(Circulation. 1995;91:1457-1460.)
© 1995 American Heart Association, Inc.
Articles |
Angiotensin II
Adrenergic Sympathetic Constrictor Action in Humans
From the Clinical Pharmacology Unit, Department of Medicine and Therapeutics, Polwarth Building, Foresterhill, Aberdeen, AB9 2ZD, UK.
Correspondence to Dr Declan Lyons, Clinical Age Research Unit, Kings College Hospital, Denmark Hill, London SE5 9RS, UK.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Angiotensin II (Ang II) facilitates adrenergic neurotransmission in normotensive and hypertensive subjects, whereas angiotensin-converting enzyme inhibitors have been shown to depress circulating catecholamine concentrations in some studies. We investigated the effect of local intra-arterial infusion of Ang II into the brachial artery of healthy volunteers during blockade of postsynaptic
-receptors with phentolamine. The response was compared
with that seen with Ang II infused during nitroprusside administration
at a dose designed to give a dilator response similar to that with
phentolamine.
Methods and Results Ang II (6.25, 25, and 100 pmol/min) was
infused alone and then together with sodium nitroprusside (4 µg/min)
and phentolamine (40 µg/min) in eight healthy volunteers. Forearm
blood flow was measured by strain-gauge plethysmography. The percentage
reduction in forearm blood flow produced by Ang II 100 pmol/min in the
phentolamine-predilated vascular bed was significantly lower than that
seen in the sodium nitroprusside–predilated forearm bed
(28.1±2.9%
versus 52.9±4.2%; P=.006). Comparison of the rate of
change of blood flow in response to quadrupling doses of Ang II during
blockade of -receptors with phentolamine and during nitroprusside
administration was calculated from the mean slope of the regression
line of log-transformed blood flow versus dose of Ang II. The mean
slope during nitroprusside administration (-0.16±0.025) was
significantly greater than that during blockade with phentolamine
(-0.098±0.020) (P=.046).
Conclusions We conclude that a significant part of the vasoconstrictive action of exogenous Ang II on forearm resistance vessels in humans is sympathetically mediated.
Key Words: angiotensin • sodium nitroprusside • phentolamine • blood volume
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The renin-angiotensin system and the sympathetic nervous system are important control mechanisms in blood pressure regulation.
Angiotensin II (Ang II) is a potent arteriolar constrictor through its action on specific AT1 receptors in vascular smooth muscle.1 Animal data indicate that Ang II also augments norepinephrine release and modifies sympathetic reflexes.2 3 Facilitation of adrenergic neuroeffector transmission by Ang II has been demonstrated in hand veins4 and resistance vessels of healthy5 and hypertensive subjects,6 whereas angiotensin-converting enzyme (ACE) inhibitors have been reported to depress circulating catecholamine concentrations in some7 8 9 but not all10 studies. The increasing use of ACE inhibitors in hypertension and cardiac failure and after myocardial infarction has focused attention on the need for a better understanding of the overall effect of Ang II in the human circulation because the mechanisms by which these drugs produce a sustained clinical benefit are not entirely clear.
We investigated the effect of local intra-arterial infusion of Ang II on forearm resistance vessels to identify the extent to which adrenergic neuroeffector transmission contributes to the overall vasoconstrictor action of Ang II.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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The study was undertaken in eight healthy, normotensive volunteers between 21 and 30 years of age, each studied on one occasion.
Investigations were performed in a temperature-controlled laboratory (25°C to 27°C) with the subjects lying supine. Forearm blood flow (mL · dL forearm-1 · min-1) was measured simultaneously in both arms by venous occlusion plethysmography with mercury-in-Silastic strain gauges.11 During the recording period, the hands were excluded from the circulation by inflation of the wrist cuffs to 200 mm Hg. The upper arm congesting cuffs were inflated to 40 mm Hg for 10 seconds in each 15-second cycle. The mean of the final five measurements of each recording period was used for analysis.
A 27-gauge unmounted steel cannula (Cooper's Needle Works) was inserted into the left brachial artery with 1% lignocaine hydrochloride (Pharma Hameln GmbH) to provide local anesthesia.
