Vol. 284, Issue 6, H1933-H1941, June 2003
SPECIAL TOPICS
Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting Enzyme Systems
ACE and
non-ACE mediated effect of angiotensin I on intracellular calcium
mobilization in rat glomerular arterioles
Jeannine
Marchetti,
Claudia M. B.
Helou,
Catherine
Chollet,
Rabary
Rajerison, and
François
Alhenc-Gelas
Institut National de la Santé et de la Recherche
Médicale Unité 367, Physiologie et Pathologie
Expérimentale Vasculaires, Université Paris VI, 75005 Paris, France
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ABSTRACT |
Because
renin and angiotensin I (ANG I) level are high in the renal
circulation, the conversion of ANG I is a critical step in the
regulation of glomerular hemodynamics. We studied this conversion by
investigating the effect of ANG I on intracellular Ca2+
concentration ([Ca2+]i) in rat
juxtamedullary glomerular afferent and efferent arterioles (AA and
EA, respectively). Two types of EA were considered, thin EA and
muscular EA, terminating as peritubular capillaries and vasa rectae,
respectively. In all arterioles, ANG I elicited
[Ca2+]i elevations. Maximal responses of
171 ± 28 (AA), 183 ± 7 (muscular EA), and 78 ± 11 nM
(thin EA) (n = 6), similar to those obtained with ANG
II, were observed with 100 nM ANG I. The EC50 values were
20 times higher for ANG I than for ANG II in AA (10.2 vs. 0.5) and
muscular EA (6.8 vs. 0.4 nM) and 150 times higher in thin EA (15.2 vs.
0.1 nM). ANG I effect was blocked by losartan, indicating that
AT1 receptors were involved. The ANG-converting enyzme
(ACE) inhibitor lisinopril inhibited the maximal response to ANG I in
AA and muscular EA by 75 ± 9% (n = 13) and
70 ± 7% (n = 13), respectively, but had no
effect in thin EA (n = 14). The serine protease
inhibitor aprotinin, the chymase inhibitor chymostatin, and the
cysteine protease inhibitors E64 and leupeptin had no effect on ANG I
action. These data show that ANG I effects are mainly mediated by ACE
in AA and muscular EA but not in thin EA. The lisinopril-insensitive
response may be related to conversion by unknown enzyme(s) and/or to
activation of AT1 receptors by ANG I.
angiotensin I-converting enzyme; calcium signaling
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INTRODUCTION |
IT IS NOW
ACCEPTED that the renin-angiotensin system (RAS) acts as a local
paracrine/autocrine system participating in the control of renal
hemodynamic (9, 13, 30). All components of RAS have been
identified in the kidney (23), and angiotensin II (ANG II)
produced by cleavage of the phenylalanyl-histidyl peptide bond of
angiotensin I (ANG I) is considered to be the major active peptide of
the system. ANG-converting enzyme (ACE) is the major enzyme responsible
for the generation of ANG II (10). Because renin and ANG I
levels are high in the renal circulation where renin is secreted by the
afferent arterioles, the conversion of ANG I is a critical step in the
regulation of the glomerular circulation. In the vessels, ACE is bound
to membranes and localized on the endothelial cells surface and also,
at least in the rat, in smooth muscle cells (7, 6). ANG II
may be formed intrarenally via ACE and other pathways, and its
concentration has been reported to be 100 to 1,000 times higher in the
kidney than in the plasma. Thus ANG II may be produced from plasma ANG
I by action of ACE localized in the apical membranes of renal arteries,
glomerular arterioles, and peritubular capillaries. ANG II may also be
generated in the interstitial fluid by ACE present in this compartment
or bound to the basolateral membrane of the proximal tubule
(18). Another possibility for the formation of ANG II is
in the wall of intrarenal vessels from in situ synthesized ANG I. Indeed, the presence of renin has been observed in several types of
renal arterioles (12, 30). Studies of the regulation of
renal RAS of diabetic rats have led Anderson et al. (3, 4)
to suggest that the intrarenal RAS might be considered as two distinct
systems: the tubulointerstitial RAS comprising primarily the proximal
tubules and the interstitium and the vascular RAS comprising the renal vessels, the arterioles, and the glomeruli. It therefore appears that
the renal glomerular arterioles are not only targets for ANG II action
but may also be sites for synthesis of components of RAS. To further
characterize the mechanisms involved in the formation of ANG II in the
different types of glomerular arterioles, we investigated the effects
of ANG I on the intracellular calcium concentration
([Ca2+]i) of juxtamedullary afferent (AA) and
efferent (EA) arterioles and examined whether the responses were
compatible with ANG II formation. This was done by studying the action
of the ANG II receptor antagonist losartan, of the ACE inhibitor
lisinopril, and of some inhibitors of serine and cysteine proteases.
