(Hypertension. 2001;37:72.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Angiotensin-(1-7)–Stimulated Nitric Oxide and Superoxide Release From Endothelial Cells
From the Medicinal Chemistry/DG Cardiovascular (H.H., G.W.), Aventis Pharma Deutschland GmbH, Frankfurt/Main, Germany; and Department of Chemistry and Biochemistry (S.B., T.M.), Ohio University, Athens, Ohio.
Correspondence to Dr Holger Heitsch, Aventis Pharma Deutschland GmbH, DI&A, Medicinal Chemistry, Building G 838, D-65926 Frankfurt am Main, Germany. E-mail holger.heitsch{at}aventis.com
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Abstract |
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Abstract—The stimulation of endothelium-dependent NO release by angiotensin-(1-7) [Ang-(1-7)] has been indirectly shown in terms of vasodilation, which was diminished by NO synthase inhibition or removal of the endothelium. However, direct measurement of endothelium-derived NO has not been analyzed. With a selective porphyrinic microsensor, NO release was directly assessed from single primary cultured bovine aortic endothelial cells. Ang-(1-7) caused a concentration-dependent release of NO of 1 to 10 µmol/L, which was attenuated by NO synthase inhibition. [D-Ala7]Ang-(1-7) (5 µmol/L), described as a selective antagonist of Ang-(1-7) receptors, inhibited Ang-(1-7)–induced NO release only by
50%, whereas
preincubation of bovine aortic endothelial cells with
the angiotensin II subtype 1 and 2 receptor
antagonists EXP 3174 and PD 123,177 (both at 0.1
µmol/L) led to an inhibition of 60% and 90%, respectively. A
complete blockade of the Ang-(1-7)–induced NO release was observed on
preincubation of the cells with 1 µmol/L concentration of the
bradykinin subtype 2 receptor antagonist icatibant (HOE
140), suggesting an important role of local kinins in the action of
Ang-(1-7). Simultaneous direct measurement of superoxide
(O2-) detected by an
O2--sensitive microsensor revealed that the
moderately Ang-(1-7)–stimulated NO release was accompanied by a very
slow concomitant O2- production with
a relative low peak concentration in comparison to the
O2- production of the strong NO
releasers bradykinin and, especially, calcium ionophore. Thus,
Ang-(1-7) might preserve the vascular system, among others, due to its
low formation of cytotoxic peroxynitrite by the reaction between NO
and O2-.
Key Words: angiotensin-(1-7) • nitric oxide • superoxide • endothelial cells • kinins
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Introduction |
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There is increasing experimental evidence that in addition to the known effector hormone angiotensin (Ang) II, the heptapeptide Ang-(1-7) is also a biologically active component of the renin-angiotensin system.1 2 3 Besides circulating Ang-(1-7), local production of the heptapeptide has been shown in the vasculature, where it is predominantly generated from Ang I by metalloendopeptidase 24.15.4 In endothelial cells from different sources, Ang-(1-7) is derived from carboxyl-terminal degradations of Ang I and Ang II by neutral endopeptidase (NEP 24.11) or by carboxypeptidases, respectively.5
In contrast to Ang II, Ang-(1-7) is neither dipsogen nor an aldosterone secretagogue, but similar to Ang II, it releases vasopressin,6 prostaglandins,7 and NO.8 9 Also unlike Ang II, Ang-(1-7) inhibits vascular smooth muscle cell growth.10 11 In the past years, some studies have indicated that Ang-(1-7) counterregulates the cardiovascular actions of Ang II by acting as a local modulator of the vascular tone.12 Ang-(1-7) is a vasodilatory agent in many vascular beds, including canine13 and porcine14 coronary arteries, rat aorta,15 and feline mesenteric arteries.16 Recently, it was demonstrated that Ang-(1-7) blocks the Ang II–induced vasoconstriction in human arteries.17 Long-term infusion of Ang-(1-7) in spontaneously hypertensive rats (SHR) produced a transient decrease in the mean arterial pressure, which was significant after 2 days and returned to baseline on day 7 of the 14-day treatment period.18 This antihypertensive effect could be the reason for the attenuated pressor response to Ang II and phenylephrine and the improved baroreceptor reflex function in SHR in response to long-term infusion of Ang-(1-7).19 These effects of Ang-(1-7) are probably mediated by an enhanced synthesis and/or release of endothelial kinins, which in turn stimulate the release of the vasodilatory and cardioprotective prostaglandins7 20 and NO.3 13 21 The presence of a unique endothelial receptor, which preferentially binds Ang-(1-7) and is distinct from Ang II subtype 1 (AT1) and subtype 2 (AT2) receptors, was postulated by the group of Ferrario22 from binding experiments on bovine aortic endothelial cells (BAECs). Recent studies demonstrated that Ang-(1-7) is not only a substrate but also an endogenous inhibitor of angiotensin-converting enzyme (ACE) by binding to the active site of ACE responsible for the inactivation of bradykinin (BK).23 Inhibition of the active site of ACE also induces "cross-talk" between ACE and BK subtype 2 (B2) receptors on plasma membranes, abolishing the desensitization of the B2 receptor.24 This kind of interaction can explain the well-documented kinin-like actions of Ang-(1-7) observed in coronary vessels3 9 and in rats,25 26 27 without having a direct effect on the B2 receptor by itself.24
The ability of Ang-(1-7) to stimulate the release of endothelial NO has been indirectly shown only by the abolishment of its vasodilatory response through removal of the endothelium or by the use of NO synthase (NOS) inhibitors.3 13 28 Therefore, we directly investigated the effect of Ang-(1-7) on NO release from primary cultured BAECs via a porphyrinic microsensor placed in close proximity to the cell surface. Second, we correlated the Ang-(1-7)–induced NO release with the endothelial production of O2-. Last, we addressed the specificity of the Ang-(1-7)–induced NO release.
