(Hypertension. 1997;30:535.)
© 1997 American Heart Association, Inc.
Articles |
Counterregulatory Actions of Angiotensin-(1-7)
From the Hypertension Center, the Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC.
Correspondence to Debra I. Diz, PhD, Wake Forest University/Bowman Gray School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1032.
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Abstract |
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 Top Abstract IntroductionPrinciples of Ang-(1-7)...Ang-(1-7) and the KidneyConcluding RemarksReferences |
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Abstract Angiotensin (Ang)-(1-7) is a bioactive component of the renin-angiotensin system that is formed endogenously from either Ang I or Ang II. The first actions described for Ang-(1-7) indicated that the peptide mimicked some of the effects of Ang II, including the release of prostanoids and vasopressin. However, Ang-(1-7) is devoid of vasoconstrictor, central pressor, or thirst-stimulating actions. In fact, new findings reveal depressor, vasodilator, and antihypertensive actions that may be more apparent in hypertensive animals or humans. Thus, the accumulating evidence suggests that Ang-(1-7) may oppose the actions of Ang II either directly or by stimulation of prostaglandins and nitric oxide. These observations are significant because they may explain the effective antihypertensive action of converting enzyme inhibitors in a variety of non–renin-dependent models of experimental and genetic hypertension as well as most forms of human hypertension. In this context, studies in humans and animals showed that the antihypertensive action of converting enzyme inhibitors correlated with increases in plasma levels of Ang-(1-7). In this review, we summarize our knowledge of the mechanisms accounting for the counterregulatory actions of Ang-(1-7) and elaborate on the emerging concept that Ang-(1-7) functions as an antihypertensive peptide within the cascade of the renin-angiotensin system.
Key Words: angiotensin II • angiotensin receptors • blood pressure • hypertension, essential • rats, inbred SHR
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Introduction |
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TopAbstractIntroductionPrinciples of Ang-(1-7)...Ang-(1-7) and the KidneyConcluding RemarksReferences |
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It is well recognized that the renin-angiotensin system has an important role in cardiovascular physiology, fluid homeostasis, and cell function. Angiotensin (Ang) II has long been considered the main biologically active product of an endocrine system that contributes significantly to the pathogenesis of arterial hypertension, renal dysfunction, and congestive heart failure. Attesting to the importance of this function is the impressive clinical therapeutic benefits achieved by angiotensin-converting enzyme (ACE) inhibitors and a new class of Ang II receptor antagonists.1 However, newer studies have revived the possibility that other peptide fragments of Ang I may either contribute to or actually oppose the pressor and proliferative actions of Ang II, endowing this hormonal system with greater capability for the regulation of tissue perfusion. Earlier studies demonstrated selective actions of the heptapeptide Ang III [Ang-(2-8)] in the secretion of aldosterone;2 more recent studies by Harding (Swanson et al3 ) suggest that a smaller carboxyl product of Ang II, Ang IV [Ang-(3-8)], is biologically active by virtue of recognizing a binding site that is not competed for by selective AT1 or AT2 Ang II receptor antagonists.
The characterization of Ang-(1-7)4 5 6 7 as the first amino-terminal angiotensin peptide product possessing biological actions provided a foundation for the pursuit of a new concept regarding the regulation of cardiovascular function by the renin-angiotensin system. While prostacyclin, bradykinin, and nitric oxide (NO) act as vasodilator hormones limiting the pressor and proliferative actions of Ang II, it had not been considered that products of Ang I could also function to counterbalance the actions of Ang II. This review updates the progress that has been made in the development of this concept since its introduction in 19937 8 and also outlines the areas where further work will be necessary to attain a mechanistic understanding of how the opposing activities of Ang II and Ang-(1-7) contribute to the long-term regulation of blood pressure.
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Principles of Ang-(1-7) Formation and Function |
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TopAbstractIntroductionPrinciples of Ang-(1-7)...Ang-(1-7) and the KidneyConcluding RemarksReferences |
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Synthesis of Ang-(1-7)
Ang I is the ultimate precursor of both Ang II and Ang-(1-7). This readily indicates a common source for the generation of the two active and functionally opposing peptides. While ACE cleaves Ang II from Ang I, processing of Ang I into Ang-(1-7) requires the participation of tissue-specific endopeptidases found in the plasma membranes of neuroepithelial (prolyl-endopeptidase [EC 3.4.24.26]), epithelial (neprilysin [EC 3.4.24.11]), vascular endothelial (prolyl-endopeptidase and neprilysin), and smooth muscle cells (metalloendopeptidase [EC 3.4.24.15]).9 10 11 The processing pathways in these various tissues have been reviewed recently.10 11 12 13 The diversity of the enzymatic pathways by which Ang-(1-7) is cleaved from Ang I suggests that the production of the heptapeptide may be regulated at the tissue level, an interpretation which favors the possibility that Ang-(1-7) functions as a true paracrine hormone.
Little is known yet about the factors that determine the rate of conversion of Ang I into Ang II and Ang-(1-7). We know that any condition that augments plasma or tissue levels of Ang I is associated with increased formation of Ang-(1-7). In several experimental conditions, Ang-(1-7) is the primary peptide produced from Ang I.9 14 15 16 These findings suggest that production of Ang-(1-7) may limit the amount of substrate that is available for the generation of Ang II. This theoretical possibility provides a glimpse into the mechanisms that may determine the balance of the opposing actions of Ang II and Ang-(1-7) in the control of cardiovascular and body fluid functions (see below). In keeping with this interpretation, studies in humans and animals17 18 19 20 21 22 showed that increased concentrations of Ang I after inhibition of ACE are associated with increases in the concentration of Ang-(1-7). While Ang I is a primary substrate for the formation of Ang-(1-7), the heptapeptide may be formed from Ang II by the cleavage of the Pro7-Phe8 bond by prolyl-endopeptidase14 23 and a postproline carboxypeptidase.24 The physiological significance of this alternate pathway has not been characterized yet; conceivably, it provides an additional route for the inactivation of Ang II.
Fig 1 provides a schematic diagram of the active pathways involved in the production of Ang-(1-7) from both Ang I and Ang II. With a more complete understanding of the biochemical routes for the processing of Ang I, it becomes apparent that the potential involvement of the endopeptidase pathways in the pathogenesis of hypertension may be a fruitful area of inquiry. One of the Ang-(1-7)–forming enzymes, neprilysin, converts the atrial natriuretic peptide and bradykinin into inactive fragments.25 Potential interactions of these enzymes with the various substrates have not been investigated yet, nor have studies been undertaken to assess whether polymorphisms in the genes encoding these enzymes might be linked to disorders of cardiovascular function.
