(Hypertension. 2001;37:1136.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Angiotensin-(1-7) Does Not Affect Vasodilator or TPA Responses to Bradykinin in Human Forearm
From the Divisions of Cardiovascular Medicine (T.W., D.E.V.) and Clinical Pharmacology (J.V.G., L.J.M., N.J.B.), Vanderbilt University Medical Center, Nashville, Tenn.
Correspondence to Nancy J. Brown, MD, 560 MRB I, Vanderbilt University Medical Center, Nashville, TN 37232-6602. E-mail nancy.brown{at}mcmail.vanderbilt.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract—Studies in isolated vessels and rat models of hypertension suggest that angiotensin (Ang)-(1-7) potentiates the vasodilator effect of bradykinin, possibly through ACE inhibition. We therefore tested the hypothesis that Ang-(1-7) potentiates the vasodilator or tissue plasminogen activator (TPA) response to bradykinin in the human forearm vasculature. Graded doses of Ang-(1-7) (10, 100, and 300 pmol/min), bradykinin (47, 94, and 189 pmol/min), and Ang I (1, 10, and 30 pmol/min) were administered through the brachial artery to 8 normotensive subjects in random order. Thirty minutes after initiation of a constant infusion of Ang-(1-7) (100 pmol/min), bradykinin and Ang I infusions were repeated. There were no systemic hemodynamic effects of the agonists. Bradykinin significantly increased forearm blood flow (P<0.001, from 3.8±0.5 to 13.9±3.1 mL/min per 100 mL at 189 pmol/min) and net TPA release (P=0.007, from 1.1±1.0 to 23.6±6.2 ng/min per 100 mL at 189 pmol/min), whereas Ang I caused vasoconstriction (P=0.003, from 3.3±0.4 to 2.5±0.3 mL/min per 100 mL at 30-pmol/min dose). There was no effect of Ang-(1-7) on either forearm blood flow (P=0.62, 3.3±0.4 to 3.5±0.4 mL/min per 100 mL at 300 pmol/min) or TPA release (P=0.52, from 0.7±0.8 to 1.0±0.7 ng/min/100 mL at 300 pmol/min). Moreover, there was no effect of 100 pmol/min Ang-(1-7) on the vasodilator [P=0.46 for Ang-(1-7) effect] or TPA [P=0.82 for Ang-(1-7) effect] response to bradykinin or the vasoconstrictor response to Ang I [P=0.62 for Ang-(1-7) effect]. These data do not support a role of Ang-(1-7), given at supraphysiological doses, in the regulation of human peripheral vascular resistance or fibrinolysis.
Key Words: angiotensin • angiotensin-converting enzyme • bradykinin • endothelium • plasminogen • vasodilator agents
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Angiotensin (Ang)-(1-7) is formed from Ang I by the action of the endopeptidase neprilysin (EC 3.4.24.11) and degraded to Ang-(1-5) by ACE.1 Ang-(1-7) concentrations may be increased during ACE inhibition.2 3 In vitro and in animal models, Ang-(1-7) acts as a vasodilator and exhibits antiproliferative effects.4 5 6 For example, in isolated canine, porcine, and human arteries, Ang-(1-7) causes nitric oxide–dependent vasodilation.4 5 7 8 Significantly, the vasodilator effect of Ang-(1-7) can be blocked by bradykinin (BK) receptor antagonism.4 5 7 This finding and the observation that Ang-(1-7) enhances the hypotensive effect of BK in rats as well as isolated arteries5 9 10 11 suggest the hypothesis that Ang-(1-7) causes vasodilation by potentiating the effects of BK. Ang-(1-7), an ACE substrate cleaved by the N-domain active site, acts as an inhibitor of the C-domain active site of the enzyme12 and thus may potentiate BK by blocking its degradation. Ang-(1-7) also may potentiate the actions of BK by resensitizing its receptor.13 In addition, studies in human coronary arteries8 and rabbit aortic rings14 suggest that Ang-(1-7) may antagonize angiotensin-mediated vasoconstriction through effects at the AT1 receptor.
