to ACE facilitating the cross-talk between ACE and the bradykinin B2 receptor as well as inhibition of the ACE C-domain (3, 8). However, it should be considered that in our study, both the dose (110 fmol/min) and the time of infusion (10 min) were lower than those used in a previous study (29) to obtain this effect (300 fmol, during 60 min). Therefore, other mechanisms such as involvement of PD-123177-sensitive receptors should be investigated in future studies (22, 48, 51).

An interesting observation was made in the adrenals, where in the presence of A-779, ANG-(1-7) produced vasodilatation while the peptide or the antagonist alone were without effect. This finding indicates the participation of a nonreceptor-mediated mechanism or the existence of an A-779-insensitive ANG-(1-7) receptor in this gland. The involvement of ANG-(1-7) fragments such as ANG-(3-7), which could have an opposite action (vasodilating) to that of ANG-(1-7), should also be considered (21). According to this hypothesis, ANG-(1-7) would have a direct vasoconstrictive effect in the adrenal gland, which could be compensated by the action of its fragment(s).

It should be pointed out that infusion of the ANG-(1-7) antagonist A-779 induced a reduction in blood flow to renal, cerebral, mesenteric, and cutaneous vascular beds due to an increased vascular resistance. This observation suggests that in these territories and under our experimental conditions, endogenous ANG-(1-7) participates in the control of regional hemodynamics. The fact that the generation of ANG-(1-7) occurs through several enzymatic cascades such as prolyl-endopeptidiase, neutral endopeptidase, and ACE2 and the interactions of this peptide in vasculature, mainly with bradykinin, indicates that the modulation of vascular tone by ANG-(1-7) is complex and probably depends on the particular vascular bed investigated (48, 51). In addition to the interaction with bradykinin, it has been shown that ANG-(1-7) is capable of modulating AT1-mediated actions of ANG II. In rabbit aorta rings, ANG-(1-7) directly inhibited ANG II-induced vasoconstriction (33). A similar effect was observed in the human forearm and human mammary artery (53, 58). Recently, Zhu et al. (61) described that ANG-(1-7) may antagonize the protein kinase C and ERK1/2 activation induced by ANG II. Moreover, this peptide acts as an ACE inhibitor, decreasing the ANG II formation and alternatively may modulate the AT1 receptor expression (6, 38). It remains to be elucidated whether the effects observed with A-779 infusion were due to blockade of a direct effect of ANG-(1-7) on blood vessels or to blockade of an indirect effect such as the interaction of ANG-(1-7) with the kallikrein-kinin system (51) or with ANG II (33, 48, 58, 61).

We observed that in contrast to the effect of fentomolic infusion of ANG-(1-7), infusion of this peptide in a 100-fold higher rate (11 pmol · min-1 · 10 min-1) produced an AT1-like effect resulting in a significant increase of vascular resistance in the kidney, brain, skin, and mesentery. A decrease in CO and an increase in TPR were also observed, resulting in negligible changes in mean arterial pressure. Observations from Osei et al. (42) demonstrated that there is a dose dependency in the response to ANG-(1-7) in different vascular beds. Depending on the dose, ANG-(1-7) can produce either vasodilatation or vasoconstriction. Other studies have shown that some vascular actions of ANG-(1-7) can be blocked by AT1 receptor antagonists, suggesting that ANG-(1-7) may act in some circumstances via this receptor or more likely, through an AT1-like receptor (18, 19, 26, 42). Further studies aimed to clarify the mechanism underlying the vasoconstriction induced by high doses of ANG-(1-7) are necessary to ascertain the possible involvement of AT1 receptors in this action.

