(Circulation. 1997;96:911-915.)
© 1997 American Heart Association, Inc.
Articles |
ACE Inhibition
Postsynaptic Adrenergic Sympatholytic Action in Men
From the Clinical Age Research Unit, King's College School of Medicine and Dentistry, London, UK.
Correspondence to Dr Declan Lyons, Limerick Regional Hospital, Dooradoyle, Limerick, Ireland. E-mail d.lyons{at}kcl.ac.uk
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background The mechanisms by which ACE inhibitors produce a sustained clinical benefit are not entirely clear but may involve the sympathetic nervous system. We compared the effect of local brachial artery infusions of an ACE inhibitor (perindoprilat) with the effect of placebo (0.9% NaCl) on endogenously mediated (lower body negative pressure [LBNP]) and exogenously mediated (brachial artery infusions of norepinephrine) sympathetic vasoconstriction.
Methods and Results Eight healthy, normotensive male volunteers (20 to 32 years) were studied on one occasion. Forearm blood flow (FABF; mL · dL forearm-1 · min-1) responses to LBNP (-20 cm H2O) and increasing increments of norepinephrine (60, 120, and 240 pmol/min) were compared when coinfused with placebo and perindoprilat (5 nmol/mL). FABF was measured simultaneously in both arms by venous occlusion plethysmography with mercury-in-Silastic strain gauges with drugs infused locally at the left brachial artery. The right arm served as a control. Baseline FABFs did not differ between the infused and control arms (3.04±0.52 versus 3.05±0.42 mL · dL forearm-1 · min-1; P=.98). Perindoprilat did not alter FABF when infused alone, but the FABF response to LBNP in the infused arm was attenuated during the perindoprilat infusion compared with placebo (-17.8±4.3% versus -33.8±3.1%, respectively; P=.015). The FABF response to the maximum dose of norepinephrine was also attenuated during the perindoprilat infusion compared with placebo (-28.3±1.4% versus -36.9±2.8%, respectively; P=.015). The mean slope of the FABF (log transformed) versus norepinephrine dose-response curve was significantly attenuated by perindoprilat compared with placebo (-0.11±0.019 versus -0.02±0.02; P=.001).
Conclusions We conclude that ACE inhibition has a significant postsynaptic sympatholytic effect in the forearm circulation of men.
Key Words: angiotensin • perindoprilat • enzymes
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The RAS and sympathetic nervous system are important control mechanisms in blood pressure regulation. Both systems interact in a number of ways, including a central action to increase sympathetic outflow,1 together with stimulatory effects on sympathetic ganglia and the adrenal medulla.2
Facilitation of adrenergic neuroeffector transmission by Ang II has been demonstrated in hand veins3 and resistance vessels of healthy4 and hypertensive5 subjects, whereas ACE inhibitors have been shown to attenuate sympathetically mediated vasoconstriction6 and depress circulating catecholamine concentrations in some7 8 9 but not all10 studies.
There is increasing evidence that ACE inhibition attenuates
sympathetic responses through an as-yet-undefined
mechanism.11 Possible mechanisms include the reduction in
tissue Ang II concentrations with a consequential reduction in the
facilitatory action of Ang II on adrenergic
neurotransmission,6 enhanced bradykinin and
prostaglandin accumulation,12 and a reduction
in 
1-adrenergic receptor number.13
The increasing use of ACE inhibitors in hypertension, cardiac failure, and postmyocardial infarction has focused attention on the need for better understanding of the overall effect of ACE inhibitors in the human circulation because the mechanisms by which these drugs produce a sustained clinical benefit are not entirely clear.
We recently demonstrated that a significant part of the vasoconstrictive action of Ang II on forearm resistance vessels in humans is sympathetically mediated.14 We have now investigated the effect of a local intra-arterial infusion of an ACE inhibitor (perindoprilat) on brachial artery infusions of NE and LBNP on forearm resistance vessels in healthy subjects to determine whether ACE inhibition has a sympatholytic effect at the level of resistance vessels and, if so, to determine whether this is a presynaptic or postsynaptic action.
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Methods |
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The study was undertaken in eight healthy, male, normotensive volunteers between 20 and 32 years of age; each was studied on one occasion.