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Methods |
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Endothelial Cell Culture
BAECs were isolated through digestion with dispase and were cultured as previously described.29 Cells were seeded onto 6-well plates (Nunc Intermed) that were precoated with collagen R and were grown to confluence. The culture medium used for BAECs was Dulbecco’s modified Eagle’s/Ham’s F-12 medium (1:1) that contained 1 mmol/L L-arginine, heat-inactivated FCS (20%), 50 IU/mL penicillin, 50 µg/mL streptomycin, 1 mmol/L L-glutamine, 5 µg/mL glutathione, and 5 µg/mL L-(+)-ascorbic acid. The purity of the primary cultured BAECs was characterized by uptake of fluorescent labeled LDL (DiI-Ac-LDL) and by negative staining for
-smooth muscle actin.
Direct NO Measurements
Primary cultures of BAECs grown to confluence in 6-well plates
were used (200 to 250 µg protein or 3x10-5
cells per well).29 30 After removal of the culture medium
through aspiration, the monolayers were washed twice with 2 mL warm
(37°C) HEPES-Tyrode’s solution, pH 7.4, containing (in mmol/L)
KCl 2.7, NaCl 137, CaCl2 1.8,
MgCl2 2,
NaH2PO4 0.36, glucose 5,
and HEPES 10. Thereafter, the cells were preincubated for 15 minutes at
37°C with 1 mL HEPES-Tyrode’s solution containing
3-isobutyl-1-methyl-xanthine (IBMX; 100 µmol/L). IBMX was added
to provide identical incubation conditions as the intracellular cGMP
measurements in previously reported experiments.30
Agonists, dissolved in HEPES-Tyrode’s solution, and superoxide
dismutase (SOD; 0.3 µmol/L) were added at the concentrations and
times indicated in Results. The detection of NO with a porphyrinic
microsensor and its preparation were performed as previously
described.31 32 The current proportional to NO
concentration was measured with the sensor, which operated in
amperometric mode (EG&G PAR model 283 Potentiostats,
Galvanostats) at constant potential of 0.68 V versus saturated calomel
electrode.
The sensor was positioned on the surface of the cell membrane with the use of a micromanipulator, and the drugs were injected with a nanoinjector, which was positioned at close proximity (5 to 7 µm) from the cell surface. The microsensor had a response time of 0.1 ms at micromolar NO concentrations and 10 ms at the detection limit of 1 nmol/L. Therefore, the sensor could detect only a concentration of NO that was not consumed by the extremely fast intracellular reaction of NO with O2-.
Direct O2- Measurements
The O2- concentration was measured
with the electrochemical sensor placed on the surface of BAECs. The
sensor was prepared according to a procedure described in detail
previously.33 34 The sensing materials were
immobilized on the surface of the carbon fiber. The carbon
fiber support was prepared as described for the NO sensor. The diameter
of the sensor was 1 to 1.5 µm, the response time was 0.05 ms,
and the detection limit was 1 nmol/L. The O2-
sensor also operated in amperometric mode at a constant potential of
-0.23 V versus standard calomel electrode. A 3-electrode system was
used for all O2- measurements with the
O2- sensor as working electrode, SCE
reference electrode, and platinum auxiliary electrode. A
Princeton Applied Research PAR model 283 voltammetric
analyzer interfaced with an IBM 80486 computer was used to
record the amperometric (current-versus-time) signal. Calibration
of the sensor was performed by constructing standard curves based on
O2- concentrations stoichiometrically
generated through the reaction of xanthine and xanthine oxidase.