Perspectives

With the use of fluorescent microspheres, which provide reliable measurements of regional and systemic blood flow, we have unveiled a potent and selective vasodilatory effect of ANG-(1-7), which was completely blocked in most territories by its antagonist A-779. In addition, we also demonstrated that ANG-(1-7) infusion produced an increase in CO and decreased the TPR. This balance masks its cardiovascular effects, which were evaluated up to now by measuring blood pressure and heart rate. The selectivity of the vasodilatory effect of ANG-(1-7), which contrasts with the more widespread vasoconstriction described for ANG II (40), suggests a differential distribution of ANG-(1-7) receptors within the vascular system. Considering that ANG-(1-7) and ANG II have in general opposing actions in blood vessels, our observations may have important implications related to physiological and physiopathological conditions in which the renin-ANG system is activated. This would be particularly important taking into account the possibility of regional differences in the biotransformation of ANG I and ANG II to ANG-(1-7) (7, 48, 51, 56). The novel information provided in this study will be important to establish ANG-(1-7) as a player as important as ANG II in mediating the cardiovascular effects of the renin-ANG system. Moreover, our data put forward the possibility of important physiological roles of ANG-(1-7) in the control of regional and systemic hemodynamics. Further studies are needed for clarifying the mechanisms conveying the ANG-(1-7) effects in each particular vascular bed.


    ACKNOWLEDGEMENTS

We are thankful to Jose R. Silva for skillful technical assistance.


    FOOTNOTES

This study was supported by Programa de Núcleos de Excelência-CNPq (PRONEX), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), and Coordenadoria de Apoio ao Pessoal de Nível Superior (CAPES). W. O. Sampaio was a recipient of CNPq fellowship (Master degree).

Address for reprint requests and other correspondence: R. A. S. Santos, Dept. of Physiology and Biophysics, Federal Univ. of Minas Gerais, Av. Antônio Carlos, 6627 31270901 Belo Horizonte-MG, (E-mail: marrob{at}dedalus.Lcc.ufmg.br).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

First published February 6, 2003;10.1152/ajpheart.01145.2002


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Almeida, AP, Fabregas BC, Madureira MM, Santos RJS, Campagnole-Santos MJ, and Santos RAS Angiotensin-(1-7) potentiates the coronary vasodilatatory effect of bradykinin in the isolated rat heart. Braz J Mol Biol Med 33: 709-713, 2000.

2.   Benter, IF, Diz DI, and Ferrario CM. Cardiovascular actions of angiotensin(1-7). Peptides 14: 679-684, 1993[Web of Science][Medline].

3.   Beril, T, Vries R, Saxena PR, and Danser AHJ Bradykinin potentiation by angiotensin-(1-7) and ACE Inhibitors correlates with ACE C-and N-domain blockade. Hypertension 38: 95-99, 2001[Abstract/Free Full Text].

4.   Braga, AN, Silva Lemos M, Silva JR, Fontes WR, and Santos RAS Effects of angiotensins on day-night fluctuations and stress-induced changes in blood pressure. Am J Physiol Regul Integr Comp Physiol 282: R1663-R1671, 2002[Abstract/Free Full Text].

5.   Brosnihan, KB, Li P, and Ferrario CM. Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide. Hypertension 27: 523-528, 1996[Abstract/Free Full Text].

6.   Clark, MA, Diz DI, and Tallant EA. Angiotensin-(1-7) downregulates the angiotensin II type I receptor in vascular smooth cells. Hypertension 37: 1141-1146, 2001[Abstract/Free Full Text].

7.   Crackower, MA, Sarao R, Oudit GY, Yagil C, Kozieradzki I, Scanga SE, Oliveira-dos-Santos AJ, Costa J, Zhang L, Pei Y, Scholey J, Ferrario CM, Manoukian AS, Chappell MC, Back PH, Yagil Y, and Penninger JS. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417: 822-828, 2002[Medline].

8.   Deddish, PA, Marcic B, Jackmann HL, Wang H, Skidgel RA, and Erdös EG. N-domain specific substrate and C-domain inhibitors of angiotensin-converting enzyme: angiotensin-(1-7) and keto-ACE. Hypertension 31: 912-917, 1998[Abstract/Free Full Text].

9.   Dounohue, M, Hsieh F, Baronas E, Gobout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breibart RE, and Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 87: e1-e9, 2000[Abstract/Free Full Text].