Two types of EA, which are differently sensitive to ANG II
(14) were studied, in parallel with AA: thin EA, which
terminate as peritubular capillaries, and muscular EA, which terminate
as vasa rectae. Our results show that ANG I increased
[Ca2+]i in the three types of glomerular
arterioles through activation of the AT1 receptors of ANG
II. The effect of ANG I can be accounted for by ANG II formation
catalyzed by ACE in AA and muscular EA but not in the thin EA.
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MATERIALS AND METHODS |
Microdissection of glomerular arterioles.
Experiments were conducted on glomerular arterioles isolated from a rat
kidney treated with collagenase as previously described (14). The arterioles were microdissected from the
juxtamedullary cortex at 4°C under a stereomicroscope (SZ3, Olympus;
Tokyo, Japan). The arterioles were isolated with their attachment to
the glomerulus and were then identified as AA and EA according to their
morphology (14) by observation under a Nikon microscope
(×40 objective). AA are characterized by a thick and regular wall
composed of uniformly distributed smooth muscle cells. Thin EA had a
smaller diameter than AA and showed a bumpy wall due to the presence of
irregularly shaped and nonclosely apposed smooth muscle cells. Muscular
EA presented a thick, muscular, and regular wall similar to that of AA
but had side branches that distinguish them from AA (14). Before [Ca2+]i measurements, each sample was
transferred on a thin glass slide in 1 µl of a standard solution
containing 1% of agarose (type IX). Agarose was set by cooling the
slide 1 min on ice. Arterioles were then loaded by the addition of 1 µl of 10 µM fura 2-AM and incubated for 1 h at room
temperature in darkness.
Measurements of
[Ca2+]i.
As in previous experiments (19),
[Ca2+]i was evaluated by using a Photoscan II
microfluorimeter (Photon Technology International; Kontron, France).
The glass slide with the sample was fixed at the bottom of a
superfusion chamber, which was then put on the stage of an inverted
fluorescent microscope (Nikon). The sample was continuously superfused
with the standard solution (0.8 ml/min, 37°C) that did or did not
carry the test substances. The microscope was fitted with a quartz
illumination system and a 40-fold magnification fluorescence
objective. The sample was alternatively excited at 340 and 380 nm (4 s/cycle), and the fluorescence emitted at 510 nm from an area
defined by an adjustable window (about 25 × 30 µm) was measured.
At the end of several experiments, autofluorescence was measured at 340 and 380 nm from the selected arteriolar area after the fura 2-AM
fluorescence was quenched with 1 mM of a solution of MnCl2
in the presence of 10 µM ionomycin. The obtained values were very
similar to the background emission from the same measurement window.
Background was routinely recorded for both wavelengths at the end of
each experiment and subtracted from all measurements. [Ca2+]i was calculated from the following
equation (11): [Ca2+]i = Kd × 
(R 
Rmin)/(Rmax R), where
Kd is the dissociation constant for the fura
2-Ca2+ complex and is 224 nM, R is the ratio of
fluorescence emitted for each wavelength (340/380 nm), Rmax
is the maximal ratio emitted in the presence of saturating calcium (2 mM), Rmin is the minimal ratio measured in absence of
calcium (0 mM), and is the ratio of fluorescence obtained at 380 nm
in absence and in presence of 2 mM calcium. The values of
Rmin, Rmax, and were periodically determined by external calibration using a buffer that mimicked intracellular medium (19).
The response to agonists was evaluated by the magnitude of the
[Ca2+]i increase and by the integral of the
Ca2+ signal. The integral of the Ca2+ signal
was calculated as
where t0 is the time at the start of the
[Ca2+]i response and
t1 is the time when the signal returns to
baseline level.
Experimental protocols.
The same protocols were applied to the three types of juxtamedullary
arterioles. Dose-response relationships were obtained by successively
superfusing the arterioles with increasing concentrations of ANG I
(from 10
10 to 106 M) or ANG II (from
1012 to 107 M). Each application lasted 5 min and was followed by a 15-min washing period, which was necessary to
decrease [Ca2+]i down to the basal level.