Concentrations of O2- were reported in
nmol/L.
Chemicals
SOD (from bovine erythrocytes, specific activity 3300 U/mg) and
collagen R were purchased from Serva. DiI-Ac-LDL was purchased from
Paesel+Lorelei. Ang-(1-7),
[D-Ala7]Ang-(1-7), BK acetate salt,
calcium ionophore (CaI) A23187, and
N
-nitro-L-arginine
methyl ester (L-NAME) were purchased from Sigma Chemical Co. EXP 3174,
PD 123,177, and icatibant (HOE 140) were synthesized at Aventis
Pharma.
Statistical Analysis
Values are expressed as mean±SEM from 5 experiments, with
P<0.05 considered statistically significant. Statistical
evaluation was made with ANOVA followed by unpaired Student’s
t test. All analyses were made with the statistical
software Microcal Origin.
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Results |
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Figure 1a shows the result of simultaneous assessment of the changes in NO and O2- concentrations with time after the addition of 10 µmol/L Ang-(1-7). The peptide stimulated NO release with a peak concentration of 280±30 nmol/L (n=5), which was accompanied after a delay of 3.0±0.3 s by a very low peak O2- production of 18±2 nmol/L (n=5). The rates of NO and O2- increases were 120±10 and 16±3 nmol · L-1 · s-1 (each n=5), respectively. In comparison with Ang-(1-7), the receptor-independent CaI A23187 and BK showed different kinetics of NO and O2- release (Figures 1b and 1c). A23187 (1 µmol/L) and BK (0.1 µmol/L) evoked significantly higher peak NO concentrations (560±25 and 490±20 nmol/L, respectively) associated with faster rates of NO increases (650±20 and 280±30 nmol · L-1 · s-1, respectively) than did Ang-(1-7). CaI A23187- and BK-induced peak concentrations of O2- were 80±6 and 32±4 nmol/L, respectively, which were significantly higher than the peak O2- concentrations induced by Ang-(1-7). In addition, the rates of increases in O2- concentrations (120±12 and 26±3 nmol · L-1 · s-1, respectively) for CaI A23187 and BK were much faster than that observed for Ang-(1-7). The peak NO concentration increased with increasing concentrations of Ang-(1-7) (Figure 2). The observed release of NO from BAECs was in exactly the same concentration range of Ang-(1-7) as determined for the release of cGMP (unpublished data).
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) and the B2 receptor antagonist icatibant (HOE 140) (
). L-NAME (200 µmol/L) and HOE 140 (1 µmol/L) were added 20 and 5 minutes, respectively, before the addition of increasing concentrations of Ang-(1-7). Data are expressed as mean±SEM of 5 experiments.
As shown in Figure 2, the Ang-(1-7)–stimulated NO release
from BAECs was significantly (and competitively) reduced by 60%
when the cells were preincubated for 20 minutes with a 200
µmol/L concentration of the NOS inhibitor L-NAME.
Complete inhibition was observed with preincubation (5 minutes) of the
cells with a 1 µmol/L concentration of the
B2 receptor antagonist icatibant (HOE
140).
The specificity of the Ang-(1-7)–stimulated NO release from BAECs was
determined through preincubation of the cells for 20 minutes with
either the Ang-(1-7) receptor antagonist
[D-Ala7]Ang-(1-7), the
AT1 antagonist EXP 3174 (active
metabolite of losartan), or the AT2
antagonist PD 123,177 (Figure 3). Preincubation of the cells with both
[D-Ala7]Ang-(1-7) (5 µmol/L)
and EXP 3174 (0.1 µmol/L) attenuated the Ang-(1-7)–induced NO
release by 50% to 60%, whereas preincubation with PD 123,177
(0.1 µmol/L) caused an inhibition of 90%. The selected
concentrations of the applied antagonists were maximally
effective on the Ang-(1-7)–induced NO release.