10.   Fernandes, L, Fortes ZB, Nigro D, Tostes RCA, Santos RAS, and Carvalho MHC Potentiation of bradykinin by angiotensin-(1-7) on arterioles of spontaneously hypertensive rats studies in vivo. Hypertension 37: 703-709, 2001[Abstract/Free Full Text].

11.   Ferrario, CM, Chappell MC, Tallant EA, Brosnihan KB, and Diz DI. Counterrregulatory action of angiotensin-(1-7). Hypertension 30: 535-541, 1997[Abstract/Free Full Text].

12.   Ferrario, CM. Does angiotensin-(1-7) contribute to cardiac adaptation and preservation of endothelial function in heart failure? Circulation 105: 1523-1525, 2002[Free Full Text].

13.   Ferreira, AJ, Santos RAS, and Almeida AP. Angiotensin- (1-7): cardioprotective effect in myocardial ischemia/reperfusion. Hypertension 38: 665-668, 2001[Abstract/Free Full Text].

14.   Ferreira, AJ, Santos RA, and Almeida AP. Angiotensin-(1-7) improves the post-ischemic function in isolated perfused rat hearts. Braz J Med Biol Res 35: 1083-1090, 2002[Web of Science][Medline].

15.   Feterik, K, Smith L, and Katusic ZS. Angiotensin-(1-7) causes endothelium-dependent relaxatation in canine middle cerebral artery. Brain Res 873: 75-82, 2000[Web of Science][Medline].

16.   Freeman, EJ, Chisolm GM, Ferrario CM, and Tallant EA. Angiotensin-(1-7) inhibits vascular smooth muscle cell growth. Hypertension 28: 104-108, 1996[Abstract/Free Full Text].

17.   Gervais, M, Demolis SP, Domerg V, Lesage M, Richer C, and Giudicelli JF. Systemic and regional hemodynamics assessment in rats with fluorescent microspheres. J Cardiovasc Pharmacol 33: 425-432, 1999[Web of Science][Medline].

18.   Gironacci, MM, Adler-Graschinsky E, Pena C, and Enero MA. Effects of angiotensin II and angiotensin-(1-7) on the release of [3H]norepinephrine from rat atria. Hypertension 24: 457-460, 1994[Abstract/Free Full Text].

19.   Gironacci, MM, Coba MP, and Pena C. Angiotensin-(1-7) binds at the type I angiotensin II receptors in rat renal cortex. Regul Pept 84: 51-54, 1998.

20.   Glenny, RW, Bernard S, and Brinkley M. Validation of fluorescent-labeled microspheres for measurement of regional organ perfusion. J Appl Physiol 74: 2585-2597, 1993[Abstract/Free Full Text].

21.   Handa, RK. Binding and signaling of angiotensin-(1-7) in bovine kidney epithelial cells involves the AT (4) receptor. Peptides 21: 729-736, 2000[Web of Science][Medline].

22.   Heitsch, H, Brovkovych S, Malinsk T, and Wiemer G. Angiotensin-(1-7)-stimulated nitric oxide and superoxide release from endothelial cells. Hypertension 37: 72-76, 2001[Abstract/Free Full Text].

23.   Hilchey, SD, and Bell-Quilley CP. Association between the natriuretic action of angiotensin-(1-7) and selective stimulation of renal prostaglandin I2 release. Hypertension 25: 1238-1244, 1995[Abstract/Free Full Text].

24.   Iyer, SN, Yamada K, Diz DI, Ferrario CM, and Chappel MC. Evidence that prostaglandins mediate the antihypertensive actions of angiotensin-(1-7) during chronic blockade of the renin-angiotensin system. J Cardiovasc Pharmacol 36: 109-117, 2000[Web of Science][Medline].

25.   Kucharewicz, I, Pawlak R, Matys T, Pawlak D, and Buczko W. Antithrombotic effect of captopril and losartan is mediated by angiotensin-(1-7). Hypertension 40: 774-779, 2002[Abstract/Free Full Text].