Investigations were performed in a temperature-controlled laboratory (25° to 27°C) with the subjects lying supine. FABF (mL · dL forearm-1 · min-1) was measured simultaneously in both arms by venous occlusion plethysmography with mercury-in-Silastic strain gauges.15 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 sec in each 15-sec 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 using 1% lidocaine hydrochloride (Pharma Hameln GmbH Germany) to provide local anesthesia.
Two infusions (Fig 1
, infusions a and b)
were administered simultaneously throughout each experiment
at a constant rate of 1 mL/min by means of two constant rate infusion
pumps (Braun Perfusor Ed 2). 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.
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) and infused
(
) arms during infusions a and b and in response to LBNP.
Infusion a consisted of saline for 10 minutes to establish baseline
FABFs in both arms; this was then continued for the duration (3
minutes) of LBNP and for an additional 10-minute washout period to
allow FABF to return to baseline. This was followed by the infusion of
three incremental doses of NE (60, 120, and 240 pmol/min,
Sanofi-Winthorp), each given for 10 minutes (Fig 1
). This infusion a
sequence of saline and NE was then repeated while infusion b was
switched from saline/placebo (0.9% NaCl; Baxter Healthcare Ltd) to
perindoprilat (5 nmol/mL; Servier Laboratories Ltd). This dose
of perindoprilat virtually abolishes the vasoconstricting action of
angiotensin I (200 pmol/min) when coinfused at the
brachial artery (unpublished data). Perindoprilat was always infused at
the end of the study due to the possibility of prolonged tissue ACE
inhibitory activity. FABF was measured for the last 3
minutes of each 10-minute infusion period and for the duration of each
LBNP application.
LBNP was applied according to the method of Browne et al.16 Subjects rested supine in a polyvinyl chloride chamber supported by an external wooden frame. The lower limbs and hips were enclosed within the chamber and sealed above the level of the anterior superior iliac spines. Suction was applied (3 minutes) using a domestic vacuum cleaner to produce a constant negative pressure of 20 cm H2O as measured with a water manometer. The alteration from atmospheric pressure was both applied and relieved rapidly.
Statistics and Calculations
FABF is expressed as mL/dL of forearm per minute according to
the method of Whitney.15 The percentage change in FABF
after NE administration was calculated as:
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All volunteers gave informed written consent. The study was approved by the Ethics Committee of King's College Hospital.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The absolute changes in FABF in response to LBNP and NE (60, 120 and 240 pmol/min) during placebo and perindoprilat are shown in Fig 1
, and percentage changes are shown in Fig 2.
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) and infused (
) arms during placebo and perindoprilat
infusions in response to 3-minute applications of LBNP (-20 cm
H2O). b, Mean percent change in FABF in the infused arm
during placebo and perindoprilat infusions in response to incremental
infusions of NE.
Placebo Infusion
Absolute baseline FABFs did not differ between the infused and
control arms (3.04±0.52 versus 3.05±0.42 mL · dL
forearm-1 ·
min-1; P=.98) and after a 10-minute
saline washout period after the initial application of LBNP returned to
baseline levels in both the infused and control arms (3.10±0.57 versus
2.93±0.43; P=.88). FABF also returned to baseline levels
after an additional 10-minute saline washout period at the end of the
incremental norepinephrine infusions in both the infused
and control arms (2.86±0.37 versus 2.88±0.32; P=.92).
Perindoprilat Infusion
Perindoprilat alone did not alter FABF compared with control at
the end of a 10-minute infusion (2.93±0.36 versus 3.00±0.54;
P=.82), and FABF remained unaltered in both the infused and
control arms (2.96±0.3 versus 2.78±0.28; P=.28) at the end
of a 10-minute perindoprilat washout period after the second
application of LBNP. FABF in the perindoprilat infused arm returned to
control arm levels within 10 minutes of substitution of
norepinephrine with saline at the end of the study
(3.26±0.46 versus 3.09±0.64; P=.84).