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Physiological Actions of Ang-(1-7)
The first studies of Ang-(1-7) revealed that the peptide
stimulates the activity of hypothalamic-neurohypophysial neurons
regulating vasopressin release with a potency equal to Ang
II.4 Subsequently, we found that Ang-(1-7) releases
prostaglandins from astrocytes, VSMCs, and
endothelial cells in culture.26 27 28 29
Prostaglandin release in human astrocytes and porcine
smooth muscle cells was mediated by AT2 receptors, whereas
a non-AT1, non-AT2 receptor accounted for these
actions in rat C6 glioma and porcine endothelial cells.
Furthermore, Ang-(1-7) elicits prostaglandin
production through calcium-independent mechanisms in cells in
culture and in the vasculature.30 Ang-(1-7) also causes a
depressor effect when injected into the circulation of the pithed rat,
and this action is blocked completely by indomethacin
but only partially by an AT1 receptor
blocker.31 The peptide induces relaxation of porcine and
canine coronary artery,32 33 piglet
arterioles,34 and the feline mesenteric bed, possibly via
release of NO through a non-AT1, non-AT2
angiotensin receptor.35 Unlike Ang II,
Ang-(1-7) does not elicit vasoconstriction, aldosterone
release, or stimulation of thirst and salt appetite, nor does it
produce a pressor response after intraventricular
administration in normotensive rats. Indeed, Ang-(1-7) facilitates the
baroreflex and displays depressor effects in sites within the dorsal
medulla.5 36 These effects in the dorsal medulla are
blocked by a selective antagonist to Ang-(1-7),
[d-Ala7]-Ang-(1-7).37 Thus, increasing
evidence supports the concept that Ang-(1-7) opposes the actions of Ang
II and may do so through a novel receptor.
Actions That Oppose the Effects of Ang II Are Enhanced in Models
of Hypertension
Ang-(1-7), similar to losartan and ACE
inhibitors, counteracts the actions of Ang
II.7 Ang-(1-7) may contribute to the antihypertensive
effects produced by ACE inhibitors, since circulating
levels of Ang-(1-7) increase 25-fold to 50-fold during ACE
inhibition19 21 22 and Ang-(1-7) alone can produce
antihypertensive effects in hypertensive animals.38 In the
spontaneously hypertensive rat (SHR), chronic infusion of Ang-(1-7)
produces significant increases in urinary excretion of
prostaglandin E2 and
6-keto-prostaglandin F1
accompanied by diuresis, natriuresis, and a decrease in blood
pressure.38 Systemic administration of Ang-(1-7)
attenuates the vasoconstrictor actions of phenylephrine and
Ang II in hypertensive but not normotensive rats,39 in
contrast with the potentiation of -adrenoceptor-mediated pressor
responses by Ang II. Moreover, intravenous infusions of
Ang-(1-7) reverse the inhibitory effects of Ang II on the
reflex control of heart rate in both SHR and Wistar-Kyoto
rats39 and improve the impaired slope of the reflex
control of heart rate in SHR after either peripheral or
central administration.36 39
A recent study in a genetic model of hypertension that is associated with heightened activity of the brain angiotensin system clearly demonstrated the opposing actions of Ang-(1-7).40 In this important research, we evaluated the hemodynamic effects of delivering either a specific, affinity-purified Ang-(1-7) antibody or an Ang II monoclonal antibody (KAA8) into the brain of conscious homozygous mRen2(27) renin transgenic [Tg(+)] rats (Fig 2). Cerebroventricular administration of the affinity-purified Ang-(1-7) antibody in conscious Tg(+) hypertensive rats caused significant dose-related elevations in blood pressure and heart rate.40 The hypertensive response was augmented in transgenic rats studied 7 to 10 days after cessation of lisinopril therapy. In contrast, all doses of the Ang II antibody produced hypotension and bradycardia. The magnitude of the depressor response was significantly augmented in transgenic rats weaned off lisinopril therapy. Central administration of either the Ang-(1-7) or Ang II antibodies had no effect on normotensive Sprague-Dawley rats. These data demonstrate that Ang-(1-7) opposes the action of Ang II on the central mechanisms that contribute to the maintenance of this model of hypertension. In addition, these studies showed an important contribution of the brain renin-angiotensin system to the maintenance of this form of monogenetic hypertension.
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, solid line) or monoclonal
angiotensin II (
, dashed line) antibody on the mean
arterial pressure of homozygous mRen2(27) transgenic
hypertensive rats. Data were redrawn from Reference 40. Values are
mean±SE.There is also evidence that Ang-(1-7) can act as an antagonist to the actions of Ang II in the vasculature.41 Therefore, mechanisms other than activation of prostaglandins and NO may play a role in mediating the depressor effects of Ang-(1-7). It is not currently possible to determine the exact contribution of prostaglandins versus other mechanisms to the effects produced by Ang-(1-7) in the SHR or Tg(+) hypertensive rats from these initial studies. In addition, the mediators stimulated by Ang-(1-7) may differ, depending on the vascular bed and species studied. In recent studies we showed that the Ang-(1-7)–induced prostacyclin release from aortic VSMCs of Tg(+) rats was greater than that from VSMCs isolated from Sprague-Dawley control rats.42 Similarly, in the renovascular hypertensive dog, the depressor component of the response to systemic Ang-(1-7) is exaggerated.43 Thus, the degree of activation of these depressor systems is influenced by the state of activation of the renin-angiotensin system.
Evidence for Ang-(1-7) Vasodilator Actions in Canine
Coronary Vessels and Interactions With Kinins
Ang-(1-7) relaxes canine or porcine coronary artery
rings,32 33 as well as isolated feline mesenteric
beds.35 This effect is blocked in both canine and porcine
rings by removal of the endothelium or pretreatment
with an NO synthase inhibitor. Moreover, the vasorelaxant
activity of Ang-(1-7) is markedly attenuated by the bradykinin
B2 receptor antagonist Hoe 140 and does not
appear to be associated with the synthesis and release of
prostaglandins.33 Assessment of the
angiotensin receptor subtypes mediating the responses to
Ang-(1-7) revealed that these effects are not inhibited by
subtype-selective AT1 or AT2 receptor
antagonists but are markedly attenuated by prior exposure
to the competitive nonselective Ang II peptide receptor
antagonist [Sar1, Thr8]-Ang II.
These results suggest that Ang-(1-7) has a direct effect on the
endothelium, through the release of NO and kinins,
mediated by an angiotensin receptor pharmacologically
distinct from AT1 and AT2 receptor subtypes.
Furthermore, Ang II and Ang-(1-7) at equivalent concentration ranges
produced diametrically opposite changes in the contractile state of
coronary artery rings (Fig 3).