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) on the Ang-(1-7) (•)–induced NO release (peak concentrations, which were reached after 2±0.5 seconds at all cases) from cultured BAECs. [D-Ala7]Ang-(1-7) (5 µmol/L), EXP 3174 (0.1 µmol/L), and PD 123,177 (0.1 mmol/L) were added 20 minutes before the addition of increasing concentrations of Ang-(1-7). Data are expressed as mean±SEM of 5 experiments. |
Discussion |
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The present study demonstrated for the first time through direct measurements of NO via a porphyrinic microsensor that exogenously added Ang-(1-7) stimulated the release of the vasodilator NO from primary cultured BAECs. The Ang-(1-7)–induced NO release was concentration dependent (ED50
3 µmol/L)
and inhibited to 60% by L-NAME. This inhibition rate is in the range
(60% to 70%) observed for NO release stimulated by other NOS agonists
(CaI, BK, etc).35 Ang-(1-7) is able to activate
endothelial NOS, which is in line with the reported
vasorelaxant effect of Ang-(1-7) on precontracted canine or porcine
coronary arteries, which could be blocked by pretreatment with
NOS inhibitors.3 13 14 The presence of a unique Ang-(1-7) receptor distinct from AT1 and AT2 receptors was postulated from binding studies with membranes from cultured BAECs and supported by the ability of the Ang-(1-7) analog [D-Ala7]Ang-(1-7) to compete the binding of [125I]Ang-(1-7) and to block some of the biological effects of Ang-(1-7).22 36 However, up to now, there has been no direct evidence of the existence of a unique Ang-(1-7) receptor, and in our study on cultured BAECs, [D-Ala7]Ang-(1-7) failed to completely block (50% blockade only) the NO release induced by Ang-(1-7). Moreover, the reduction of the Ang-(1-7)–stimulated NO release by the AT1 antagonist EXP 3174 and, even more pronounced, by the AT2 antagonist PD 123,177 of 60% and 90%, respectively, observed in our experiments supports the view that AT2, but also AT1, receptors might be involved in the reported actions of Ang-(1-7).
Reports that describe the effects of AT1 and AT2 antagonists on the Ang-(1-7)–induced functional responses are not consistent, possibly due to organ and species differences in Ang II receptor subtype specificity. Attenuation only by an AT2 antagonist in porcine aortic smooth muscle cells37 or only by an AT1 antagonist in canine coronary arteries9 or a lack of inhibition in canine coronary arteries13 by both AT1 and AT2 antagonists was reported. Hence, it might be speculated that Ang-(1-7) interacts with multiple binding site on endothelial cells, all of which promote the activity of the endothelial kinin system. This hypothesis is supported by the observed complete inhibition of the Ang-(1-7)–induced NO release on BAECs by the B2 receptor antagonist icatibant and clearly indicates that the observed NO release is correlated with an enhanced synthesis and release of endogenous kinins followed by subsequent stimulation of B2 receptors.38 At the present, the mechanisms by which Ang-(1-7) exerts its kinin-mediated NO release are still a matter of speculation (Figure 4). From experiments in canine coronary arteries that show an inhibition of the Ang-(1-7)–induced nitrite production by protease inhibitors, which block the local formation of kinins, it was suggested that the kallikrein-kinin system becomes activated via stimulation of a specific receptor for Ang-(1-7).9 Similarly, prior findings of our group revealed that the NO release from BAECs induced by Ang II is associated with an enhanced synthesis and/or release of endogenous kinins.8 More recent investigations demonstrated the ability of Ang-(1-7) to inhibit ACE activity with an IC50 value of 3 and 0.65 µmol/L in human plasma17 and canine lung,23 28 respectively. Thus, the applied Ang-(1-7) concentrations of 1 to 10 µmol/L, at which we observed an increased NO synthesis on BAECs, could have partially inhibited endothelial ACE activity. Furthermore, Ang-(1-7) has been shown to indirectly resensitize B2 receptors via induction of a cross-talk between the B2 receptors and ACE on plasma membranes without having a direct effect on the B2 receptors and the BK hydrolyses.23 Activation of the unique non-AT1, non-AT2 receptor deduced from binding studies on membranes from cultured BAECs22 is also a possible explanation for the observed stimulated synthesis and release of NO by Ang-(1-7). However, the signal transduction pathway coupled to this putative Ang-(1-7) receptor is unknown. We found that Ang-(1-7) (10 and 100 µmol/L) did not change intracellular free Ca2+ (fluorimetrically assessed with the Ca2+ indicator dye Fura-2) in BAECs in comparison with a 5- to 6-fold rise in intracellular free Ca2+ induced by 0.1 µmol/L BK. This finding is in line with the reported failure of Ang-(1-7) to stimulate Ca2+ in human astrocytes.1 These findings together with the demonstrated kinin-mediated action of Ang-(1-7) are difficult to explain because the stimulation of endothelial B2 receptors is correlated with an increase in intracellular cytosolic Ca2+.39 However, very recent data indicate that there are other intracellular mechanisms that are able under certain conditions, such as, fluid shear stress and insulin, to activate endothelial NOS through phosphorylation of the enzyme at basal levels of intracellular Ca2+.40
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We could show through the simultaneous measurement of NO and O2- that the moderate NO release by Ang-(1-7) is associated with very low concomitant production of O2-. The kinetics of the Ang-(1-7)–induced NO and O2- release are much different than those particularly observed for CaI and BK. In comparison, the stronger NO releasers BK and CaI caused faster O2- production with significantly higher peak O2- concentrations. Consequently, our data imply that rapid NO generation is correlated to high O2- production. Because it has been suggested that the generation of O2- and subsequent fast reaction between O2- and NO to form peroxynitrite and cytotoxic radicals may play a role in endothelial dysfunction and vascular injury, Ang-(1-7) with its NO/O2- –releasing profile might be able to preserve a functional vascular system.