26.   Kumagai, H, Khosla MC, Ferrario C, and Fouad-Tarazi FM. Biological activity of angiotensin-(1-7) heptaptide in the hamster heart. Hypertension 29: 394-400, 1990.

27.   Lemos, VS, Cortes SF, Silva DM, Campgnole-Santos MJ, and Santos RA. Angiotensin-(1-7) is involved in the endothelium-dependent modulation of phenylefrine-induced contraction in the aorta of m-Ren transgenic rats. Br J Pharmacol 135: 1743-1748, 2002[Web of Science][Medline].

28.   Li, P, Chappell MC, Ferrario CM, and Brosnihan KB. Angiotensin-(1-7) augments bradikinin-induced vasodilation by competing with ACE and releasing nitric oxide. Hypertension 29: 394-400, 1997[Abstract/Free Full Text].

29.   Lima, CV, Paula RD, Resende FL, Khosla MC, and Santos RAS Potentiation of the hypotensive effect of bradykinin by short-term infusion of angiotensin-(1-7) in normotensive and hypertensive rats. Hypertension 30: 542-548, 1997[Abstract/Free Full Text].

30.   Loot, AE, Roks AJ, Henning Rh Tio RA, Suurmeijer AJ, Boosmasma F, and van Gilst WH. Angiotensin-(1-7) attenuates the development of heart failure after myocardial infarction in rats. Circulation 105: 1548-1550, 2002[Abstract/Free Full Text].

31.   Machado, RD, Ferreira MA, Belo AV, Santos RA, and Andrade SP. Vasodilator effect of angiotensin-(1-7) in mature and sponge-induced neovasculature. Regul Pept 107: 105-113, 2002[Web of Science][Medline].

32.   Machado, RP. Estudo Autorradiográfico da Ligação da 125I-Ang-(1-7) em Rim de Rato. Belo Horizonte, MG, Brazil: Universidade Federal de Minas Gerais, 1999, Thesis.

33.   Mahon, JM, Carr RD, Nicol AK, and Henderson IW. Angiotensin-(1-7) is an antagonist at the type I angiotensin II receptor. J Hypertens 12: 1377-1381, 1994[Web of Science][Medline].

34.   Marcic, B, Deddish PA, Jackman HL, and Erdös EG. Enhancement of bradykinin and resensitization of its B2 receptor. Hypertension 33: 835-843, 1999[Abstract/Free Full Text].

35.   Mendes, EP, Vieira MAR, and Santos RAS Interaction between angiotensin-(1-7) and kinins in renal hemodynamic (Abstract). Hypertension 37: 1026, 2001.

36.   Meng, W, and Busija DW. Comparative effects of angiotensin-(1-7) and angiotensin II on piglet pial arterioles. Stroke 24: 2041-2045, 1993[Abstract/Free Full Text].

37.   Metzger, R, Bader M, Ludwig T, Berberich C, Bunnemann B, and Ganten D. Expression of the mouse and rat mas proto-oncogene in the brain and peripheral tissues. FEBS Lett 357: 27-32, 1995[Web of Science][Medline].

38.   Moritz, KM, Campbell DJ, and Wintour EM. Angiotensin- (1-7) in the ovine fetus. Am J Physiol Regul Integr Comp Physiol 280: R404-R409, 2001[Abstract/Free Full Text].

39.   Muthalif, MM, Benter IF, Uddin MR, Haper JL, and Malik KU. Signal transduction mechanism involved in angiotensin- (1-7)-stimulated arachidonic acid release and prostanoid synthesis in rabbit aortic smooth cells. J Pharmacol Exp Ther 284: 388-398, 1998[Abstract/Free Full Text].

40.   Nishiyama, A, Fukui T, Fujisawa Y, Rahman M, Tian RX, Kimura S, and Abe Y. Systemic and regional hemodynamic responses to tempol in angiotensin II-infused hypertensive rats. Hypertension 37: 77-83, 2001[Abstract/Free Full Text].

41.   Oliveira, MA, Fortes ZB, Santos RAS, Khosla MC, and De Carvalho MHC Synergistic effect of angiotensin-(1-7) on bradykinin arteriolar dilation in vivo. Peptides 20: 1195-1201, 1999[Web of Science][Medline].