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Additionally, Ang-(1-7) potentiated synergistically bradykinin-induced vasodilation. These actions of Ang-(1-7) may contribute to the cardioprotective effects of chronic ACE inhibition. Ang-(1-7)’s potentiating effect on the response to bradykinin was first described by Paula et al,44 who showed that low concentrations of Ang-(1-7) given intravenously augmented by 2-fold to 10-fold the vasodepressor response elicited by bradykinin. In isolated canine coronary arteries, Ang-(1-7) has a synergistic, concentration-dependent action on bradykinin-induced vasodilation that is dependent on the release of NO but not prostaglandins.45 The response is specific for Ang-(1-7), since neither acetylcholine, sodium nitroprusside, nor prostaglandins were able to augment the bradykinin-induced relaxation.45 This synergistic effect of Ang-(1-7) is not mediated by a known angiotensin receptor, since the effect persists in the presence of AT1, AT2, and [Sar1, Thr8]-Ang II receptor antagonists. In fact, in contrast to a receptor-mediated effect of Ang-(1-7),33 the peptide may augment vasodilation in coronary arteries by acting as a local modulator of ACE activity. Li et al45 found that Ang-(1-7) significantly inhibits the degradation of 125I-[Tyr0]-bradykinin and the appearance of the bradykinin-(1-7) and bradykinin-(1-5) metabolites in coronary vascular rings while it also inhibits purified canine ACE activity with an IC50 of 0.65 µmol/L. These findings indicate that Ang-(1-7) may inhibit ACE activity to elevate bradykinin levels as one mechanism of promoting vasodepressor actions.
Antiproliferative Actions of Ang-(1-7) in VSMCs
In previous studies in porcine and rat VSMCs, Ang II
activates phospholipase C and D and releases
prostaglandins, whereas Ang-(1-7) releases only
prostaglandins.29 30 46 47 The activation of
phospholipase C by Ang II in VSMCs is known to stimulate growth.
Because prostaglandins inhibit vascular growth, we
speculated that Ang-(1-7) might also prevent the growth of VSMCs. The
effect of Ang-(1-7) on cell growth was determined by measuring
[3H]thymidine incorporation into rat aortic VSMCs in the
presence and absence of various mitogens.48 The amount of
[3H]thymidine incorporation was increased by treatment
with fetal bovine serum, platelet-derived growth factor, or Ang II.
In the presence of Ang-(1-7), the incorporation of
[3H]thymidine in response to fetal bovine serum,
platelet-derived growth factor, and Ang II was significantly
attenuated in a dose-dependent manner (Fig 4). Thus, Ang II and Ang-(1-7) have
opposite effects on VSMC growth.
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Attenuation of serum-stimulated thymidine incorporation by Ang-(1-7) is unaffected by antagonists selective for AT1 or AT2 receptors. However, the sarcosine derivatives of Ang II are effective antagonists, indicating that growth inhibition by Ang-(1-7) is a result of angiotensin receptor activation. In contrast, Ang II stimulation of [3H]thymidine incorporation is attenuated by the AT1-selective antagonists. Thus Ang-(1-7) inhibits VSMC growth through activation of a non-AT1, non-AT2 receptor.48
Novel Receptor Identified in Bovine Aortic Endothelial
Cells
The inhibition of vascular growth by Ang-(1-7) through a
non-AT1, non-AT2 receptor suggests that the
heptapeptide activates a unique angiotensin peptide
receptor. Since previous studies strongly suggested that the
endothelium also responds to Ang-(1-7) through
activation of a non-AT1, non-AT2
angiotensin peptide receptor,28 33 we isolated
endothelial cells from bovine thoracic aorta to
determine whether they contain a high-affinity
125I-Ang-(1-7) binding site. Scatchard analysis of
saturation isotherms of endothelial cells showed that
125I-Ang-(1-7) binds to bovine aortic
endothelial cells with an affinity of 19 nmol/L
and a density of 1351 fmol/mg protein.49 In
competition studies, the specific binding of 125I-Ang-(1-7)
is blocked by [Sar1, Ile8]-Ang II and by
[d-Ala7]-Ang-(1-7), a selective blocker of responses to
Ang-(1-7).49 In contrast, neither the
AT1-selective nor the AT2-selective
antagonists significantly competes for
125I-Ang-(1-7) binding. Further proof that Ang-(1-7) does
not bind to a typical AT1 or AT2 receptor is
derived from studies showing that bovine aortic
endothelial cells do not contain the mRNA encoding an
AT1 or AT2 receptor. In preliminary
experiments, we also showed that 125I-Ang-(1-7) binds
specifically and with high affinity to the endothelial
layer of canine coronary arteries, using the technique of in
vitro emulsion autoradiography, as previously
described50 (Fig 5). Binding
to canine coronary endothelium was effectively
competed for by either unlabeled Ang-(1-7) or
[d-Ala7]-Ang-(1-7). These results are in agreement with
endothelial cell binding data49 as well as
previous studies in which we showed that Ang-(1-7) causes vasodilation
of canine coronary arteries by a non-AT1,
non-AT2 receptor.33
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Ang-(1-7) and the Kidney |
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TopAbstractIntroductionPrinciples of Ang-(1-7)...Ang-(1-7) and the KidneyConcluding RemarksReferences |
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A critically important target organ for Ang II is the kidney. Ang II causes renal vasoconstriction, release of aldosterone, reduced glomerular filtration rate, stimulation of sodium and bicarbonate transport in the proximal tubules, and mesangial cell hypertrophy.51 In contrast, Ang-(1-7) exhibits diuretic and natriuretic properties in hypertensive animals, as evidenced by our studies in SHR.38 Similar natriuretic and diuretic actions occur in the in vivo isolated and in vivo perfused kidney.52 53 54 The natriuretic and diuretic responses to Ang-(1-7) are associated with increases in prostaglandin release,53 and the majority of the renal effect of Ang-(1-7) is attenuated with the cyclooxygenase inhibitor indomethacin. In isolated proximal tubules, very low doses (10-13 to 10-9 mol/L) of Ang-(1-7) inhibit transport-dependent oxygen consumption54 and bicarbonate transport.55 These actions of Ang-(1-7) are at least partially blocked by antagonists selective for the AT1 receptor. In marked contrast to the effects of Ang II on the kidney, Ang-(1-7) does not alter renal blood flow or stimulate aldosterone release.53 54 56
The renal excretory response to low doses of Ang-(1-7) is markedly different from the antinatriuresis and antidiuresis reported for low doses of Ang II. Subthreshold vasoconstrictor doses of Ang II activate AT1 receptors on the proximal tubule, leading to a decrease in urinary sodium and water excretion. The natriuretic effect of Ang-(1-7) may be due to decreased AT1 receptor activation resulting from receptor competition with endogenous Ang II. However, the renal vascular constrictor response to Ang II (AT1 receptor mediated) is unaltered when coinjected with nonvasoconstrictor doses of Ang-(1-7), suggesting that Ang-(1-7) does not functionally antagonize the AT1-mediated actions of Ang II in the kidney.54 Alternatively, the natriuretic effects of high doses of Ang II may be due to conversion of Ang II to Ang-(1-7).