Solutions were infused at a constant rate of 1 mL/min throughout the experiment by means of a constant-rate infusion pump (Braun Perfusor Ed 2). When two drugs were infused simultaneously, a Y-connector delayed mixing until the solutions entered the cannula. The right arm was not cannulated and served as a control. Output from the strain gauges was through a plethysmograph and onto the screen of a dedicated Apple Macintosh computer via a Maclab interface.
Preliminary studies showed that blood flow returned to baseline within 10 minutes after the Ang II infusion was stopped. We also determined that in the forearm vascular bed, both sodium nitroprusside and phentolamine achieved their maximal effect within 10 minutes after infusion was commenced and produced a similar degree of vasodilation at the doses used in this study.
Saline (0.9% NaCl; Baxter Healthcare Ltd) was infused for 10 minutes to establish resting control values. This was followed by infusion of three incremental doses of Ang II (6.25, 25, and 100 pmol/min, CIBA Laboratories), each given for 10 minutes, followed in turn by a second saline infusion for 10 minutes to allow blood flow to return to baseline. Sodium nitroprusside (4 µg/min, Roche) alone was then infused for 10 minutes. The infusion was continued for a further 30 minutes with simultaneous infusion of the same three incremental doses of Ang II, each given for 10 minutes. This in turn was followed by a 10-minute saline washout period, allowing blood flow to return to baseline. Phentolamine (CIBA Laboratories) alone was then infused for 10 minutes at 40 µg/min and then continued for a further 30 minutes with simultaneous infusion of the same three incremental doses of Ang II given for 10 minutes each. Phentolamine was always infused at the end of the study because of its long duration of action.
Forearm blood flow was measured for the last 3 minutes of each 10-minute infusion period.
Statistics and Calculations
Forearm blood flow is expressed
as milliliters per deciliter
forearm volume per minute according to the method of
Whitney.11 The percentage change in forearm blood flow
after drug administration was calculated as
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where I and NI represent measured blood flow in the infused and noninfused arm, respectively, during periods of angiotensin (a) and preceding vehicle (v) administration in the case of Ang II when infused alone or preceding vasodilator (v) (ie, sodium nitroprusside or phentolamine) when coinfused with these drugs. This method is essentially that used by Greenfield and Patterson12 to minimize the effects of variation in blood flow caused by minor external factors. Results are expressed as mean±SEM. Comparison of blood flow changes was by ANOVA. Where the ANOVA showed a significant treatment effect, data from individual time points were compared by Student's paired t test, with P being corrected for the total number of comparisons using the Bonferroni correction; P<.05 is taken as statistically significant.
All volunteers gave informed written consent to the study. The study was approved by the Joint Ethics Committee of the University of Aberdeen and Grampian Health Board.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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The changes in forearm blood flow in response to Ang II (6.25, 25, and 100 pmol/min), Ang II/sodium nitroprusside, and Ang II/phentolamine are shown in Figs 1
and 2.
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indicates
control arm; 
, infused arm.
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Saline
Absolute resting blood flows (saline infusion 1) did
not differ
significantly between the control and infused arms (4.0±0.52 versus
4.4±0.67
mL · dL-1 · min-1;
P=.55). After infusion of Ang II alone, blood flow returned
to baseline with a 10-minute saline washout (3.97±0.65
mL · dL-1 · min-1;
P=.22).
After infusion of Ang II/sodium nitroprusside, blood flow again
returned to baseline with a 10-minute saline washout (3.85±0.68
mL · dL-1 · min-1;
P=.21).
SNP and Phentolamine
Sodium nitroprusside (4 µg/min) and
phentolamine (40 µg/min)
produced a similar degree of vasodilation, with blood flow increasing
to 9.6±1.4 and 9.3±0.94
mL · dL-1 · min-1,
respectively; P=.74.