The interaction between Ang-(1-7) and BK has not been studied extensively in humans. Davie and McMurray15 recently reported that intrabrachial administration of Ang-(1-7) did not cause vasodilation and did not potentiate the vasodilator response to BK in patients with heart failure treated with an ACE inhibitor. However, in this study, pretreatment with an ACE inhibitor may have obscured any BK-potentiating effect of Ang-(1-7). In addition, no studies have reported whether Ang-(1-7) potentiates the effect of BK-stimulated tissue plasminogen activator (TPA) release. BK is known to stimulate endothelial TPA release through its B2 receptor.16 17 We therefore investigated the effect of intrabrachial administration of Ang-(1-7) on forearm blood flow (FBF) and endothelial TPA release when given alone and in combination with BK.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
Eight healthy subjects were studied. The study was approved by the Vanderbilt University Institutional Review Board and conducted according to the Declaration of Helsinki. Each subject underwent a history, physical examination, ECG, and routine laboratory analysis. None had any evidence of hypertension, hyperlipidemia, cardiovascular disease, or other systemic condition. One subject smoked. Six men and 2 women were studied. Six subjects were white and 2 were black. The mean age was 33.7±3.6 years; mean body mass index was 25.8±1.3 kg/m2. Mean arterial pressure (MAP) and heart rate were 85.8±3.6 mm Hg and 64.1±3.8 bpm, respectively.
Experimental Protocol
Studies were performed in the morning, in a
temperature-controlled room. Subjects were studied in the supine
position and in the fasting state. After subdermal administration of
1% lidocaine, a 20-gauge polyurethane catheter (Cook Inc) was inserted
into the brachial artery of the nondominant arm, allowing for
intra-arterial administration of drugs and
arterial sampling. A catheter was inserted in the
antecubital vein of the same arm for venous sampling. Before the
infusion of vasoactive drugs, arterial catheter patency was
maintained by infusion of 5% dextrose in water at a rate of 1 mL/min.
After placement of the intravenous and
intra-arterial catheters, subjects were allowed to rest 30
minutes before baseline measurements were made. Blood pressure was
monitored in the contralateral arm with an automated blood pressure
cuff throughout the study. After measurement of basal FBF and blood
sampling, graded doses of Ang-(1-7) (Clinalfa AG), Ang I (Clinalfa AG),
or BK (Calbiochem; sterilized and tested for pyrogenicity by the
Vanderbilt Investigational Drug Pharmacy) were infused in random order.
Ang-(1-7) was infused at 10, 100, and 300 pmol/min; Ang I was infused
at 1, 10, and 30 pmol/min; and BK was infused at 50, 100, and 200
ng/min (47, 94, and 189 pmol/min). Each dose was infused for 5 minutes,
and FBF was measured during the last 2 minutes. Before infusion of each
drug, the 30-minute rest period and basal measurements were repeated.
Ang I and BK were each infused twice, in the presence and absence
(order randomized) of a 100-pmol/min continuous infusion of Ang-(1-7).
Continuous Ang-(1-7) infusion was initiated 30 minutes before
concurrent administration of either BK or Ang I. The shortest interval
between BK and BK+Ang-(1-7) infusion in any subject was 75 minutes. We
have previously determined that tachyphylaxis to BK does not occur over
a time interval as short as 1 hour. Throughout the study, drug
concentrations in the infusate were adjusted to maintain infusion
volumes at 1 mL/min. The doses of Ang I and BK were chosen on the basis
of previously published studies from this laboratory and others. The
doses of Ang-(1-7) were chosen to be 10-fold higher than the
pharmacologically active doses of Ang I.