In the above studies, differences were observed to infusions of Ang-(1-7) in normotensive and hypertensive rats. While transient depressor and diuretic/natriuretic effects and suppression of plasma vasopressin levels were seen in the SHR, minimal changes occurred in the Wistar-Kyoto rats.38 Interestingly, Ang-(1-7) stimulates antinatriuresis and a nonsignificant rise in plasma vasopressin in water-loaded Wistar rats.57 Santos et al58 recently reported antidiuretic effects in an isolated collecting duct preparation, which were blocked by the [d-Ala7]-Ang-(1-7) antagonist. These antidiuretic effects are in direct contrast to the effects observed in the isolated and in situ perfused kidney. One obvious difference in the studies with intact animals was that the experiments were performed after water loading. Burnier et al59 reported conflicting results concerning AT1 treatment of patients after an acute water load. In addition, in isolated tubules, the route for administration of the Ang-(1-7) and the segment of the nephron accessed was different than in isolated kidneys or whole-animal experiments. These findings suggest that the overall state of sodium and water balance (and perhaps the overall activity of the renin-angiotensin system) may influence the effects of Ang-(1-7) in the kidney, as discussed below. In addition, these results emphasize that the route of administration and the site of the nephron exposed to Ang-(1-7) may determine the direction of observed actions.
Ang-(1-7) was reported to inhibit transcellular sodium flux in cultured renal tubular epithelial cells, an action that may be mediated through the activation of phospholipase A2.60 Interestingly, the phospholipase A2 activation in response to Ang I is markedly potentiated by captopril. These data indicate that Ang-(1-7) plays an important role in modulating sodium handling, most likely at the level of the tubule, and reinforce the concept that Ang-(1-7) is a biologically active member of the renin-angiotensin system. The data also suggest that the tubular epithelium can convert Ang I to Ang-(1-7) with only minor amounts of Ang II formed. Inhibition of neprilysin blocked the majority of Ang-(1-7) formation.61 In contrast, Ang II was metabolized preferentially to Ang-(1-4) by neprilysin and shorter N-terminal fragments such as Ang-(2-8) and Ang-(3-8) by peptidyl and dipeptidyl aminopeptidases. Thus, the kidney contains the necessary substrates and enzymes for the intrarenal generation of Ang-(1-7).
Presence of Angiotensin-(1-7) in Urine: A Marker of
Renal Function?
A further insight into the role of Ang-(1-7) in renal function was
gained by demonstration of large quantities of the heptapeptide in rat
urine. Urinary excretion of Ang-(1-7) averages 4.8±0.4 pmol/24
h compared with 0.73±0.04 pmol/24 h for Ang II.62
Urinary Ang-(1-7) levels are increased by 88% after a 5-day exposure
of the rats to lisinopril (20 mg/kg, PO). Combined
treatment with lisinopril and a neprilysin
inhibitor returned the concentration and excretion of
Ang-(1-7) to control levels and augmented Ang II concentration. These
data suggest that the kidneys are an important source for the
production of Ang-(1-7) and reinforce the concept that
neprilysin participates in the renal processing of Ang I into
Ang-(1-7).
The demonstration of high concentrations of Ang-(1-7) in rat urine is an important finding that could lead to greater knowledge of the mechanisms that account for the progressive decline in renal function associated with hypertension and end-stage renal disease. A significant step into this problem has been gained with the characterization of Ang-(1-7) in the urine of 31 healthy volunteers and 18 untreated essential hypertensive subjects.63 In these studies, the concentration of Ang-(1-7) in the urine of normal subjects averaged 62.6±22.6 (SD) pmol/L, corresponding to a urinary excretion rate of 98.9±44.7 pmol/24 h. Concurrent measurements of plasma Ang-(1-7) showed that the content of Ang-(1-7) in urine was 2.5-fold higher than that measured in the plasma. In contrast, untreated essential hypertensive subjects had lower concentrations and 24-hour urinary excretion rates of Ang-(1-7) averaging 39.4±18.0 pmol/L and 60.2±14.6 pmol/24 h, respectively (P<.001). Differences in the excretory rate of Ang-(1-7) between normal volunteers and essential hypertensive subjects were not modified by normalization of the data by urinary creatinine excretion rates. In addition, urinary concentrations of Ang-(1-7) correlated inversely with arterial pressures (r=-.48, P<.001), whereas both urinary Ang-(1-7) (odds ratio of 0.92 [95% confidence interval: 0.88-0.97]) and age were independent predictors of systolic blood pressure.
These studies demonstrate the presence of Ang-(1-7) in urine and the existence of reduced levels of the heptapeptide in individuals with untreated essential hypertension. The relatively higher concentrations of Ang-(1-7) in urine compared with plasma are in agreement with data showing that Ang-(1-7) may contribute to the regulation of blood pressure. The inverse association between Ang-(1-7) and arterial pressure provides a potential marker for the characterization of forms of essential hypertension associated with reduced production or activity of vasodilator hormones.
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Concluding Remarks |
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TopAbstractIntroductionPrinciples of Ang-(1-7)...Ang-(1-7) and the KidneyConcluding RemarksReferences |
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Studies of the role of Ang-(1-7) in the control of blood pressure suggest that the renin-angiotensin system possesses the ability to limit the pressor and proliferative actions of Ang II through a mechanism that relies on the alternative generation of Ang-(1-7). In this context, Ang-(1-7) may act as the signal peptide for the activation of the negative feedback limb that limits the pressor and proliferative actions of Ang II through stimulation of vasodilator prostacyclin, NO, or both. Increased Ang II production is a critical component of the short-term cardiovascular response to acute changes in blood pressure and blood volume. Therefore, regulatory mechanisms must exist to ensure that increased production of Ang-(1-7) will not negate the important compensatory actions of Ang II in both the short- and long-term regulation of blood pressure. The specific feedback mechanisms that regulate the formation of Ang-(1-7) independently from Ang II have yet to be determined. Our working hypothesis is that one aspect of the regulatory feedback mechanism may entail modulation of Ang II production by ACE, since Ang-(1-7) is metabolized by ACE and exhibits an affinity comparable to that for bradykinin (approximately 0.7 mol/L).45 Our studies also suggest that the actions of Ang-(1-7) are most evident in situations associated with long-term rather than short-term increases in Ang II production or activity. Likewise, augmented Ang-(1-7) formation follows chronic rather than acute inhibition of ACE.20 While further studies are required to assess the mechanisms that determine the factors that control production of Ang-(1-7) over Ang II formation from their common Ang I substrate, the data gathered to date suggest that the net actions of the renin-angiotensin system in the long-term regulation of blood pressure may depend on a balance between the tissue concentrations of Ang II and Ang-(1-7; Fig 6).
