(Hypertension. 2000;35:998.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Angiotensin-(1-7) Attenuates Vasoconstriction Evoked by Angiotensin II but Not by Noradrenaline in Man
From the Department of Medicine II, Yokohama City University School of Medicine, Yokohama, Japan.
Correspondence to Dr Shinichiro Ueda, Human Vascular Research Laboratory, Department of Medicine, Yokohama City University School of Medicine, 3-9, Fuku-ura, Kanazawa-ku, Yokohama 236-0004 Japan. E-mail sueda{at}med.yokohama-cu.ac.jp
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Abstract |
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Abstract—Angiotensin-(1-7) has been suggested to be a novel vasodilating peptide. We investigated the direct vascular effect of angiotensin-(1-7) in human forearm resistant vessels, particularly with regard to the interaction with angiotensin II, in healthy normotensive men by strain-gauge venous occlusion plethysmography with intra-arterial infusions of peptides. Intra-arterial infusion of angiotensin-(1-7) at 0.1 to 2000 pmol/min did not cause vasodilatation but rather reduced forearm blood flow by
10% at the highest dose. A placebo-controlled
study showed that angiotensin-(1-7) at 0.5 to 40 nmol/min
caused weak but significant vasoconstriction (P=0.0016
by ANOVA). Angiotensin-(1-7) at 100 pmol/min, but not at 10
pmol/min, significantly shifted the angiotensin II
dose-response curve toward the right (mean±SD of percent changes in
forearm blood flow: -19±17%, -33±22%, -55±12%, -63±10%, and
-68±5% at 5, 10, 25, 50, and 100 pmol/min of angiotensin
II, respectively, with saline; 5±13%, 0.9±18%, -40±16%,
-54±9%, and -61±6% with angiotensin-(1-7),
P=0.0021 by ANOVA). Angiotensin-(1-7) did
not affect the dose-response curve of noradrenaline
[3±12%, 5±16%, -20±22%, -31±18%, and -40±12% at 25, 50,
100, 300, and 600 pmol/min of noradrenaline, respectively,
with saline; -4±15%, -2±23%, -29±22%, -34±16%, and
-42±9% with angiotensin-(1-7)]. Our results suggest
that angiotensin-(1-7) antagonizes vasoconstriction by
angiotensin II in human resistant vessels and might
act as an endogenous angiotensin II
antagonist.
Key Words: angiotensin • angiotensin II • noradrenaline • blood flow velocity
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Introduction |
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It has been suggested that angiotensin-(1-7) [Ang-(1-7)], which is one of bioactive components of the renin-angiotensin system and reportedly formed from angiotensin I (Ang I) and angiotensin II (Ang II),1 2 is a novel vasodilating peptide. Release of nitric oxide,3 production of prostaglandins,4 5 and potentiation of effect of bradykinin6 7 8 by Ang-(1-7) have been postulated as possible mechanisms for vasodilatation. Ang-(1-7) is also thought to contribute to a reduction in blood pressure after the blockade of the renin-angiotensin system.9 10 11 However, the subtype of angiotensin receptors involved in the vascular effect of Ang-(1-7) remains unknown. Benter et al12 failed to inhibit the hypotensive effect of Ang-(1-7) in pithed rats by either angiotensin type 1 (AT1) or type 2 (AT2) receptor antagonists. On the other hand, Mahon et al13 showed no vasodilating effect of Ang-(1-7) itself but significant attenuation of Ang II–induced vasoconstriction by a relatively low dose of Ang-(1-7) possibly via an AT1 receptor. Therefore, Ang-(1-7) appears to have 2 different vascular effects that are mediated through the different subtypes of angiotensin receptors.
The vascular effect of this peptide has not been documented well in humans. Unlike results from animal studies, a human study by Kono and colleagues14 showed increased blood pressure during intravenous Ang-(1-7) infusion at a comparable dose as that in the animal studies that showed a hypotensive effect. This is not surprising because Ang-(1-7) has been known to have a weak agonistic effect.15 16 In fact, a short-term pressor effect has been demonstrated in pithed rats.11 However, interspecies differences in the response to Ang-(1-7) may also exist. We investigated the direct vascular effect of Ang-(1-7), particularly with regard to the interaction with Ang II, in human resistant vessels in vivo.