Forearm Perfusion Measurements
FBF was measured by mercury-in-silastic strain-gauge
plethysmography.18 The wrist
was supported in a sling to raise the forearm to above the level of the
atrium, and the strain gauge was placed at the widest part of the
forearm. The strain gauge was connected to a plethysmograph (model
EC-5, D.E. Hokanson), calibrated to measure the percent change in
volume, and connected to a chart recorder to record the flow
measurements. For each measurement, a cuff placed around the upper arm
was inflated to 40 mm Hg with a rapid cuff inflater (model E-10,
Hokanson) to occlude venous outflow from the extremity. The hand was
excluded from the measurement of blood flow by inflation of a pediatric
sphygmomanometer cuff around the wrist to 200 mm Hg before and
during measurement of FBF. Flow measurements were recorded for 
7
of 15 seconds, and the slope was derived from the first 3 to 4 pulses;
5 to 7 such readings were obtained for each mean
value.
Blood Sampling and Biochemical Assays
After measurement of FBF, simultaneous
arterial and venous samples were obtained from the infused
arm before and after each dose of study drug. Infusion of drug was
interrupted during arterial sampling. All samples were
obtained after the first 3 mL of blood was discarded.
Blood samples were collected on ice and centrifuged immediately, and plasma was stored at -70°C until the time of assay. Blood for measurement of plasminogen activator inhibitor-1 and TPA was collected in tubes containing 0.105 mol/L acidified sodium citrate, and antigen levels were determined with a 2-site enzyme-linked immunosorbent assay (Biopool AB), as previously described.19 Because increases in TPA activity parallel increases in TPA antigen in response to BK,17 TPA activity was not measured separately.
Arteriovenous concentration gradients were calculated by subtracting the plasma level measured in simultaneously collected venous and arterial blood. Forearm plasma flow was calculated from the FBF and arterial hematocrit corrected for 1% trapped plasma. Thus, individual net release or uptake rates at each time point were calculated by the formula
Net release=(CV-CA)x[FBFx(101-hematocrit)/100)] where CV and CA represent the concentration of TPA in the brachial vein and artery, respectively.
Statistics
Data are presented as mean±SEM. Because
there was no effect of Ang-(1-7), Ang I, or BK on systemic blood
pressure, data are presented in terms of FBF. The effect of
Ang-(1-7) on the response to agonist was assessed by ANOVA with
repeated measures in which the within-subject variables were the
presence and absence of Ang-(1-7) and the dose of agonist. Post hoc
comparisons were made with the paired
t test or Wilcoxon
signed rank test, as appropriate. A 2-tailed probability value of
<0.05 was considered statistically
significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Local infusions of Ang-(1-7), BK, and Ang I did not affect MAP or heart rate. For example, MAP was 83.3±3.1 mm Hg during 300 pmol/min Ang-(1-7) versus 83.6±2.5 mm Hg at baseline. MAP was 83.6±3.6 at 189 pmol/min BK versus 87.5±3.1 baseline and 86.6±2.7 at 30 pmol/min Ang I versus 85.1±2.5 mm Hg at baseline.
Forearm Blood Flow
Figure 1 shows the effect of Ang-(1-7), Ang I, and BK on
FBF. There was no effect of Ang-(1-7) on FBF at doses up to 300
pmol/min (P=0.62,
Figure 1A). BK significantly increased FBF from 3.8±0.5
mL/min per 100 mL at baseline to 13.9±3.1 mL/min per 100 mL at the
189-pmol/min dose (P<0.001,
Figure 1B). There was no effect of concurrent Ang-(1-7)
administration on the vasodilator response to BK
[P=0.46 for Ang-(1-7)
effect]. Ang I caused a significant decrease in FBF from 3.3±0.4
mL/min per 100 mL at baseline to 2.5±0.3 mL/min per 100 mL at the 30
pmol/min dose (P=0.003,
Figure 1C). There was no effect of concurrent Ang-(1-7)
administration on the vasoconstrictor response to Ang I
[P=0.62 for Ang-(1-7)
effect].
|
) and absence (
) of 100 pmol/min Ang-(1-7); and C, Ang I in presence (
Net TPA Release
Figure 2 shows net TPA release across the forearm during
Ang-(1-7) and BK infusion. There was no effect of Ang-(1-7) on net TPA
release (P=0.52). BK caused a
significant increase in net TPA release from 1.1±1.0 ng/min per 100 mL
at baseline to 23.6±6.2 ng/min per 100 mL at the 189-pmol/min dose
(P=0.007) without a concomitant
increase in plasminogen activator
inhibitor-1 antigen
(P=0.44). There was no effect
of Ang-(1-7) on the TPA response to BK
[P=0.82 for effect of
Ang-(1-7)].
