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(Hypertension. 1997;30:535.)
© 1997 American Heart Association, Inc.

Articles

Counterregulatory Actions of Angiotensin-(1-7)

Carlos M. Ferrario; Mark C. Chappell; E. Ann Tallant; K. Bridget Brosnihan; Debra I. Diz

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.

	Abstract

Top Abstract Introduction Principles of Ang-(1-7)... Ang-(1-7) and the Kidney Concluding Remarks References

 
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

	Introduction

Top Abstract Introduction Principles of Ang-(1-7)... Ang-(1-7) and the Kidney Concluding Remarks References

 
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 1993^{7 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.

	Principles of Ang-(1-7) Formation and Function

Top Abstract Introduction Principles of Ang-(1-7)... Ang-(1-7) and the Kidney Concluding Remarks References

 
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 animals^{17 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-endopeptidase^{14 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.

View larger version (17K): [in this window] [in a new window]   Figure 1. Diagram showing the active pathways involved in the production of Ang-(1-7). Ang I is processed to biologically active peptides by distinct enzymes. Ang I is hydrolyzed at Phe8-His9 by angiotensin-converting enzyme (ACE) or chymase (CHYM) to yield Ang II. Ang-(1-7) is produced by the hydrolysis of Ang I at Pro7-Phe8 by neutral endopeptidases 24.11 and 24.15 (NEP) and prolyl endopeptidase (PE). PE and prolyl carboxypeptidase (PCP) hydrolyze Ang II to Ang-(1-7).

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 inhibition^{19 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.

View larger version (20K): [in this window] [in a new window]   Figure 2. Contrasting effects of cerebroventricular injection of either a specific polyclonal Ang-(1-7) (, 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).

View larger version (18K): [in this window] [in a new window]   Figure 3. Average cumulative dose response to angiotensin (Ang) II (left) and Ang-(1-7) (right) in canine left anterior descending coronary vessels precontracted with 10 nmol/L U46 619, a thromboxane A2 analogue. All concentrations of Ang II and Ang-(1-7) are given as negative logs. The ordinate shows the percent contraction or relaxation of the precontracted coronary vessels. Data were redrawn from Reference 33.

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.

View larger version (21K): [in this window] [in a new window]   Figure 4. Vascular smooth muscle cells made quiescent by 48 hours in serum-free media and then treated for an additional 48 hours with either Ang-(1-7) in the presence of 1% fetal bovine serum (serum stimulated) or Ang II. Left axis, Inhibition of serum-stimulated [3H]thymidine incorporation by increasing concentrations of Ang-(1-7) is presented as the percentage of serum-stimulated activity (29 442±3253 cpm per well). Right axis, Stimulation of [3H]thymidine incorporation by increasing concentrations of Ang II is presented as the percentage of basal activity (13 217±228 cpm per well). Data were redrawn from Reference 48.

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

View larger version (75K): [in this window] [in a new window]   Figure 5. In vitro emulsion autoradiography showing specific binding of 125I-Ang-(1-7) to endothelial cells on a canine coronary artery frozen-sectioned at 14 µm and incubated with 0.75 nmol/L 125I-Ang-(1-7) in the presence or absence of either 1 µmol/L Ang-(1-7) or d-Ala7-Ang-(1-7). Sections were processed for emulsion autoradiography as previously described.50 The arrows indicate the endothelium lining the lumen. Abundant silver grains, indicative of specific binding of the radiolabeled peptide to the endothelial layer, are seen (A, Total). Fewer silver grains were observed over the smooth muscle layer, and nonspecific binding is apparent in the surrounding fat. The endothelial 125I-Ang-(1-7) binding was effectively competed for by either unlabeled Ang-(1-7) (B) or [d-Ala7]-Ang-(1-7) (C). Inset shows hematoxylin and eosin–stained histological section.

	Ang-(1-7) and the Kidney

Top Abstract Introduction Principles of Ang-(1-7)... Ang-(1-7) and the Kidney Concluding Remarks References

 
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.

	Concluding Remarks

Top Abstract Introduction Principles of Ang-(1-7)... Ang-(1-7) and the Kidney Concluding Remarks References

 
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).

View larger version (30K): [in this window] [in a new window]   Figure 6. Diagram showing a balance between the opposing actions of angiotensin-(1-7) (shaded area) and angiotensin II (open area), denoting the two opposing conditions determining the relative contribution of the effector peptides of the renin-angiotensin system in the regulation of blood pressure.

	Acknowledgments

 
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.

	References

Top Abstract Introduction Principles of Ang-(1-7)... Ang-(1-7) and the Kidney Concluding Remarks References

 
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