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Methods |
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Subjects
Twenty-two healthy normotensive men (8 for protocol 1, 6 for protocol 2, and 8 for protocol 3) were recruited for the present study. All subjects underwent normal routine physical and laboratory examinations. Written informed consent was obtained from each subject after a full explanation of the study. All study protocols were approved by the Yokohama City University Hospital Ethics Committee.
Forearm Blood Flow Measurement
All experiments were performed in a quiet,
temperature-controlled room. After an overnight fast, all subjects
attended our Clinical Research Unit on the study day. Subjects
abstained from cigarettes, alcohol, and caffeine-containing drinks for
12 hours before the study. Forearm blood flow was measured by
bilateral strain-gauge venous occlusion plethysmography. The details of
the method and the reproducibility of the measurement were described
elsewhere.17 18 Briefly, pediatric cuffs placed around
wrists were inflated to 200 mm Hg during each measurement.
Collecting cuffs placed around the upper arms were inflated to 40
mm Hg and deflated every 15 seconds. Strain gauges were placed around
the forearms 5 cm distal to the olecranon. All drugs were infused into
the catheter inserted into the brachial artery of the nondominant arm
under local anesthesia with 1% lidocaine. The infusion
rate was maintained at 1 mL/min throughout the study unless otherwise
indicated.
Protocol 1: Effect of Ang-(1-7) on Forearm Blood Flow
Eight subjects [body mass index (BMI) 22.1±2.7
kg/m2, mean±SD, age 20 to 25] received
Ang-(1-7) (Clinalfa AG) intra-arterially at 0.1, 1.0, 5.0,
10, 50, 100, 250, 500, 1000, and 2000 pmol/min, for 10 minutes per
dose, on a single study day. Forearm blood flow was measured after each
dose of Ang-(1-7).
Protocol 2: Effect of Relatively High Dose of Ang-(1-7) on Forearm
Blood Flow
Six subjects (BMI 19.7±2.4 kg/m2, age 20
to 25) received placebo (0.9% saline) and Ang-(1-7) at 0.1, 0.5, 1,
2.5, 5, 10, 20, and 40 nmol/min for 10 minutes per dose in a
double-blind, crossover fashion on a single study day. There was a
washout period of 30 minutes between the administration of placebo and
Ang-(1-7). The order of infusions was randomized.
Protocol 3: Effect of Ang-(1-7) on Vasoconstriction Induced by Ang
II and Noradrenaline
Eight subjects (BMI 22.0±2.7 kg/m2, age
20 to 25) received noradrenaline (25, 50, 100, 300, and 600
pmol/min, at 10 minutes per dose) (Sankyo) and Ang II (5, 10, 25, 50,
and 100 pmol/min, at 10 minutes per dose) (Yamanouchi)
intra-arterially with concomitant
intra-arterial infusions of Ang-(1-7) at 10 pmol/min, 100
pmol/min, or placebo (isotonic saline) on 3 study days in a
double-blind, crossover fashion. There was a washout period for 30
minutes between Ang II and noradrenaline. The order of
these 2 vasoconstrictors was randomized but kept the same in the same
subject.
Analysis of Forearm Blood Flow Data
All forearm blood flow data were obtained via a Mac Laboratory 4
chart recorder (AD instruments). The percentage change in ratio of
forearm blood flow from baseline was calculated as
[F(i)D/F(ni)D-
F(i)B/F(ni)B]/[F(i)B/F(ni)B]x100%.
F(i) and F(ni) represent forearm blood flow in the infused arm
and noninfused arm, respectively, during baseline measurement (B) and
drug infusion (D).
Statistical Analysis
Data are shown as mean±SD unless otherwise indicated.
Comparison between changes in forearm blood flow with infusions of
Ang-(1-7) and saline (protocol 2) was made by repeated measure of
ANOVA. Comparison between changes in forearm blood flow during Ang II
and noradrenaline infusion with concomitant infusions of
Ang-(1-7) or saline was made by repeated measure of ANOVA, ie,
interaction between treatment [Ang-(1-7) or placebo] and the doses of
agonists.
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Results |
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Protocol 1: Effect of Ang-(1-7) on Forearm Blood Flow
Figure 1 shows forearm blood flow during the infusion of Ang-(1-7) at various doses. There were no significant changes in forearm blood flow at 0.5 to 250 pmol/min of Ang-(1-7). Forearm blood flow during infusions of Ang-(1-7) at 500 to 2000 pmol/min tended to be reduced but the changes did not reach statistical significance.