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Acknowledgments |
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This work was supported in part by grants HL38535, HL56973, HL50066, and HL51952 from the National Institutes of Health, Bethesda, Md.
Received March 18, 1997; first decision April 30, 1997; accepted May 20, 1997.
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References |
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TopAbstractIntroductionPrinciples of Ang-(1-7)...Ang-(1-7) and the KidneyConcluding RemarksReferences |
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1. Ferrario CM, Flack JM. Pathologic consequences of increased angiotensin II activity. Cardiovasc Drugs Ther. 1996;10:511-518.[Medline] [Order article via Infotrieve]
2. Ackerly JA, Felger TS, Peach MJ. Des-Asp1-angiotensin I: a metabolite of angiotensin I in the perfused feline adrenal. Eur J Pharmacol. 1976;38:113-121.[Medline] [Order article via Infotrieve]
3. Swanson GN, Hanesworth JM, Sardinia MF, Coleman JKM, Wright JW, Hall KL, Miller-Wing AV, Stobb JW, Cook VI, Harding EC, Harding JW. Discovery of a distinct binding site for angiotensin II (3-8) a putative angiotensin IV receptor. Regul Pept. 1992;40:409-419.[Medline] [Order article via Infotrieve]
4. Schiavone MT, Santos RAS, Brosnihan KB, Khosla MC,
Ferrario CM. Release of vasopressin from the rat
hypothalamo-neurohypophysial system by angiotensin-(1-7)
heptapeptide. Proc Natl Acad Sci U S A. 1988;85:4095-4098.
5. Campagnole-Santos MJ, Diz DI, Santos RAS, Khosla MC, Brosnihan KB, Ferrario CM. Cardiovascular actions of angiotensin-(1-7) microinjected into the dorsomedial medulla of rats. Am J Physiol. 1989;257:H324-H329.[Medline] [Order article via Infotrieve]
6. Ferrario CM, Brosnihan KB, Diz DI, Jaiswal N, Khosla MC, Milsted A, Tallant EA. Angiotensin-(1-7): a new hormone of the angiotensin system. Hypertension. 1991;18(suppl III):III-126-III-133.
7. Ferrario CM. Biological roles of angiotensin-(1-7). Hypertens Res. 1992;15:61-66.
8. Ferrario CM, Brosnihan KB. Angiotensin formation and degradation. In: Izzo JL Jr, Black HR, eds. Hypertension Primer. Dallas, Tex: American Heart Association; 1993: chap 9:17.
9. Chappell MC, Tallant EA, Brosnihan KB, Ferrario CM. Conversion of angiotensin I to angiotensin-(1-7) by thimet oligopeptidase (EC 3.4.24.15) in vascular smooth muscle cells. J Vasc Med Biol. 1994;5:129-137.
10. Ferrario CM, Chappell MC. A new myocardial conversion of angiotensin I. Curr Opin Cardiol. 1994;9:520-526.[Medline] [Order article via Infotrieve]
11. Ferrario CM, Chappell MC, Tallant EA. Divergent pathways in the formation and function of the angiotensin system. Receptors in Cardiovascular Disease, III. Whitehouse Station, NJ: Merck & Co, Inc. Vol. 3(1);1996:5-12.
12. Welches WR, Brosnihan KB, Ferrario CM. A comparison of the properties, and enzymatic activity of three angiotensin processing enzymes: angiotensin converting enzyme, prolyl endopeptidase and neutral endopeptidase 24.11. Life Sci. 1993;52:1461-1480.[Medline] [Order article via Infotrieve]
13. Ferrario CM, Barnes KL, Block CH, Brosnihan KB, Diz DI, Khosla MC, Santos RAS. Pathways of angiotensin formation and function in the brain. Hypertension. 1990;15(suppl I):I-13-I-19.
14. Welches WR, Santos RAS, Chappell MC, Brosnihan KB, Greene LJ, Ferrario CM. Evidence that prolyl endopeptidase participates in the processing of brain angiotensin. J Hypertens. 1991;9:631-638.[Medline] [Order article via Infotrieve]
15. Chappell MC, Tallant EA, Brosnihan KB, Ferrario CM. Processing of angiotensin peptides by NG108-15 neuroblastoma x glioma hybrid cell line. Peptides. 1990;11:375-380.[Medline] [Order article via Infotrieve]
16. Santos RAS, Brosnihan KB, Jacobsen DW, DiCorleto PE, Ferrario CM. Production of angiotensin-(1-7) by human vascular endothelium. Hypertension. 1992;19(suppl II):II-56-II-61.
17. Campbell DJ, Lawrence AC, Towrie A, Kladis A, Valentijn
AJ. Differential regulation of angiotensin peptide
levels in plasma and kidney of the rat.
Hypertension. 1991;18:763-773.
18. Kohara K, Brosnihan KB, Chappell MC, Khosla MC,
Ferrario CM. Angiotensin-(1-7): a member of
circulating angiotensin peptides.
Hypertension. 1991;17:131-138.
19. Kohara K, Brosnihan KB, Ferrario CM. Angiotensin-(1-7) in the spontaneously hypertensive rat. Peptides. 1993;14:883-891.[Medline] [Order article via Infotrieve]
20. Luque M, Martin P, Martell N, Fernandez C, Brosnihan KB, Ferrario CM. Effects of captopril related to increased levels of prostacyclin and angiotensin-(1-7) in essential hypertension. J Hypertens. 1996;14:799-805.[Medline] [Order article via Infotrieve]
21. Moriguchi A, Brosnihan KB, Kumagai H, Ganten D, Ferrario CM. Mechanisms of hypertension in transgenic rats expressing the mouse Ren-2 gene. Am J Physiol. 1994;266:R1273-R1278.[Medline] [Order article via Infotrieve]
22. Campbell DJ, Kladis A, Duncan AM. Effects of
converting enzyme inhibitors on angiotensin and
bradykinin peptides. Hypertension. 1994;23:439-449.
23. Koida M, Walter R. Post-proline cleaving
enzyme. J Biol Chem. 1976;251:7593-7599.
24. Kumamoto K, Stewart TA, Johnson AR, Erdos EG. Prolylcarboxypeptidase (angiotensinase C) in human lung and cultured cells. J Clin Invest. 1981;67:210-215.[Medline] [Order article via Infotrieve]
25. Nomura N, Shimamoto K, Ura N, Iwata M, Aoyama T, Takagawa Y, Iimura O. The role of kinins and atrial natriuretic peptide on the renal effects of neutral endopeptidase inhibitor in normotensive and hypertensive rats. Clin Exp Hypertens. 1995;17:1219-1231.[Medline] [Order article via Infotrieve]
26. Jaiswal N, Tallant EA, Diz DI, Khosla MC, Ferrario
CM. Subtype 2 angiotensin receptors mediate
prostaglandin synthesis in human astrocytes.