The sensitivity of the ANG I effect to inhibitors was investigated in
two ways. Either the tested inhibitor was added at the plateau phase of
the response to ANG I (100 nM) or the arterioles received three
successive 5-min applications of ANG I (100 nM), each followed by a
15-min washing period, and the inhibitor was added to the superfusate
10 min before and during the second application of ANG I. We verified
that the inhibitors did not change the basal [Ca2+]i level when superfused alone.
Solutions and products.
The arterioles were superfused with a "standard solution" having
the following composition (in mmol/l): 127 NaCl, 5 KCl, 0.8 MgSO4, 0.33 Na2HPO4, 0.44 KH2PO4, 1 MgCl2, 4 NaHCO3, 2 CaCl2, 5 D-glucose, 10 CH3CO2Na, 20 HEPES, pH 7.4, and 0.1% BSA.
Fura 2-AM was purchased from Molecular Probes (Leiden, The
Netherlands); aprotinin was from Calbiochem (San Diego, CA); and DMSO,
agarose, ANG I, ANG II, lisinopril, chymostatin,
4-(2-aminoethyl)benzenesulfonyl fluoride (AEBSF),
transepoxysuccinyl-L-leucylamido-(4-guanidino) butane
(E64), and leupeptin were from Sigma (France).
Stock solutions of fura 2-AM (10 mM), chymostatin (20 mM), and E64 (20 mM) were prepared in DMSO. Stock solutions of all other drugs were
prepared in distilled water. In the superfusion solutions, the
concentrations of DMSO were equal or inferior to 0.5%. The superfusion
solution containing 0.5% DMSO modified neither the basal
[Ca2+]i level nor the
[Ca2+]i response to ANG I.
Statistics.
Results are reported as means ± SE. When each arteriole was its
own control, significance was obtained by paired Student's t-test. Differences between two groups were analyzed using
unpaired Student's t-test. Multiple comparisons in similar
protocol were evaluated by ANOVA, followed by Bonferroni's test. The
commercially available software (Prism 2.0, GraphPad Software; San
Diego, CA) was used to fit dose-response curves and to estimate the
EC50 value (concentration of ANG I or ANG II giving half of
maximal response). Values were considered significantly different at
P < 0.05.
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RESULTS |
Characterization of the
[Ca2+]i responses induced
by ANG I in AA, muscular EA, and thin EA.
In AA and both types of EA, superfusion of 100 nM ANG I elicited a
rapid increase in [Ca2+]i followed by a
sustained plateau (Fig. 1). The magnitude
of the responses was similar in AA and muscular EA (145 ± 12 nM, n = 13 and 140 ± 16 nM, n = 12)
but was significantly lower in thin EA (57 ± 5 nM,
n = 17, P < 0.05). On ANG I removal,
[Ca2+]i slowly decreased to the basal level
within about 10 min. The duration of the responses did not
significantly differ among the three types of arterioles. It was of
13.9 ± 0.9 min in AA (n = 13), 13.5 ± 1.0 min in muscular EA (n = 12), and 16 ± 1 min in thin EA (n = 17). In all arterioles, a second
application of ANG I elicited a response that had a magnitude similar
to that of the first response, indicating the absence of homologous
desensitization phenomenon.
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Fig. 1.
Typical intracellular Ca2+ concentration
([Ca2+]i) responses of afferent arterioles
(AA; A), muscular efferent arterioles (EA; B),
and thin EA (C) to two successive applications of 100 nM ANG
I. Each application of ANG I lasted 5 min, and the second application
was performed 10-15 min after the first one. Five to six similar
tests were performed for each type of arteriole with similar results.
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The dependency of the [Ca2+]i responses on
ANG I and ANG II concentration is illustrated in Figs.