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Protocol 2: Effect of Ang-(1-7) on Forearm Blood Flow,
Double-Blind, Crossover Study
Figure 2 shows changes in
forearm blood flow during infusions of Ang-(1-7) and placebo. Reduction
of forearm blood flow during Ang-(1-7) infusion was significantly
greater than that during placebo infusion (P=0.0016, by
ANOVA).
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) on forearm blood flow compared with
placebo (isotonic saline, 
). *P=0.0016 by
ANOVA.
Protocol 3: Effect of Ang-(1-7) on Vasopressor Responses to Ang II
and Noradrenaline
Figure 3 shows the effect of
concomitant infusion of Ang-(1-7) on vasoconstriction evoked by Ang II
and noradrenaline. No significant differences existed in
baseline forearm blood flow in the infused arm between before Ang II
with saline and with Ang-(1-7) (2.78±0.79 versus 2.91±0.69 mL
· min-1 · dL-1)
and between before noradrenaline with saline and with
Ang-(1-7) (2.64±0.76 versus 2.58±0.53 mL ·
min-1 · dL-1). The
magnitude of reduction of forearm blood flow by Ang II infusion was
significantly attenuated by the infusion of Ang-(1-7) at 100 pmol/min
[percent changes in forearm blood flow; -19±17%, -33±22%,
-55±12%, -63±10%, and -68±5% at 5, 10, 25, 50, and 100
pmol/min of Ang II with saline; 5±13%, 0.9±18%, -4±16%,
-54±9%, and -61±6% with Ang-(1-7) at 100 pmol/min,
P=0.0021, by ANOVA, placebo versus 100 pmol/min of
Ang-(1-7)] but not at 10 pmol/min. Ang-(1-7) infusion at either 10
pmol/min or 100 pmol/min did not affect the noradrenaline
dose-response curve.
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), and placebo (isotonic saline, |
Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Is Ang-(1-7) a Vasodilating Peptide?
We demonstrated that the intra-arterial infusion of Ang-(1-7) itself had no direct vasodilating effect, at least at the doses that we used in human forearm resistant vessels. Ang-(1-7) caused weak but significant vasoconstriction at the high doses. The forearm concentration of Ang-(1-7) in our study (protocol 2) was assumed to be 2 to 3 µmol/L at the highest dose (40 nmol/min), which was almost the same as the concentration that caused 50% vasorelaxation in canine coronary arteries (2.7 µmol/L)19 and in porcine coronary arteries (2.2 µmol/L).3 Thus, our results are the antithesis of several previous reports that showed the direct vasodilating effect of Ang-(1-7) in isolated arteries3 19 and in vivo hypotensive effect.12 20 However, there has not necessarily been universal agreement with the vasodilating property of this peptide. Abbas et al8 showed that Ang-(1-7) at 20 to 380 nmol/rat had an angiotensin type 1 (AT1) receptor-mediated hypertensive effect unless exogenous bradykinin was administrated. This suggests that the vasodilating effect of Ang-(1-7) may require sufficient bradykinin. Kono and colleagues14 showed the hypertensive effect of Ang-(1-7) at 18 nmol · kg-1 · min-1 for 15 minutes, which was comparable with the dose used in the study by Abbas et al, in normotensive healthy subjects. These various vascular and blood pressure responses to Ang-(1-7) among studies may result in part from methodological differences. Different vascular beds (eg, forearm vessels versus coronary artery) from different species (rat versus human) may have different responses to Ang-(1-7). The duration of infusion of Ang-(1-7) might also affect the result. Indeed, Benter et al12 demonstrated a biphasic acute blood pressure response to Ang-(1-7), which consisted of an initial pressor component and a subsequent depressor component after a bolus injection of Ang-(1-7) at 300 nmol/rat in rats.