Hypertension. 1991;17:1115-1120.
27. Jaiswal N, Diz DI, Tallant EA, Khosla MC, Ferrario CM. Characterization of angiotensin receptors mediating prostaglandin synthesis in C6 glioma cells. Am J Physiol. 1991;260:R1000-R1006.[Medline] [Order article via Infotrieve]
28. Jaiswal N, Diz DI, Chappell MC, Khosla MC, Ferrario CM. Stimulation of endothelial cell prostaglandin production by angiotensin peptides: characterization of receptors. Hypertension. 1992;19(suppl II):II-49-II-55.
29. Jaiswal N, Tallant EA, Jaiswal RK, Diz DI, Ferrario
CM. Differential regulation of prostaglandin
synthesis by angiotensin peptides in porcine aortic smooth
muscle cells: subtypes of angiotensin receptors
involved. J Pharmacol Exp Ther. 1993;265:664-673.
30. Tallant EA, Jaiswal N, Diz DI, Ferrario CM.
Human astrocytes contain two distinct angiotensin receptor
subtypes. Hypertension. 1991;18:32-39.
31. Benter IF, Diz DI, Ferrario CM. Cardiovascular actions of angiotensin-(1-7). Peptides. 1993;14:679-684.[Medline] [Order article via Infotrieve]
32. Porsti I, Bara AT, Busse R, Hecker M. Release of nitric oxide by angiotensin-(1-7) from porcine coronary endothelium: implications for a novel angiotensin receptor. Br J Pharmacol. 1994;111:652-654.[Medline] [Order article via Infotrieve]
33. Brosnihan KB, Li P, Ferrario CM.
Angiotensin-(1-7) dilates canine coronary arteries
through kinins and nitric oxide. Hypertension. 1996;27:523-528.
34. Meng W, Busija DW. Comparative effects of
angiotensin-(1-7) and angiotensin II on piglet
pial arterioles. Stroke. 1993;24:2041-2045.
35. Osei SY, Ahima RS, Minkes RK, Weaver JP, Khosla MC, Kadowitz PJ. Differential responses to angiotensin-(1-7) in the feline mesenteric and hindquarters vascular beds. Eur J Pharmacol. 1993;234:35-42.[Medline] [Order article via Infotrieve]
36. Campagnole-Santos MJ, Heringer SB, Batista EN, Khosla MC, Santos RAS. Differential baroreceptor reflex modulation by centrally infused angiotensin peptides. Am J Physiol. 1992;263:R89-R94.[Medline] [Order article via Infotrieve]
37. Santos RAS, Campagnole-Santos MJ, Baracho NCV, Fontes MAP, Silva LCS, Neves LAA, Oliveira DR, Caligiorne SM, Rodrigues ARV, Gropen C Jr, Carvalho WS, Silva ASCE, 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. 1994;35:293-398.[Medline] [Order article via Infotrieve]
38. Benter IF, Ferrario CM, Morris M, Diz DI. Antihypertensive actions of angiotensin-(1-7) in spontaneously hypertensive rats. Am J Physiol. 1995;269:H313-H319.[Medline] [Order article via Infotrieve]
39. Benter IF, Diz DI, Ferrario CM. Pressor and
reflex sensitivity is altered in spontaneously hypertensive rats
treated with angiotensin-(1-7).
Hypertension. 1995;26:1138-1144.
40. Moriguchi A, Tallant EA, Matsumura K, Reilly TM, Walton
H, Ganten D, Ferrario CM. Opposing actions of
angiotensin-(1-7) and angiotensin II in the
brain of transgenic hypertensive rats. Hypertension. 1995;25:1260-1265.
41. Mahon JM, Carr RD, Nicol AK, Henderson IW. Angiotensin-(1-7) is an antagonist at the type 1 angiotensin II receptor. J Hypertens. 1994;12:1377-1381.[Medline] [Order article via Infotrieve]
42. Tallant EA, Ganten D, Ferrario CM. Attenuated responses to angiotensin II in vascular smooth muscle cells from transgenic (mREN2)27 rats. J Hypertens. 1994;12:S178.
43. Nakamoto H, Ferrario CM, Fuller SB, Robaczwski DL,
Winicov E, Dean RH. Angiotensin-(1-7) and nitric
oxide interaction in renovascular hypertension.
Hypertension. 1995;25:796-802.
44. Paula RD, Lima CV, Khosla MC, Santos RAS.
Angiotensin-(1-7) potentiates the hypotensive effect of
bradykinin in conscious rats. Hypertension. 1995;26:1154-1159.
45. Li P, Chappell MC, Ferrario CM, Brosnihan KB.
Angiotensin-(1-7) augments bradykinin-induced vasodilation
by competing with ACE and releasing nitric oxide.
Hypertension. 1997;29:394-400.
46. Jaiswal N, Jaiswal RK, Tallant EA, Diz DI, Ferrario
CM. Alterations in prostaglandin production
in spontaneously hypertensive rat smooth muscle cells.
Hypertension. 1993;21:900-905.
47. Freeman EJ, Ferrario CM, Tallant EA. Angiotensins differentially activate phospholipase D in vascular smooth muscle cells from spontaneously hypertensive and Wistar-Kyoto rats. Am J Hypertens. 1995;8:1105-1111.[Medline] [Order article via Infotrieve]
48. Freeman EJ, Chisolm GM, Ferrario CM, Tallant EA.
Angiotensin-(1-7) inhibits vascular smooth muscle cell
growth. Hypertension. 1996;28:104-108.
49. Tallant EA, Lu X, Weiss RB, Chappell MC, Ferrario
CM. Bovine aortic endothelial cells contain an
angiotensin-(1-7) receptor.
Hypertension. 1997;29:388-392.
50. Szigethy EM, Barnes KL, Diz DI. Light microscopic localization of angiotensin II binding sites in canine medulla using high resolution autoradiography. Brain Res Bull. 1992;29:813-819.[Medline] [Order article via Infotrieve]
51. Ichikawa I, Harris RC. Angiotensin actions in the kidney: renewed insight into the old hormone. Kidney Int. 1991;40:583-596.[Medline] [Order article via Infotrieve]
52. DelliPizzi A, Hilchey SD, Bell-Quilley CP. Natriuretic actions of angiotensin-(1-7). Br J Pharmacol. 1994;111:1-3.[Medline] [Order article via Infotrieve]
53. Hilchey SD, Bell-Quilley CP. Association between
the natriuretic action of angiotensin-(1-7) and
selective stimulation of renal prostaglandin I2
release. Hypertension. 1995;25:1238-1244.