42.   Osei, SY, Ahima RS, Minkes RK, Weaver JP, Khosla MC, and Kadowitz PJ. Differential responses to Ang-(1-7) in the feline mesenteric and hindquarter vascular beds. Eur J Pharmacol 234: 35-42, 1993[Web of Science][Medline].

43.   Paula, RD, Lima CV, Khosla MC, and Santos RAS Angiotensin-(1-7) potentiates the hypotensive effect of bradykinin in conscious rats. Hypertension 26: 1154-1156, 1995[Abstract/Free Full Text].

44.   Pörsti, I, Bara AT, Busse R, and Hecker M. Release of oxide nitric by angiotensin-(1-7) from porcine coronary endothelium: implications for a novel angiotensin receptor. Br J Pharmacol 111: 652-654, 1994[Web of Science][Medline].

45.   Ren, Y, Garvin JL, and Carretero OA. Vasodilator action of angiotensin-(1-7) on isolated rabbit afferent arterioles. Hypertension 39: 799-802, 2002[Abstract/Free Full Text].

46.   Roks, AMJ, Van Geel PP, Pinto YM, Buikema H, Henning RH, De Zeeuw D, and Van Gilst WH. Angiotensin-(1-7) is a modulator of the human renin angiotensin system. Hypertension 34: 296-301, 1999[Abstract/Free Full Text].

47.   Santos, RAS, Brosnihan KB, Jacobsen NDW, Dicorleto PE, and Ferrario CM. Production of angiotensin-(1-7) by human vascular endothelium. Hypertension 19, Suppl II: II56-II61, 1992[Medline].

48.   Santos, RAS, Campgnole-Santos MJ, and Andrade SP. Angiotensin-(1-7): an update. Regul Pept 91: 45-62, 2000[Web of Science][Medline].

49.   Santos, RAS, Campagnole-Santos MJ, Baracho NCV, Fontes MA, Silva LC, Neves LA, Oliveira DR, Caligiorne SM, Rodrigues ARV, Gropen C, Jr, Carvalho WS, Silva AC, and Khosla MC. Characterization of a new angiotensin antagonist selective for angiotensin-(1-7): evidence that the actions of angiotensin-(1-7) are mediated by specific angiotensin receptors. Brain Res Bull 35: 293-298, 1994[Web of Science][Medline].

50.   Santos, RAS, Simões e Silva AC, Marie C, Speth R, Machado RP, Pinheiro SV, Lopes MT, Mendes EP, Bader M, Schultheiss HP, Campagnole-Santos MJ, and Walther T. Evidence that angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas (Abstract). Hypertension 40: 387, 2002.

51.   Santos, RAS, Passaglio KT, Pesquero JB, Bader M, and Simões e and Silva AC. Interactions between kinins and angiotensin-(1-7) in kidney and blood vessels. Hypertension 38: 660-664, 2001[Abstract/Free Full Text].

52.  Santos RAS, Simões e Silva AC, Maric C, Speth R, Machado RP, Pinheiro SV, Lopes MT, Mendes EP, Bader M, Schultheiss HP, Campagnole-Santos MJ, and Walther T. Evidence that angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor mass. 56th Annual Fall Conference and Scientific Sessions of the Council for High Blood Pressure Research in Association with the Council on the Kidney in Cardiovascular Disease, September 25-28, 2002.

53.   Sasaki, S, Higashi Y, Nakagawa K, Matsuura H, Kajiyama G, and Oshima T. Angiotensin-(1-7) induces endothelium-independent vasodilation in normotensive control subjects and essential hypertensive patients. Hypertension 38: 90-94, 2001[Abstract/Free Full Text].

54.   Simões e Silva, AC, Baracho NC, Passaglio KT, and Santos RA. Renal actions of angiotensin-(1-7). Braz J Med Biol Res 30: 503-513, 1997[Web of Science][Medline].