Interaction With Ang II
The present study also demonstrated that Ang-(1-7)
significantly and dose dependently attenuated vasoconstriction evoked
by Ang II but not by noradrenaline. This result raises the
possibility that Ang-(1-7) may be an endogenous
antagonist of AT1 receptor although
the concentration of Ang-(1-7) in the forearm vascular beds (0.01
µmol/L) during the infusion at 100 pmol/min was much lower than
IC50 (>1 µmol/L) for
AT1 receptor.21 Interestingly, Mahon
et al13 showed a significant rightward shift of the
dose-response curve of Ang II by Ang-(1-7) in rabbit aortic rings and
attenuation of the pressor response to Ang II by Ang-(1-7) in rats,
whereas the administration of Ang-(1-7) itself had no hypotensive
effect. Because this effect was observed specifically with Ang II, but
not with other vasoconstrictors, and was reversed by losartan,
they speculated that Ang-(1-7) modulated the effect of Ang II via the
AT1 receptor. Our results are consistent
with their report. There are, however, several other possible
mechanisms for Ang-(1-7) mediated attenuation of the vascular effect of
Ang II. Evidence suggests that Ang-(1-7) stimulates releases of
vasodilating prostaglandin4 5 and
NO3 and also potentiates the effect of
bradykinin.6 7 8 Although this effect has not been confirmed
in human vessels, these agents could attenuate the vascular effect of
Ang II.22 23 This, however, may not be the case for our
results, because these vasodepressor agents must affect the effect of
noradrenaline as well.24 25 Therefore, albeit
no experiment with angiotensin receptor
antagonists was conducted in our study, we speculate that
Ang-(1-7) attenuated the vascular action of Ang II via the
AT1 receptor. Experiments to investigate
the interaction among Ang-(1-7), and Ang II, AT1
receptor antagonist and inhibitors of
prostaglandins, nitric oxide, and bradykinin in man are
clearly warranted to confirm this hypothesis. One would claim that
Ang-(1-7) should show direct vasodilating effect if it has an
AT1 receptor antagonistic effect.
However, evidence suggests that Ang II does not contribute to
maintaining vascular tone in salt-repleted healthy
subjects.26 Therefore, it is not surprising that Ang-(1-7)
alone has no vasodilating effect on our subjects.
Two different mechanisms seem at work for the vascular effect of Ang-(1-7). First through the AT1 receptor directly and second through the production of vasodilating agents that might involve non-AT1 and AT2 angiotensin receptor(s). In contrast to our study, Benter et al27 showed nonspecific effect of Ang-(1-7), ie, pressor responses to not only Ang II but also phenylephrine, was attenuated by the chronic administration of Ang-(1-7) in spontaneously hypertensive rats. This nonspecific vasodilating effect of Ang-(1-7) may be explained by stimulated production of vasodepressor agents by Ang-(1-7).
Are These Results Physiologically or
Pathophysiologically Significant?
Our study showed that the vascular effects of Ang II at 2.5 to 5
nmol/L was inhibited by Ang-(1-7) at 10 nmol/L.28
Therefore, although the concentration of Ang-(1-7) in this study was
1000x higher than the physiological concentration
in man (10 pmol/L), the ratio of the concentration of Ang II to
Ang-(1-7) was 0.25 to 0.5, which could be seen after ACE
inhibition.28 29 The hypotensive effect of ACE
inhibitors was not necessarily associated only with
reduction in plasma Ang II levels.30 Increased Ang-(1-7)
after ACE inhibition may, at least in part, contribute to effect of ACE
inhibitors by attenuation of the effect of Ang II. Our
results also suggest that Ang-(1-7) might work as an
endogenous Ang II antagonist in the presence of
high Ang II from the activated renin-angiotensin
system, whereas Ang-(1-7) appears to be, as shown in protocol 1 and 2,
weak Ang II in salt-repleted subjects with normal or inhibited
renin-angiotensin system. Ang-(1-7), therefore, can be
regarded as a counterregulatory peptide to Ang II in patients with
high-renin activity, such as patients with heart failure and
renovascular hypertension. Thus, the roles of Ang-(1-7) in these
cardiovascular diseases should be investigated.
Conclusion
We conclude that Ang-(1-7) itself does not have a vasodilating
effect, at least at the dose that we used, but attenuates
vasoconstriction evoked only by Ang II in human forearm resistance
vessels. Thus, Ang-(1-7) is supposed to act as an
endogenous angiotensin receptor
antagonist and might be
physiologically relevant when the
renin-angiotensin system is activated.
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Acknowledgments |
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This study was supported by grants from the Grant in Support of the Promotion of Research at Yokohama City University, the Uehara Memorial Foundation, and the Ueda Memorial Trust Fund for Research of Heart Disease (S. Ueda).
Received April 6, 1999; first decision May 12, 1999; accepted November 15, 1999.
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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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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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