54. Handa RK, Ferrario CM, Strandhoy JW. Renal actions of angiotensin-(1-7): in vivo and in vitro studies. Am J Physiol. 1996;270:F141-F147.[Medline] [Order article via Infotrieve]
55. Garcia NH, Garvin JL. Angiotensin 1-7 has a biphasic effect on fluid absorption in the proximal straight tubule. J Am Soc Nephrol. 1994;5:1133-1138.[Abstract]
56. Kono T, Taniguchi A, Imura H, Oseko F, Khosla MC. Pressor activity of angiotensin II-(2-7)-hexapeptide in man. Endocrinol Jpn. 1985;32:767-769.[Medline] [Order article via Infotrieve]
57. Santos RAS, Baracho NCV. Angiotensin-(1-7) is a potent antidiuretic peptide in rats. Braz J Med Biol Res. 1992;25:651-654.[Medline] [Order article via Infotrieve]
58. Santos RAS, Silva ACS, Magaldi AJ, Khosla MC, Ceasr KR,
Passaglio KT, Baracho NCV. Evidence for a
physiological role of angiotensin-(1-7)
in the control of hydroelectrolyte balance.
Hypertension. 1996;27:875-884.
59. Burnier M, Pechere-Bertschi A, Nussberger J, Waeber B, Brunner HR. Studies of the renal effects of angiotensin II receptor blockade: the confounding factor of acute water loading on the action of vasoactive systems. Am J Kidney Dis. 1995;26:108-115.[Medline] [Order article via Infotrieve]
60. Andreatta-Van Leyen S, Romero MF, Khosla MC, Douglas JG. Modulation of phospholipase A2 activity and sodium transport by angiotensin-(1-7). Kidney Int. 1993;44:932-936.[Medline] [Order article via Infotrieve]
61. Stephenson SL, Kenny AJ. Metabolism of neuropeptides. Biochem J. 1987;241:237-247.[Medline] [Order article via Infotrieve]
62. Chappell MC, Diz DI, Ferrario CM. Urinary angiotensin-(1-7): influence of converting enzyme and neprilysin inhibition. Hypertension. 1995;26:542. Abstract.
63. Ferrario CM, Martell N, Pinillas C, Brosnihan KB, Chappell MC, Novikov S, Perez D, Flack JM, Luque M. Essential hypertension is associated with low urinary levels of angiotensin-(1-7). Hypertension. 1996;28:515. Abstract.
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|
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|
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|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
I. Haulica, W. Bild, C. N Mihaila, T. Ionita, C. P Boisteanu, and B. Neagu Biphasic effects of angiotensin (1-7) and its interactions with angiotensin II in rat aorta Journal of Renin-Angiotensin-Aldosterone System, June 1, 2003; 4(2): 124 - 128. [Abstract] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
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W. O. Sampaio, A. A. S. Nascimento, and R. A. S. Santos Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting Enzyme Systems: Systemic and regional hemodynamic effects of angiotensin-(1-7) in rats Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H1985 - H1994. [Abstract] [Full Text] [PDF]
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D. J. Campbell Vasopeptidase Inhibition: A Double-Edged Sword? Hypertension, March 1, 2003; 41(3): 383 - 389. [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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G. Wiemer, L. W. Dobrucki, F. R. Louka, T. Malinski, and H. Heitsch AVE 0991, a Nonpeptide Mimic of the Effects of Angiotensin-(1-7) on the Endothelium Hypertension, December 1, 2002; 40(6): 847 - 852. [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. Xu, O. A. Carretero, Y.-H. Liu, E. G. Shesely, F. Yang, A. Kapke, and X.-P. Yang Role of AT2 Receptors in the Cardioprotective Effect of AT1 Antagonists in Mice Hypertension, September 1, 2002; 40(3): 244 - 250. [Abstract] [Full Text] [PDF]
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 W. F. van Rodijnen, T. A. van Lambalgen, M. H. van Wijhe, G.-J. Tangelder, and P. M. ter Wee Renal microvascular actions of angiotensin II fragments Am J Physiol Renal Physiol, July 1, 2002; 283(1): F86 - F92. [Abstract] [Full Text] [PDF]
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 C. Vickers, P. Hales, V. Kaushik, L. Dick, J. Gavin, J. Tang, K. Godbout, T. Parsons, E. Baronas, F. Hsieh, et al. Hydrolysis of Biological Peptides by Human Angiotensin-converting Enzyme-related Carboxypeptidase J. Biol. Chem., April 19, 2002; 277(17): 14838 - 14843. [Abstract] [Full Text] [PDF]
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C. M. Ferrario Does Angiotensin-(1-7) Contribute to Cardiac Adaptation and Preservation of Endothelial Function in Heart Failure? Circulation, April 2, 2002; 105(13): 1523 - 1525. [Full Text] [PDF]
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C. Llorens-Cortes and F. A. Mendelsohn Organisation and functional role of the brain angiotensin system Journal of Renin-Angiotensin-Aldosterone System, March 1, 2002; 3(1_suppl): S39 - S48. [PDF]
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 M. Fischer, A. Baessler, and H. Schunkert Renin angiotensin system and gender differences in the cardiovascular system Cardiovasc Res, February 15, 2002; 53(3): 672 - 677. [Abstract] [Full Text] [PDF]
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 C.-C. Wei, C. M. Ferrario, K. B. Brosnihan, D. M. Farrell, W. E. Bradley, A. A. Jaffa, and L. J. Dell'Italia Angiotensin Peptides Modulate Bradykinin Levels in the Interstitium of the Dog Heart in Vivo J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 324 - 329. [Abstract] [Full Text] [PDF]
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T. Mustafa, Joo Hyung Lee, Siew Yeen Chai, A. L Albiston, S. G McDowall, and F. A. Mendelsohn Bioactive angiotensin peptides: focus on angiotensin IV Journal of Renin-Angiotensin-Aldosterone System, December 1, 2001; 2(4): 205 - 210. [PDF]
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C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2337 - H2365. [Abstract] [Full Text] [PDF]
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C. Oliveri, M. P. Ocaranza, X. Campos, S. Lavandero, and J. E. Jalil Angiotensin I-Converting Enzyme Modulates Neutral Endopeptidase Activity in the Rat Hypertension, September 1, 2001; 38(3): 650 - 654. [Abstract] [Full Text] [PDF]
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B. Tom, R. de Vries, P. R. Saxena, and A.H. J. Danser Bradykinin Potentiation by Angiotensin-(1-7) and ACE Inhibitors Correlates With ACE C- and N-Domain Blockade Hypertension, July 1, 2001; 38(1): 95 - 99. [Abstract] [Full Text] [PDF]