2 and 3
and summarized in Table 1. The arterioles
were superfused with increasing concentrations of the peptide for 5 min
at 15-min intervals. The concentration-response curves obtained with
ANG I show that the maximal responses of all arterioles were reached
with 100 nM. The magnitude of these responses were 171 ± 28, 183 ± 7, and 78 ± 11 nM for AA, muscular, and thin EA,
respectively. These values did not significantly differ from those
obtained with a first application of 100 nM ANG I (see above). When
compared with the maximal increases induced by ANG II, the maximal
responses to ANG I were of greater magnitude in the muscular and thin
EA, but the differences were not statistically significant. In the AA,
the maximal responses were the same for both peptides. The peptide
concentrations required for the half-maximal responses
(EC50) were about 20 times higher for ANG I than for ANG II
in AA (10.2 vs. 0.5 nM) and muscular EA (6.8 vs. 0.4 nM). The
difference between ANG I and ANG II was more marked (~150 times) in
thin EA for which the EC50 values were 15.2 nM and 0.1 nM
for ANG I and ANG II, respectively. Note that the magnitude of the
[Ca2+]i response was significantly smaller in
the thin EA than in AA and muscular EA as judged by the response
plateau levels and the integrals of Ca2+ signals (Table 1).
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Fig. 2.
Representative [Ca2+]i recordings
obtained with AA, muscular EA, and thin EA in response to successive
applications of increasing concentrations of ANG I (from
1010 to 106 M, left) and ANG II
(from 1012 to 107 M, right).
Each application lasted 5 min and was followed by a 15-min washing
period.
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Fig. 3.
Dose-response curves of ANG I and ANG II effects in AA
(A), muscular EA (B), and thin EA (C).
 [Ca2+]i corresponds to the magnitude at
the plateau phase of the [Ca2+]i response
induced by ANG I and ANG II.
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Effect of the AT1 antagonist losartan on the
[Ca2+]i responses to ANG I.
Losartan (1 µM) inhibited the [Ca2+]i
increases induced by 100 nM ANG I in AA and muscular and thin EA by
94 ± 6%, 95 ± 4%, and 87 ± 5%, respectively (Fig.
4), indicating that the AT1
receptors of ANG II are involved in the
[Ca2+]i responses to ANG I of the three types
of arterioles.
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Fig. 4.
Effect of losartan on [Ca2+]i
responses of AA (A), muscular EA (B), and thin EA
(C) to ANG I. Losartan (1 µM) was applied during the
plateau phase. It reversed the [Ca2+]i
increases induced by 100 nM ANG I in all arterioles.
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Effect of the ACE inhibitor lisinopril on the
[Ca2+]i responses to ANG I.
To determine whether the effects of ANG I is due to ANG II formed by
ANG I hydrolysis by ACE, the effect of 10 µM lisinopril was
investigated. When lisinopril was applied before (10 min) and during
the superfusion of 100 nM ANG I, it inhibited the
[Ca2+]i responses to ANG I of AA and muscular
EA by 75 ± 11% (n = 6) and 65 ± 8%
(n = 5), respectively, but it did not alter those of
thin EA (n = 7) (Fig. 5).
Inhibition was also observed when lisinopril was applied at the plateau
of the [Ca2+]i response to ANG I (Fig.
6). Under these conditions,
[Ca2+]i increases were reversed by 74 ± 7% and 75 ± 6% in AA (n = 7) and muscular EA
(n = 8), respectively, but the effect of lisinopril was
very low and was not significant in thin EA (8 ± 6%,
n = 6). In separate experiments, we demonstrated that
10 µM lisinopril neither altered the basal level of
[Ca2+]i nor the
[Ca2+]i increases induced by ANG II in any
arteriole. Taken together, the above results indicate that the
[Ca2+]i responses to ANG I of AA and muscular
EA, but not of thin EA, are largely mediated by ANG II formed from ANG
I by arteriolar ACE.
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Fig. 5.
Effect of lisinopril on [Ca2+]i responses
of juxtamedullary arterioles to ANG I. Lisinopril (10 µM) was applied
10 min before and during the second superfusion of 100 nM ANG I. It
inhibited the [Ca2+]i responses of AA
(A) and muscular EA (B) but not those of thin EA
(C). ANG II (10 nM) added at the end of the experiment
increased [Ca2+]i, proving the viability of
arteriole. Note that the [Ca2+]i responses to
ANG I remained inhibited in AA and muscular EA after withdrawn of
lisinopril. Bars represent means ± SE of
[Ca2+]i increases induced by ANG I or ANG II
(hatched bars), by ANG I in the presence of lisinopril (open bars), or
by ANG I alone superfused 10-15 min after withdrawn of lisinopril
(shaded bars). ***P < 0.001, significant difference
from the first response to ANG I alone.
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Fig. 6.