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
In this study, we set out to test the hypothesis that Ang-(1-7) causes vasodilation in the peripheral human vasculature, either through direct or indirect effects. We examined the effect of Ang-(1-7) on both the vasodilator and the TPA responses to BK because previous studies in humans have demonstrated that BK acts as a potent stimulus to TPA release from the human endothelium through effects at its B2 receptor.16 17 In addition, we examined the effect of Ang-(1-7) on the vasoconstrictor response to Ang I. We hypothesized that if Ang-(1-7) acts through ACE inhibition,12 then it would both potentiate responses to BK and attenuate the vasoconstrictor response to Ang I. In contrast, if Ang-(1-7) acts by altering BK receptor sensitivity,13 we hypothesized that it would potentiate the responses to BK but not the response to Ang I. Finally, if Ang-(1-7) acts as an AT1 receptor antagonist,8 14 we hypothesized that it would attenuate the vasoconstrictor effect of Ang I without potentiating the responses to BK. The results suggest that Ang-(1-7), given at supraphysiological doses, does not cause vasodilation of the human peripheral vasculature. Moreover, the study results do not support an effect of Ang-(1-7) on either ACE activity or BK receptor function in the human peripheral vasculature.
Data from this study are consistent with those from 3 prior studies in humans. In 1986, Kono et al20 reported that Ang-(1-7) acted as a weak pressor when administered systemically to humans, with a potency 0.028% of that of Ang II. Because Ang-(1-7) was administered systemically, however, it has been proposed that a compensatory baroreflex response may have masked any vasodepressor effect of Ang-(1-7). In the present study, Ang-(1-7) was administered directly into the brachial artery, and there were no systemic effects of any of the agonists administered. More recently, Ueda et al21 reported no vasodilator response to intra-arterial Ang-(1-7) at doses up to 2000 pmol/min, although these investigators observed a vasoconstrictor response to intra-arterial Ang-(1-7) at higher doses. In contrast, Davie and McMurray15 reported no significant vasoactive effect of intra-arterial Ang-(1-7) administered at doses up to 50 000 pmol/min in the forearm vasculature of patients with congestive heart failure. The authors also reported that Ang-(1-7) did not potentiate the vasodilator response to BK in the presence of ACE inhibition. However, this study could not exclude the possibility that Ang-(1-7) potentiates the effects of BK by inhibiting ACE. This study, performed in the absence of ACE inhibitor therapy, does not support this possibility.
Although previous investigators have examined the effect of Ang-(1-7) on BK-mediated vasodilation, this study is unique in measuring the effect of Ang-(1-7) on the TPA response to BK. TPA is stored in small dense granules in endothelial cells.22 Recent studies indicate that BK stimulates the release of TPA through a B2-dependent but nitric oxide synthase–independent, cyclooxygenase-independent, pathway.17 The observation that coadministration of Ang-(1-7) does not potentiate BK-stimulated TPA release provides additional and complementary evidence that Ang-(1-7) does not alter B2-mediated responses, whether by affecting BK degradation or B2-receptor sensitivity.
The finding that Ang-(1-7) does not potentiate the vasodilator effects of BK in the human forearm conflicts with data from many in vitro studies4 5 as well as studies in normotensive and hypertensive animal models.9 10 23 Several possible factors may account for the discrepancy between the vasodilator effect of Ang-(1-7) observed in vitro and in animal studies and the lack of such an effect on BK-mediated vasodilation in this and other human studies.15 20 21 First, there may be interspecies differences in the effects of Ang-(1-7). Second, Ang-(1-7) may contribute to vascular tone in hypertensive but not in normotensive animals or humans. In this regard, Benter et al23 have reported differential susceptibility to the effects of Ang-(1-7) in hypertensive versus normotensive rat models.