55.   Tallant, EA, Lu X, Weiss RB, Chappel MC, and Ferrario C. Bovine endothelial cells contain an angiotensin-(1-7) receptor. Hypertension 29: 388-393, 1997[Abstract/Free Full Text].

56.   Tipnis, SR, Hooper NM, Hyde R, Karran E, Christie G, and Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 275: 33238-33243, 2000[Abstract/Free Full Text].

57.   Tran, Y, and Forster C. Angiotensin-(1-7) and the rat aorta: modulation by endothelium. J Cardiovasc Pharmacol 30: 676-682, 1997[Web of Science][Medline].

58.   Ueda, S, Masumori-Maemoto S, Ashino K, Nagahara T, Gotoh E, Umemura S, and Ishii M. Angiotensin-(1-7) attenuates vasoconstriction evoked by angiotensin II but not by noradrenaline in man. Hypertension 35: 998-1001, 2000[Abstract/Free Full Text].

59.   Van Oosterhout, MFM, Willigers MM, Renaman RS, and Prizen FW. Fluorescent microspheres to measure organ perfusion: validation of a simplified sample processing technique. Am J Physiol Heart Circ Physiol 269: H725-H733, 1995[Abstract/Free Full Text].

60.   Widdop, RE, Sampey DB, and Jarrott B. Cardiovascular effects of angiotensin-(1-7) in conscious spontaneously hypertensive rats. Hypertension 34: 964-968, 1999[Abstract/Free Full Text].

61.   Zhu, Z, Zhong J, Zhu S, Liu D, Vander Giet M, and Tepel M. Angiotensin-(1-7) inhibits angiotensin-II-induced signal transduction. J Cardiovasc Pharmacol 40: 693-700, 2002[Web of Science][Medline].

Am J Physiol Heart Circ Physiol 284(6):H1985-H1994
0363-6135/03 $5.00 Copyright © 2003 the American Physiological Society


This article has been cited by other articles:


Home page
 HypertensionHome page
B. Rentzsch, M. Todiras, R. Iliescu, E. Popova, L. A. Campos, M. L. Oliveira, O. C. Baltatu, R. A. Santos, and M. Bader
Transgenic Angiotensin-Converting Enzyme 2 Overexpression in Vessels of SHRSP Rats Reduces Blood Pressure and Improves Endothelial Function
Hypertension, November 1, 2008; 52(5): 967 - 973.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
K. M. Gauthier, D. X. Zhang, L. Cui, K. Nithipatikom, and W. B. Campbell
Angiotensin II Relaxations of Bovine Adrenal Cortical Arteries: Role of Angiotensin II Metabolites and Endothelial Nitric Oxide
Hypertension, July 1, 2008; 52(1): 150 - 155.
[Abstract] [Full Text] [PDF]

Home page
 Exp PhysiolHome page
A. G. Filho, A. J. Ferreira, S. H. S. Santos, S. R. S. Neves, E. R. Silva Camargos, L. K. Becker, H. A. Belchior, M. F. Dias-Peixoto, S. V. B. Pinheiro, and R. A. S. Santos
Selective increase of angiotensin(1-7) and its receptor in hearts of spontaneously hypertensive rats subjected to physical training
Exp Physiol, May 1, 2008; 93(5): 589 - 598.
[Abstract] [Full Text] [PDF]