A rapid consumption of local L-arginine, the substrate of endothelial NOS, due to rapid NO production may be the reason for a disarrangement of NOS, which starts to produce O2-. It has been demonstrated that isolated neuronal NOS may also produce O2- when tetrahydrobiopterin and L-arginine are not present in sufficient amounts.35 Moreover, dysfunctional NOS seems to be the main source of CaI-stimulated O2- production in aortas of prehypertensive41 and old42 SHR. Whether the Ang-(1-7)– and BK-mediated O2- production is formed via a dysfunctional NOS and/or other enzymes such as xanthine oxidases and NAD(P)H-dependent oxidases remains to be elucidated.
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Acknowledgments |
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This work was supported by a grant from the US Public Health Service (HL-55397).
Received April 13, 2000; first decision May 8, 2000; accepted July 6, 2000.
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 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]
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 R. Faria-Silva, F. V. Duarte, and R. A.S. Santos Short-Term Angiotensin(1-7) Receptor Mas Stimulation Improves Endothelial Function in Normotensive Rats Hypertension, October 1, 2005; 46(4): 948 - 952. [Abstract] [Full Text] [PDF]
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J.-C. Zhong, D.-Y. Huang, Y.-M. Yang, Y.-F. Li, G.-F. Liu, X.-H. Song, and K. Du Upregulation of Angiotensin-Converting Enzyme 2 by All-trans Retinoic Acid in Spontaneously Hypertensive Rats Hypertension, December 1, 2004; 44(6): 907 - 912. [Abstract] [Full Text] [PDF]
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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]
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 A. Schafer, D. Fraccarollo, P. Tas, I. Schmidt, G. Ertl, and J. Bauersachs Endothelial dysfunction in congestive heart failure: ACE inhibition vs. angiotensin II antagonism Eur J Heart Fail, March 1, 2004; 6(2): 151 - 159. [Abstract] [Full Text] [PDF]
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A. H. Schmaier The kallikrein-kinin and the renin-angiotensin systems have a multilayered interaction Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R1 - R13. [Abstract] [Full Text] [PDF]
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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]
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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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 F. S. Gragasin, Y. Xu, I. A. Arenas, N. Kainth, and S. T. Davidge Estrogen Reduces Angiotensin II-Induced Nitric Oxide Synthase and NAD(P)H Oxidase Expression in Endothelial Cells Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 38 - 44. [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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 U. Raj and L. Shimoda Oxygen-dependent signaling in pulmonary vascular smooth muscle Am J Physiol Lung Cell Mol Physiol, October 1, 2002; 283(4): L671 - L677. [Abstract] [Full Text] [PDF]
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A. N. G. Braga, M. Da Silva Lemos, J. R. Da Silva, W. R. P. Fontes, and R. Augusto Souza Dos Santos Effects of angiotensins on day-night fluctuations and stress-induced changes in blood pressure Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2002; 282(6): R1663 - R1671. [Abstract] [Full Text] [PDF]
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R. A. Souza dos Santos, K. T. Passaglio, J. B. Pesquero, M. Bader, and A. C. Simoes e Silva Interactions Between Angiotensin-(1-7), Kinins, and Angiotensin II in Kidney and Blood Vessels Hypertension, September 1, 2001; 38(3): 660 - 664. [Abstract] [Full Text] [PDF]
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A. J. Ferreira, R. A.S. Santos, and A. P. Almeida Angiotensin-(1-7): Cardioprotective Effect in Myocardial Ischemia/Reperfusion Hypertension, September 1, 2001; 38(3): 665 - 668. [Abstract] [Full Text] [PDF]
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