Differences in dose of Ang-(1-7) used may account to a large extent for the discrepancy between data from human and prior in vitro and animal studies. The EC50 for the vasodilator effect of Ang-(1-7) has been reported to be 2.2±0.4 µmol/L in porcine coronary rings4 and 2.73±0.58 µmol/L in canine coronary arteries,5 although the EC50 appears to be lower in rat aorta.24 Roks et al8 have reported an IC50 for inhibition of ACE activity in human plasma in the 10-5 mol/L range. In contrast, the concentration of Ang-(1-7) in human plasma appears to be in the range of 10-11 mol/L.3 25
The maximal dose of Ang-(1-7) infused in this study was
calculated to give local concentrations of Ang-(1-7)
10-8 mol/L or 1000-fold higher than
physiological concentrations. In addition, the
constant dose of Ang-(1-7) infused was 10-fold higher than the minimal
vasoconstrictor dose of Ang I and 30-fold higher than the minimal
vasodilator dose of BK. By comparison, the molar ratio of Ang-(1-7) to
Ang I in human plasma is
<1.3 25 Thus, the
study does not support the hypothesis that Ang-(1-7) contributes to
BK-mediated peripheral vasodilation in humans at
physiologically relevant concentrations. On the
other hand, the study does not address the possibility that Ang-(1-7)
affects BK-mediated peripheral vasodilation when given at
the micromolar concentrations used in many in vitro studies. Similarly,
the study does not address the possibility that Ang-(1-7) may act as an
autocoid in microenvironments where concentrations may be greatest;
studies with specific inhibitors will be necessary to
address the role of endogenous Ang-(1-7) in
humans.
The finding that Ang-(1-7) did not attenuate the forearm vasoconstrictor effect of Ang I contrasts with data from Roks et al,8 who demonstrated that Ang-(1-7) (10-5 mol/L) antagonized the vasoconstrictor effects of Ang I and Ang II in human internal mammary arteries. Our findings also diverge from those of Ueda et al,21 who reported that Ang-(1-7), at the same concentration used in this study, attenuated the forearm vasoconstrictor response to Ang II in 8 healthy volunteers. It is possible that the use of Ang I, which must be converted to Ang II, rather than Ang II in the present study may have obscured an effect of Ang-(1-7) at the level of the AT1 receptor. Indeed, the vasoconstrictor response to Ang I measured in the present study was markedly less than that reported by Ueda et al in response to similar concentrations of Ang II.
The finding that Ang-(1-7) does not cause peripheral vasodilation or potentiate the effects of BK in normotensive subjects also does not exclude a role for Ang-(1-7) in the regulation of blood pressure in humans through other mechanisms. For example, Ang-(1-7) could contribute to blood pressure regulation through its central nervous system effects.26 In the kidney, Ang-(1-7) causes natriuresis independent of changes in renal blood flow or glomerular filtration.27 Urinary Ang-(1-7) concentrations appear to be decreased in animal models of hypertension28 and in patients with essential hypertension.29 Thus, it is possible that Ang-(1-7) plays a role in the regulation of blood pressure through local paracrine effects in the brain or kidney, without causing peripheral vasodilation.
Summary
We examined the interactive effect of Ang-(1-7) on
BK-stimulated vasodilation and vascular TPA release, two
B2-receptor–mediated responses, in the forearm
of healthy humans. The results do not support the hypothesis that
Ang-(1-7), given at supraphysiological
concentrations, potentiates the peripheral effects of BK in
humans.
|
Acknowledgments |
|---|
This study was supported by National Institutes of Health grants HL-60906, HL-56963, GM-07569, K23-HL-04445, K23-HL-04221, T32-HL-07411, and 5M01-RR-0095.
Received July 18, 2000; first decision August 14, 2000; accepted September 20, 2000.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Ferrario CM, Chappell MC, Tallant EA, Brosnihan KB, Diz DI. Counterregulatory actions of angiotensin-(1-7). Hypertension. 1997;30:535–541.