Reversion of ANG I-induced [Ca2+]i
increases by lisinopril in juxtamedullary arterioles. Lisinopril (10 µM) was applied at the plateau phase of the response to ANG I. It
inhibited the [Ca2+]i responses to 100 nM ANG
I of AA (A) and muscular EA (B) but did not alter
those of thin EA (C).
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Effect of serine and cysteine protease inhibitors on the
[Ca2+]i responses to ANG I.
To investigate whether other proteases (5) are
susceptible to hydrolyze ANG I into ANG II, we tested three inhibitors
of serine proteases, the selective chymase inhibitor chymostatin, aprotinin, and the irreversible serine protease inhibitor AEBSF and two cysteine protease inhibitors E64 and leupeptin
(24). As indicated in Table
2, only AEBSF produced a partial
inhibition (36 ± 6%) of the [Ca2+]i
increases induced by ANG I in the muscular EA.
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DISCUSSION |
There is much evidence that most intrarenal ANG II is locally
formed to act as a paracrine/autocrine agent regulating renal hemodynamics (23). Intrarenal ANG II can be generated from
systemically delivered ANG I or from ANG I formed in the kidney by
hydrolysis of plasma or renal angiotensinogen (21). The
amount of intrarenally synthesized ANG II is believed to depend
essentially on the local level of ACE. This enzyme was found in the
kidney vessels, tubules, and interstitium. In the present work, we were
interested in the RAS of three types of juxtamedullary glomerular
arterioles, namely AA, muscular EA, and thin EA. Except for the facts
that these arterioles express the AT1 and AT2
ANG II receptors (22) and that AA and to a lesser extent
EA possess a renin activity (12) that hydrolyzes
angiotensinogen into ANG I, nothing was known about the fate of ANG I
in these arterioles. Here we investigated the effect of ANG I in
juxtaglomerular arterioles and tried to understand the mechanisms
involved in the conversion of ANG I into active metabolites. The
experimental approach consisted of superfusing isolated arterioles with
the peptide and studying the effect of an AT1 ANG II
receptor antagonist, an ACE inhibitor, or serine and cysteine protease
inhibitors. This should allow the establishment of whether the effect
of ANG I is due to activation of AT1 receptors and needs
the conversion of ANG I into other active metabolites by ACE or other enzymes.
Our finding that ANG I was able to increase
[Ca2+]i in the three types of arterioles and
that this increase was inhibited by losartan demonstrates that the
observed effects resulted from activation of AT1 ANG II
receptors. With regard to the fact that the effect of superfused ANG I
was sensitive to lisinopril in AA and muscular EA but not in the thin
EA, it should be pointed that this was not related to differential
accessibility of the endothelial cell layer where ACE is usually
present. Indeed, we have previously reported that bradykinin, a direct
endothelial activator, was able to produce
[Ca2+]i increases when it was superfused on
the thin EA or AA and muscular EA (25). Moreover, the
[Ca2+]i increases of thin EA and those of AA
and muscular EA occurred after almost the same time delay (about 1 min)
after the bradykinin superfusion was started. The responses developed
even more rapidly in thin EA than in AA and muscular EA. We therefore
interpret the lack of a lisinopril effect on the thin EA as an
indication of the absence or the presence at a very low level of ACE
activity in this type of arteriole. To date we do not know whether the effect of ANG I in thin EA is due to ANG I itself or to its conversion into ANG II and/or other active metabolites. It has indeed been reported that ANG I is able to bind to the AT1 receptor
expressed in Chinese hamster ovary cells lacking ACE and to activate
the phospholipase C activity of these cells (27) with an
EC50 value ~200 times higher than that for ANG II. The
observation of a similar difference (150 times) between the
EC50 values of ANG I and ANG II for increasing
[Ca2+]i in the thin EA supports the
hypothesis that ANG I can directly activate the arteriolar
AT1 receptor without prior cleavage into ANG II or other
active products, as suggested by Itskovitz and Odya (16).
Nevertheless, the conversion of ANG I into active metabolites is also a
likely possibility. Alternative pathways to ACE for generating ANG II
involving serine proteases such as chymase or a kallikrein-like
protease sensitive to aprotinin have been described in the heart and
kidney (1, 2, 17, 26, 29). However, these two proteases
probably do not participate in the generation of ANG II from ANG I in
the thin EA, because the effect of ANG I was not altered by the chymase
inhibitor chymostatin, by aprotinin, or by the irreversible serine
protease inhibitor AEBSF. Also, the participation of cysteine proteases
is unlikely because neither leupeptin nor E64 had an effect on the ANG
I response. The same applies to ACE2, a carboxypeptidase recently found
in the heart, testis, and kidney (8, 28), because it
produces ANG (1-9), which is then converted into ANG
(1-7), which was found to be an inactive peptide in
our system (see below).