Ang II
Ang II produced a dose-dependent decrease in forearm
blood flow,
with the maximum dose producing a reduction of 64.2±3.8%. With the
forearm vascular bed predilated nonadrenergically with sodium
nitroprusside (producing a blood flow of 9.6±1.4
mL · dL-1 · min-1), Ang II
caused a
similar dose-dependent reduction in blood flow, with the maximum dose
of Ang II reducing flow to 3.95±0.25
mL · dL-1 · min-1 (ie,
52.9±4.2%).
With the forearm vascular bed predilated to a similar extent (9.3±0.94 mL · dL-1 · min-1) with phentolamine, the maximum dose of Ang II reduced blood flow to 6.01±0.67 mL · dL-1 · min-1 (ie, 28.1±2.9%). The percentage reduction in forearm blood flow produced by Ang II 100 pmol/min in the phentolamine-predilated vascular bed was significantly lower than that seen in the sodium nitroprusside–predilated forearm bed (28.1±2.9% versus 52.9±4.2%; P=.002). There was no significant difference between the Ang II 6.25- and 25-pmol/min doses.
Comparison of the rate of change of
blood flow in response to
quadrupling doses of Ang II during blockade of postsynaptic
-receptors with phentolamine and during nitroprusside administration
was calculated from the mean slope of the regression line of
log-transformed blood flow versus dose of Ang II. The mean slope during
nitroprusside administration (-0.16±0.025) was significantly
greater
than that during phentolamine blockade (-0.098±0.02;
P=.04).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The renin-angiotensin system interacts with the sympathetic nervous system in a number of ways, including a central action to increase sympathetic outflow,13 together with stimulatory effects on sympathetic ganglia and the adrenal medulla.14
This study assesses the interaction between the sympathetic
nervous system and the renin-angiotensin system in the forearm
circulation of humans. Most previous studies in humans have assessed
subpressor doses of Ang II in stimulating or augmenting sympathetic
activity,4 5 15 16 whereas
methods using pressor doses
have tended to be confounded by the activation of baroreceptor
reflexes, which has made interpretation of results more
complicated.17 18 Animal studies that support an
interaction between the renin-angiotensin and sympathetic nervous
systems have done so only when the renin-angiotensin system is
activated,19 which may explain the conflicting results of
studies in which the renin-angiotensin system is manipulated by the use
of ACE inhibitors or subpressor doses of Ang II. The present study
assesses the vasoconstrictor response to Ang II with prior
pharmacological blockade of -adrenergic receptors and also uses
forearm venous plethysmography with brachial artery infusions of doses
of Ang II,20 sodium nitroprusside,21 and
phentolamine22 that were insufficient to cause a systemic
response while attaining high local concentrations in the forearm
vascular bed.
The results show that in healthy volunteers, the vasoconstrictive action of intra-arterial Ang II is attenuated in forearm resistance vessels predilated with phentolamine. This contrasts with its effect on nonadrenergically predilated resistance vessels with an equivalent dose of sodium nitroprusside.
It was the explicit intention of this study to assess the contribution, if any, of the sympathetic nervous system to the vasoconstrictor action of Ang II, and as such we cannot differentiate between a presynaptic and postsynaptic action for Ang II. We previously provided evidence for a presynaptic action in the augmentation of sympathetic neurotransmission in the forearm model,5 while Reams and Bauer23 demonstrated postsynaptic potentiation of norepinephrine by Ang II. Seidelin et al15 found no effect of Ang II on plasma norepinephrine during a variety of sympathetic stimuli, whereas Goldsmith and Hasking16 did not find any stimulating effects of subpressor or pressor Ang II infusions on norepinephrine spillover in normal humans or patients with congestive heart failure. Matsukawa et al18 found that Ang II had no effect on muscle sympathetic nerve activity when the pressor effect of Ang II was abolished.
Phentolamine is a competitive -adrenergic receptor antagonist acting
on the 1- and 2-adrenergic receptors and
has other minor ancillary vasodilator properties, including serotonin
receptor antagonism, potassium channel antagonism, and a direct
vasodilator action on smooth muscle.24 25 It would
have
been preferable if a pure -adrenergic receptor antagonist such as
prazosin could have been used, but phentolamine is currently the only
-blocker available for use intra-arterially. The vasodilatory action
of sodium nitroprusside depends on its nitrosyl group and does not
directly interfere with - and ß-adrenergic
receptors.26 We defined doses of sodium nitroprusside and
phentolamine that, when infused into the brachial artery, resulted in
similar increases in forearm blood flow.