2.
Campbell DJ,
Lawrence AC, Towrie A, Kladis A, Valentijn AJ. Differential regulation
of angiotensin peptide levels in plasma and kidney of the
rat. Hypertension. 1991;18:763–773.
3. Lawrence AC, Evin G, Kladis A, Campbell DJ. An alternative strategy for the radioimmunoassay of angiotensin peptides using amino-terminal-directed antisera: measurement of eight angiotensin peptides in human plasma. J Hypertens. 1990;8:715–724.[Medline] [Order article via Infotrieve]
4. Porsti I, Bara AT, Busse R, Hecker M. Release of nitric oxide by angiotensin-(1-7) from porcine coronary endothelium: implications for a novel angiotensin receptor. Br J Pharmacol. 1994;111:652–654.[Medline] [Order article via Infotrieve]
5.
Brosnihan KB, Li P,
Ferrario CM. Angiotensin-(1–7) dilates canine
coronary arteries through kinins and nitric oxide.
Hypertension. 1996;27:523–528.
6.
Freeman EJ, Chisolm
GM, Ferrario CM, Tallant EA. Angiotensin-(1-7) inhibits
vascular smooth muscle cell growth.
Hypertension. 1996;28:104–108.
7.
Li P, Chappell MC,
Ferrario CM, Brosnihan KB. Angiotensin-(1-7) augments
BK-induced vasodilation by competing with ACE and releasing nitric
oxide. Hypertension. 1997;29:394–400.
8.
Roks AJ, van Geel
PP, Pinto YM, Buikema H, Henning RH, de Zeeuw D, van, Gilst WH.
Angiotensin-(1-7) is a modulator of the human
renin-angiotensin system.
Hypertension. 1999;34:296–301.
9.
Paula RD, Lima CV,
Khosla MC, Santos RA. Angiotensin-(1-7) potentiates the
hypotensive effect of bradykinin in conscious rats.
Hypertension. 1995;26:1154–1159.
10.
Abbas A, Gorelik
G, Carbini LA, Scicli AG. Angiotensin-(1-7) induces
bradykinin-mediated hypotensive responses in anesthetized rats.
Hypertension. 1997;30:217–221.
11.
Gorelik G,
Carbini LA, Scicli AG. Angiotensin 1-7 induces
bradykinin-mediated relaxation in porcine coronary artery.
J Pharmacol Exp Ther. 1998;286:403–410.
12.
Deddish PA,
Marcic B, Jackman HL, Wang HZ, Skidgel RA, Erdos EG. N-domain-specific
substrate and C-domain inhibitors of
angiotensin-converting enzyme:
angiotensin-(1-7) and keto-ACE.
Hypertension. 1998;31:912–917.
13.
Marcic B, Deddish
PA, Jackman HL, Erdos EG. Enhancement of bradykinin and resensitization
of its B2 receptor.
Hypertension. 1999;33:835–843.
14. Mahon JM, Carr RD, Nicol AK, Henderson IW. Angiotensin(1-7) is an antagonist at the type 1 angiotensin II receptor. J Hypertens. 1994;12:1377–1381.[Medline] [Order article via Infotrieve]
15.
Davie AP,
McMurray JJ. Effect of angiotensin-(1-7) and bradykinin in
patients with heart failure treated with an ACE inhibitor.
Hypertension. 1999;34:457–460.
16.
Brown NJ, Gainer
JV, Stein CM, Vaughan DE. Bradykinin stimulates tissue
plasminogen activator release in human
vasculature. Hypertension. 1999;33:1431–1435.
17.
Brown NJ,
Gainer JV, Murphey LJ, Vaughan DE. Bradykinin stimulates tissue
plasminogen activator release from human forearm vasculature through
B2 receptor–dependent, NO
synthase–independent, and cyclooxygenase-independent pathway.
Circulation.. 2000;102:2190–2196.