Home page
 Exp PhysiolHome page
R. A. S. Santos, A. J. Ferreira, and A. C. Simoes e Silva
Recent advances in the angiotensin-converting enzyme 2-angiotensin(1-7)-Mas axis
Exp Physiol, May 1, 2008; 93(5): 519 - 527.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
C. Tikellis, K. Bialkowski, J. Pete, K. Sheehy, Q. Su, C. Johnston, M. E. Cooper, and M. C. Thomas
ACE2 Deficiency Modifies Renoprotection Afforded by ACE Inhibition in Experimental Diabetes
Diabetes, April 1, 2008; 57(4): 1018 - 1025.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. Joyner, L. A. A. Neves, K. Stovall, C. M. Ferrario, and K. B. Brosnihan
Angiotensin-(1-7) serves as an aquaretic by increasing water intake and diuresis in association with downregulation of aquaporin-1 during pregnancy in rats
Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R1073 - R1080.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
M. B.L. Carvalho, F. V. Duarte, R. Faria-Silva, B. Fauler, L. T. da Mata Machado, R. D. de Paula, M. J. Campagnole-Santos, and R. A.S. Santos
Evidence for Mas-Mediated Bradykinin Potentiation by the Angiotensin-(1-7) Nonpeptide Mimic AVE 0991 in Normotensive Rats
Hypertension, October 1, 2007; 50(4): 762 - 767.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
S. Heeneman, J. C. Sluimer, and M. J.A.P. Daemen
Angiotensin-Converting Enzyme and Vascular Remodeling
Circ. Res., August 31, 2007; 101(5): 441 - 454.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
J. C. Q. Velez, A. M. Bland, J. M. Arthur, J. R. Raymond, and M. G. Janech
Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes
Am J Physiol Renal Physiol, July 1, 2007; 293(1): F398 - F407.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
G. A. Botelho-Santos, W. O. Sampaio, T. L. Reudelhuber, M. Bader, M. J. Campagnole-Santos, and R. A. Souza dos Santos
Expression of an angiotensin-(1-7)-producing fusion protein in rats induced marked changes in regional vascular resistance
Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2485 - H2490.
[Abstract] [Full Text] [PDF]

Home page
 Cardiovasc ResHome page
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]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
J. L. Grobe, A. P. Mecca, H. Mao, and M. J. Katovich
Chronic angiotensin-(1-7) prevents cardiac fibrosis in DOCA-salt model of hypertension
Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2417 - H2423.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
R. A.S. Santos, C. H. Castro, E. Gava, S. V.B. Pinheiro, A. P. Almeida, R. D. de Paula, J. S. Cruz, A. S. Ramos, K. T. Rosa, M. C. Irigoyen, et al.
Impairment of In Vitro and In Vivo Heart Function in Angiotensin-(1-7) Receptor Mas Knockout Mice
Hypertension, May 1, 2006; 47(5): 996 - 1002.
[Abstract] [Full Text] [PDF]

Home page
 Journal of Renin-Angiotensin-Aldosterone SystemHome page
B. Gurzu, M. Costuleanu, S. M. Slatineanu, A. Ciobanu, and G. Petrescu
Are Multiple Angiotensin Receptor Types Involved in Angiotensin (1-7) Actions on Isolated Rat Portal Vein?
Journal of Renin-Angiotensin-Aldosterone System, June 1, 2005; 6(2): 90 - 95.
[Abstract] [PDF]

Home page
 HypertensionHome page
S. V. B. Pinheiro, A. C. Simoes e Silva, W. O. Sampaio, R. D. de Paula, E. P. Mendes, E. D. Bontempo, J. B. Pesquero, T. Walther, N. Alenina, M. Bader, et al.
Nonpeptide AVE 0991 Is an Angiotensin-(1-7) Receptor Mas Agonist in the Mouse Kidney
Hypertension, October 1, 2004; 44(4): 490 - 496.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
R. A. S. Santos, A. J. Ferreira, A. P. Nadu, A. N. G. Braga, A. P. de Almeida, M. J. Campagnole-Santos, O. Baltatu, R. Iliescu, T. L. Reudelhuber, and M. Bader
Expression of an angiotensin-(1-7)-producing fusion protein produces cardioprotective effects in rats
Physiol Genomics, May 19, 2004; 17(3): 292 - 299.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
R. A. Skidgel, F. Alhenc-Gelas, and W. B. Campbell
Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting Enzyme Systems: Prologue: Kinins and related systems. New life for old discoveries
Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H1886 - H1891.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
284/6/H1985    most recent
01145.2002v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (40)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sampaio, W. O.
Right arrow Articles by Santos, R. A. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sampaio, W. O.
Right arrow Articles by Santos, R. A. S.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2003 by the American Physiological Society.