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 J. C. Rodriguez-Perez, F. Rodriguez-Esparragon, O. Hernandez-Perera, A. Anabitarte, A. Losada, A. Medina, E. Hernandez, D. Fiuza, O. Avalos, C. Yunis, et al. Association of angiotensinogen m235t and a(-6)g gene polymorphisms with coronary heart disease with independence of essential hypertension: the procagene study J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1536 - 1542. [Abstract] [Full Text] [PDF]
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R. Bravo, B. Somoza, M. Ruiz-Gayo, C. Gonzalez, L. M. Ruilope, and M. S. Fernandez-Alfonso Differential Effect of Chronic Antihypertensive Treatment on Vascular Smooth Muscle Cell Phenotype in Spontaneously Hypertensive Rats Hypertension, May 1, 2001; e10(5): . [Abstract] [Full Text] [PDF]
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R. D. P. Machado, R. A. S. Santos, and S. P. Andrade Mechanisms of angiotensin-(1-7)-induced inhibition of angiogenesis Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2001; 280(4): R994 - R1000. [Abstract] [Full Text] [PDF]
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T. Wilsdorf, J. V. Gainer, L. J. Murphey, D. E. Vaughan, and N. J. Brown Angiotensin-(1-7) Does Not Affect Vasodilator or TPA Responses to Bradykinin in Human Forearm Hypertension, April 1, 2001; 37(4): 1136 - 1140. [Abstract] [Full Text] [PDF]
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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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K. M. Moritz, D. J. Campbell, and E. M. Wintour Angiotensin-(1-7) in the ovine fetus Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2001; 280(2): R404 - R409. [Abstract] [Full Text] [PDF]
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H. Heitsch, S. Brovkovych, T. Malinski, and G. Wiemer Angiotensin-(1-7)-Stimulated Nitric Oxide and Superoxide Release From Endothelial Cells Hypertension, January 1, 2001; 37(1): 72 - 76. [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. DE GRACIA, A. OSUNA, F. O'VALLE, R. G. DEL MORAL, R. WANGENSTEEN, C. G. DEL RIO, and F. VARGAS Deoxycorticosterone Suppresses the Effects of Losartan in Nitric Oxide--Deficient Hypertensive Rats J. Am. Soc. Nephrol., November 1, 2000; 11(11): 1995 - 2000. [Abstract] [Full Text]
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I. Kucharewicz, E. Chabielska, D. Pawlak, T. Matys, R. Rolkowski, and W. Buczko The antithrombotic effect of angiotensin-(1--7) closely resembles that of losartan Journal of Renin-Angiotensin-Aldosterone System, September 1, 2000; 1(3): 268 - 272. [Abstract] [PDF]
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R. K. HANDA Metabolism Alters the Selectivity of Angiotensin-(1-7) Receptor Ligands for Angiotensin Receptors J. Am. Soc. Nephrol., August 1, 2000; 11(8): 1377 - 1386. [Abstract] [Full Text]
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D. Roccatello, G. Mengozzi, G. Gigliola, D. Rossi, R. Mosso, G. Cacace, R. Polloni, G. Cesano, G. Picciotto, L. Paradisi, et al. Effects of angiotensin II blockade on nitric oxide blood levels in IgA nephropathy Nephrol. Dial. Transplant., July 1, 2000; 15(7): 988 - 993. [Abstract] [Full Text] [PDF]
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D. C. Braga, E. Mori, K. T. Higa, M. Morris, and L. C. Michelini Central oxytocin modulates exercise-induced tachycardia Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2000; 278(6): R1474 - R1482. [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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 A. Reaux, M. C. Fournie-Zaluski, C. David, S. Zini, B. P. Roques, P. Corvol, and C. Llorens-Cortes Aminopeptidase A inhibitors as potential central antihypertensive agents PNAS, November 9, 1999; 96(23): 13415 - 13420. [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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K. C Wollert and H. Drexler The renin-angiotensin system and experimental heart failure Cardiovasc Res, September 1, 1999; 43(4): 838 - 849. [Abstract] [Full Text] [PDF]
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A. J. M. Roks, P. P. van Geel, Y. M. Pinto, H. Buikema, R. H. Henning, D. de Zeeuw, and W. H. van Gilst Angiotensin-(1–7) Is a Modulator of the Human Renin-Angiotensin System Hypertension, August 1, 1999; 34(2): 296 - 301. [Abstract] [Full Text] [PDF]
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R. K. Handa Angiotensin-(1-7) can interact with the rat proximal tubule AT4 receptor system Am J Physiol Renal Physiol, July 1, 1999; 277(1): F75 - F83. [Abstract] [Full Text] [PDF]
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A. Kurtz and C. Wagner Role of nitric oxide in the control of renin secretion Am J Physiol Renal Physiol, December 1, 1998; 275(6): F849 - F862. [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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G. Gorelik, L. A. Carbini, and A. G. Scicli Angiotensin 1-7 Induces Bradykinin-Mediated Relaxation in Porcine Coronary Artery J. Pharmacol. Exp. Ther., July 1, 1998; 286(1): 403 - 410. [Abstract] [Full Text]
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S. N. Iyer, M. C. Chappell, D. B. Averill, D. I. Diz, and C. M. Ferrario Vasodepressor Actions of Angiotensin-(1–7) Unmasked During Combined Treatment With Lisinopril and Losartan Hypertension, February 1, 1998; 31(2): 699 - 705. [Abstract] [Full Text] [PDF]
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S. N. Iyer, C. M. Ferrario, and M. C. Chappell Angiotensin-(1-7) Contributes to the Antihypertensive Effects of Blockade of the Renin-Angiotensin System Hypertension, January 1, 1998; 31(1): 356 - 361. [Abstract] [Full Text] [PDF]
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D. I. Diz, B. Westwood, S. M. Bosch, D. Ganten, and C. Ferrario NK1 Receptor Antagonist Blocks Angiotensin II Responses in Renin Transgenic Rat Medulla Oblongata Hypertension, January 1, 1998; 31(1): 473 - 479. [Abstract] [Full Text] [PDF]
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K. B. Brosnihan, P. Li, D. Ganten, and C. M. Ferrario Estrogen protects transgenic hypertensive rats by shifting the vasoconstrictor-vasodilator balance of RAS Am J Physiol Regulatory Integrative Comp Physiol, December 1, 1997; 273(6): R1908 - R1915. [Abstract] [Full Text] [PDF]
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A. E. Loot, A. J.M. Roks, R. H. Henning, R. A. Tio, A. J.H. Suurmeijer, F. Boomsma, and W. H. van Gilst Angiotensin-(1-7) Attenuates the Development of Heart Failure After Myocardial Infarction in Rats Circulation, April 2, 2002; 105(13): 1548 - 1550. [Abstract] [Full Text] [PDF]
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