In all studies, sodium nitroprusside was administered before phentolamine, since its effect disappeared rapidly when the infusion was stopped, whereas the effect of phentolamine was still seen up to 20 minutes after infusion. Since each study lasted between 2.5 and 3 hours, it was felt undesirable to prolong the studies any further by random administration of these drugs.
The reduced response to Ang II with phentolamine could possibly be explained by tachyphylaxis in response to Ang II in the forearm vessels. Although this may occur in vitro, it does not occur with prolonged intra-arterial infusion in humans.27
The constrictor effect of Ang II alone was comparable to that seen in conjunction with sodium nitroprusside, but during sympathetic blockade with phentolamine, there was a marked reduction in constriction. This suggests that part of the vasoconstrictive action of Ang II is sympathetically mediated either presynaptically by potentiation of the release of norepinephrine at sympathetic nerve terminals or postsynaptically by potentiation of the postjunctional actions of norepinephrine.
The sympathetically mediated action of Ang II may explain the reduction in sympathetic tone, as measured by plasma concentrations of norepinephrine, that accompanies the use of ACE inhibitors in cardiac failure.7 8 Removal of Ang II–initiated sympathetic vasoconstriction may also be the explanation as to why ACE inhibition attenuates sympathetic coronary vasoconstriction in patients with coronary artery disease.28
In conclusion, in this study we suggest that a significant part of the vasoconstrictive action of exogenous Ang II on forearm resistance vessels in humans is sympathetically mediated, giving further support for a major neuromodulatory role for this peptide.
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Acknowledgments |
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This study was supported by a grant from the Grampian Hospitals Endowments Research Fund.
Received August 1, 1994; accepted September 5, 1994.
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References |
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|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Mendelsohn FAO. Localization and properties of angiotensin receptors. J Hypertens. 1985;3:307-316. [Medline] [Order article via Infotrieve]
2. Antonaccio MJ, Kerwin L. Pre- and post junctional inhibition of vascular sympathetic function by captopril in SHR: implication of vascular angiotensin II in hypertension and antihypertensive actions of captopril. Hypertension. 1981;3(suppl 1):I-54-I-62.
3. Hatton R, Conway J, Adigun SA. Angiotensin activates sympathetic reflexes in the anaesthetized cat. Clin Sci. 1980;59(suppl 6):287s-289s.
4. Benjamin N, Collier JG, Webb DJ. Angiotensin II augments sympathetically induced venoconstriction in man. Clin Sci. 1988;75: 337-340.
5. Seidelin PH, Collier JG, Struthers AD, Webb DJ. Angiotensin II augments sympathetically mediated arteriolar constriction in man. Clin Sci. 1991;81:261-266. [Medline] [Order article via Infotrieve]
6. Struthers AD, Pai S, Seidelin PH, Coutie WRJ, Morton JJ. Evidence in humans for post synaptic interaction between noradrenaline and angiotensin II with regard to systolic but not diastolic blood pressure. J Hypertens. 1987;5:671-676. [Medline] [Order article via Infotrieve]
7. Cleland J, Semple P, Hodsman P, Ball S, Ford I, Dargie H. Angiotensin II levels, hemodynamics and sympathoadrenal function after low-dose captopril in heart failure. Am J Med. 1984;77: 880-886.
8. Cody RJ, Franklin KW, Kluger J, Laragh JH. Sympathetic responsiveness and plasma noradrenaline during therapy of chronic congestive heart failure. Am J Med. 1982;72:791-797. [Medline] [Order article via Infotrieve]
9.
Wenting GJ, Man in't Veld AJ, Woittiez AJ. Effects of
captopril in acute and chronic heart failure. Br Heart J. 1983;49:65-76.