Additional investigation is required to identify the putative enzyme(s)
metabolizing ANG I in the thin EA. A study of the effect of ANG I
metabolites on calcium mobilization in the arterioles might help to
understand the pathways involved in the effect of ANG I. Among all
peptides tested, only desp-Asp1-ANG II (ANG III) and
des-Asp1-ANG I increased the [Ca2+]i level in
the thin EA and also in the AA and the muscular EA (15).
The responses obtained with maximal concentrations of these peptides
were of a similar magnitude as those obtained with ANG II. Very small
responses were observed with des-Asp1-Arg2-ANG
II (ANG IV) and no response at all with des-Phe8-ANG II
(ANG 1-7). Interestingly, des-Asp1-ANG I, which can be
cleaved by ACE to produce ANG III, behaved like ANG I, in that its
effects were inhibited by losartan in the three types of arterioles,
not sensitive to lisinopril in thin EA, but sensitive to this ACE
inhibitor in the AA and muscular EA (data not shown). This confirms
that, contrary to AA and muscular EA, the thin EA lacks ACE. The
presence of lisinopril-sensitive ACE activity in AA and muscular EA,
but apparently not in the thin EA, could contribute to fact that the
EC50 value of ANG I for increasing
[Ca2+]i is largely different from that of ANG
II (150 times higher) in the thin, whereas the difference is less
marked in AA and muscular EA (about only 20 times). Thus the activation
of ANG I into ANG II, if any, would be much less efficient in the thin EA.
The physiological implications of these observations remain unknown at
the present time. Our study shows that ACE is present in AA but not in
all EA. In the muscular EA, which divide into several branches to form
vasa rectae and supply blood flow to renal medulla, ANG II synthetized
locally by ACE can influence medulla microcirculation. On the contrary,
the thin EA, which terminate in the inner cortex as peritubular
capillaries, do not contain ACE, and ANG I activation is either nil or
very slow in that vessel. This may be a mechanism protecting
the glomerular and peritubular circulation against excess
vasocontriction and protecting renal excretory functions. This remains
however speculative. Moreover, ANG II can be produced by ACE present in
plasma and interstitium and acts on thin EA.
In conclusion, the present work shows that AA and muscular EA, but not
the thin EA, contain ACE activity able to generate ANG II from ANG I
that is responsible for a large fraction (up to 70%) of the
[Ca2+]i increase induced by ANG I. The
observation of ACE-independent effects of ANG I and des-Asp-ANG I
requires further investigation to establish whether these peptides are
converted into ANG II and III by arteriolar enzymes other than ACE. A
search for such enzymes in the kidney of ACE knockout mice is a
possible approach to this question.
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ACKNOWLEDGEMENTS |
This study was supported by Institut National de la Santé et
de la Recherche Médicale and grants from the Bristol Myers-Squibb Institute for Medical Research (Princeton, NJ). C. M. B. Helou was
supported in part by a grant for foreign scientists from the Fondation
pour la Recherche Médicale and is a member of Laboratório de Pesquisa Básica (LIM-12), Nephrology, HC-Faculdade de Medicina da Universidade de São Paulo.
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FOOTNOTES |
Address for reprint requests and other correspondence: J. Marchetti, INSERM U367, 17 rue du Fer à Moulin, 75005 Paris, France (E-mail:
marchett{at}ifm.inserm.fr).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published February 13, 2003;10.1152/ajpheart.00042.2003
Received 17 January 2003; accepted in final form 10 February 2003.
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Am J Physiol Heart Circ Physiol 284(6):H1933-H1941
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ABSTRACT
INTRODUCTION
![<LIM><OP>∫</OP><LL>t<SUB>0</SUB></LL><UL>t<SUB>1</SUB></UL></LIM> &Dgr;[Ca<SUP>2+</SUP>]<SUB>i</SUB>·d<IT>t</IT> (nM·s)](/content/vol284/issue6/fulltext/H1933/img001.gif)