18. Hokanson DE, Sumner DS, Strandness DEJ. An electrically calibrated plethysmograph for direct measurement of limb blood flow. IEEE Trans Biomed Eng. 1975;22:25–29.[Medline] [Order article via Infotrieve]
19.
Ridker PM,
Vaughan DE, Stampfer MJ, Manson JE, Shen C, Newcomer LM, Goldhaber SZ,
Hennekens CH. Baseline fibrinolytic state and the risk of future venous
thrombosis: a prospective study of endogenous tissue
plasminogen activator and
plasminogen activator inhibitor.
Circulation. 1992;85:1822–1827.
20. Kono T, Taniguchi A, Imura H, Oseko F, Khosla MC. Biological activities of angiotensin II-(1–6)-hexapeptide and angiotensin II-(1-7)-heptapeptide in man. Life Sci. 1986;38:1515–1519.[Medline] [Order article via Infotrieve]
21.
Ueda S,
Masumori-Maemoto S, Ashino K, Nagahara T, Gotoh E, Umemura S, Ishii M.
Angiotensin-(1-7) attenuates vasoconstriction evoked by
angiotensin II but not by noradrenaline in man.
Hypertension. 2000;35:998–1001.
22.
Emeis JJ, van den
Eijnden-Schrauwen Y, van den Hoogen CM, de Priester W, Westmuckett A,
Lupu F. An endothelial storage granule for tissue-type
plasminogen activator.
J Cell Biol. 1997;139:245–256.
23.
Benter IF,
Ferrario CM, Morris M, Diz DI. Antihypertensive actions of
angiotensin-(1-7) in spontaneously hypertensive rats.
Am J Physiol. 1995;269:H313–H319.
24. le Tran Y, Forster C. Angiotensin-(1-7) and the rat aorta: modulation by the endothelium. J Cardiovasc Pharmacol. 1997;30:676–682.[Medline] [Order article via Infotrieve]
25. Luque M, Martin P, Martell N, Fernandez C, Brosnihan KB, Ferrario CM. Effects of captopril related to increased levels of prostacyclin and angiotensin-(1-7) in essential hypertension. J Hypertens. 1996;14:799–805.[Medline] [Order article via Infotrieve]
26.
Campagnole-Santos
MJ, Diz DI, Santos RA, Khosla MC, Brosnihan KB, Ferrario CM.
Cardiovascular effects of angiotensin-(1-7)
injected into the dorsal medulla of rats.
Am J Physiol. 1989;257:H324–H329.
27. DelliPizzi AM, Hilchey SD, Bell-Quilley CP. Natriuretic action of angiotensin(1-7). Br J Pharmacol. 1994;111:1–3.[Medline] [Order article via Infotrieve]
28. Yamada K, Iyer SN, Chappell MC, Brosnihan KB, Fukuhara M, Ferrario CM. Differential response of angiotensin peptides in the urine of hypertensive animals. Regul Pept. 1999;80:57–66.[Medline] [Order article via Infotrieve]
29. Ferrario CM, Martell N, Yunis C, Flack JM, Chappell MC, Brosnihan KB, Dean RH, Fernandez A, Novikov SV, Pinillas C, Luque M. Characterization of angiotensin-(1-7) in the urine of normal and essential hypertensive subjects. Am J Hypertens. 1998;11:137–146.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  M. C. Chappell Emerging Evidence for a Functional Angiotensin-Converting Enzyme 2-Angiotensin-(1-7)-Mas Receptor Axis: More Than Regulation of Blood Pressure? Hypertension, October 1, 2007; 50(4): 596 - 599. [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Grobe, A. P. Mecca, H. Mao, and M. J. Katovich Chronic angiotensin-(1-7) prevents cardiac fibrosis in DOCA-salt model of hypertension Am J Physiol Heart Circ Physiol, June 1, 2006; 290(6): H2417 - H2423. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Oliver, D. J. Webb, and D. E. Newby Stimulated Tissue Plasminogen Activator Release as a Marker of Endothelial Function in Humans Arterioscler Thromb Vasc Biol, December 1, 2005; 25(12): 2470 - 2479. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||