10. Nicholls MG, Espiner EA, Mils KB, Swifler AJ, Julius S. Evidence against an interaction of angiotensin II with the sympathetic nervous system in man. Clin Endocrinol. 1981;15:423-430.[Medline] [Order article via Infotrieve]
11. Whitney RJ. The measurement of volume changes in human limbs. J Physiol. 1953;121:1-27.
12. Greenfield ADM, Patterson GC. Reactions of the blood vessels of the human forearm to increases in transmural pressure. J Physiol. 1954;125:508-524.
13. Bickerton RK, Buckley JP. Evidence for a central mechanism in angiotensin induced hypertension. Proc Soc Exp Biol Med. 1961;106:834-836.
14. Reit E. Actions of angiotensin on the adrenal medulla and autonomic ganglia. Fed Proc. 1972;31:1338-1343. [Medline] [Order article via Infotrieve]
15. Seidelin PH, Coutie WJR, Struthers AD. The effect of angiotensin II on endogenous noradrenaline release in man. Br J Clin Pharmacol. 1987;24:699-704. [Medline] [Order article via Infotrieve]
16.
Goldsmith SR, Hasking GJ. Subpressor infusions of angiotensin
II do not stimulate sympathetic activity in humans. Am J
Physiol. 1990;258:H179-H182.
17.
Goldsmith SR, Hasking GJ. Effect of a pressor infusion of
angiotensin II on sympathetic activity and heart rate in normal humans.
Circ Res. 1991;68:263-268.
18. Matsukawa T, Gotoh E, Minirinijawa K, Kihara M, Veda S, Shionari H, Ishii M. Effects of intravenous infusions of angiotensin II on muscle sympathetic nerve activity in humans. Am J Physiol. 1991;26:1690-1696.
19. Zimmerman BG, Sybertz EJ, Wong PC. Interaction between sympathetic and renin-angiotensin system. J Hypertens. 1984;2:581-587. [Medline] [Order article via Infotrieve]
20. Chinn RH, Düsterdieck G. The response of blood pressure to infusion of angiotensin II; in relation to plasma concentrations of renin and angiotensin II. Clin Sci. 1972;42:489-504. [Medline] [Order article via Infotrieve]
21. Collier JG, Lorge RE, Robinson BF. Comparison of effects of tolmesoxide (RX71107), diazoxide, hydralazine, prazosin, glyceryl trinitrate and sodium nitroprusside on forearm arteries and dorsal hand veins of man. Br J Clin Pharmacol. 1978;5:35-44. [Medline] [Order article via Infotrieve]
22.
Collier JG, Nachev CH, Robinson BF. Comparison of blockade at
-adrenoceptors by thymoxamine and phentolamine in peripheral
arteries and veins of man. Br J Pharmacol. 1972;44:294-300. [Medline]
[Order article via Infotrieve]
23. Reams GP, Bauer JH. Angiotensin II potentiates the vasoconstrictive effect of norepinephrine in normotensive and hypertensive man. J Clin Hypertens. 1987;3:610-616. [Medline] [Order article via Infotrieve]
24. Das PK, Parrat JR. Myocardial and haemodynamic effects of phentolamine. Br J Pharmacol. 1971;41:437-444. [Medline] [Order article via Infotrieve]
25. McPhearson GA, Angus JA. Phentolamine and structurally related compounds selectively antagonize the vascular actions of the K+ channel opener, cromromakalim. Br J Pharmacol. 1989;97:941-942. [Medline] [Order article via Infotrieve]
26.
Vernier IR. Sodium nitroprusside: theory and practice.
Postgrad Med J. 1974;50:576-581.
27.
Clarke JG, Benjamin N, Larkin SW. Endothelin is a
potent long-lasting vasoconstrictor in men. Am J
Physiol. 1989;257:H2033-H2035.
28.
Saino A, Tio RA, Pomidossi G, Gregorini L, Alessio P, Morganti
A, Zanchetti A, Mancia G. ACE inhibition attenuates sympathetic
coronary vasoconstriction in patients with coronary artery disease.
Circulation. 1992;85:2004-2013.
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