LBNP
During the placebo infusion, LBNP reduced FABF in the infused and
control arms by 33.8±3.1% and 27.3±4.1%, respectively
(P=.52). The control arm blood flow responses to LBNP did
not differ between the perindoprilat and placebo infusions
(-28.1±3.2% versus -27.3±4.1%, respectively; P=.89).
However, the response to LBNP in the infused arm was attenuated during
the perindoprilat infusion compared with placebo (-17.8±4.3% versus
-33.8±3.1%, respectively; P=.015).
NE Infusions
NE produced dose-dependent reductions in FABF during both
the perindoprilat and placebo infusions. However, the FABF response to
the maximum dose of NE was attenuated during the perindoprilat infusion
compared with placebo (-28.3±1.4% versus -36.9±2.8%,
respectively; P=.015). Comparison of the rate of change of
blood flow in response to doubling doses of NE during placebo and
perindoprilat administration was calculated from the slopes of the
regression lines of log transformed blood flow versus dose of NE. The
mean slope during placebo administration was significantly greater than
that during perindoprilat (-0.11±0.019 versus -0.02±0.02;
P=.001).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The blood pressure–lowering action of ACE inhibitors is complex. Their antihypertensive and ancillary effects (eg, antimitogenic effects) are due not only to their actions on the circulating and tissue RASs but also on other neuroendocrine systems, including kinins, arginine/nitric oxide, aldosterone, and prostaglandins.18 Attenuation of sympathetic activity could conceivably contribute further to their antihypertensive properties and explain, at least in part, their established benefits in heart failure and after myocardial infarction.
We recently demonstrated that a significant portion of the
peripheral vasoconstrictive action of
exogenous Ang II on forearm resistance vessels in men is
sympathetically (1) mediated,14 whereas the
facilitatory action of Ang II on adrenergic neurotransmission is well
established.6 Whether this interaction occurs
presynaptically or postsynaptically at adrenergic nerve endings has not
been conclusively demonstrated. Several investigators have provided
evidence for a presynaptic action of Ang II in the augmentation of
sympathetic neurotransmission in the forearm model,4 19 20
whereas Reams and colleagues21 demonstrated postsynaptic
potentiation of NE by Ang II.
The effect of ACE inhibition on sympathetic activity has also been
studied. ACE inhibitors have been demonstrated to reduce
circulating catecholamine concentrations11 and
attenuate sympathetically mediated vasoconstriction due to
LBNP22 and cold pressor tests.23 Matsui et
al24 demonstrated a reduction in
1-adrenergic receptor number during ACE
inhibitor–induced regression of cardiac
hypertrophy and postulated that this occurred due to the
nonhemodynamic actions of the ACE
inhibitor, probably via modulation of
peripheral sympathetic activity.
In the present study in healthy subjects, we have shown that an intra-arterial infusion of an ACE inhibitor (perindoprilat), at a dose that had no effect on local blood flow, attenuated the response to both LBNP and locally infused increments of NE to a similar degree. The attenuated responses were not due to a direct vasodilating effect of the ACE inhibitor as FABF in the infused arm was unchanged by the ACE inhibitor alone compared with the control arm. During the ACE inhibitor infusion, FABF in the infused arm also reverted to control arm levels after LBNP and NE. We thus confirmed the previously noted observation that local infusion of ACE inhibitors to the brachial artery has little if no effect on basal blood flow.25 26
The possibility that the reduced response to infused NE occurs due to
the development of 1-adrenoceptor downregulation or to
the development of tachyphylaxis is most unlikely over such short
infusion periods. This is supported by the observations of Clarke et
al,27 who did not find a difference in response with
repeated incremental infusions of NE on the same occasion.
Perindoprilat attenuated the vasoconstriction induced by both LBNP (endogenously mediated) and brachial artery infusions of NE (exogenously mediated), indicating that the ACE inhibitor exerts its sympatholytic effect postsynaptically. Attenuation of LBNP responses alone indicates a presynaptic adrenergic site of action. In this study, we used local, low doses of NE that were insufficient to cause a systemic pressor response5 ; hence, the effects of the infusions used in the present study were limited to the infused forearm.
LBNP has been shown to be a reliable stimulus for reflex sympathetic
vasoconstriction in the upper limb.28 Negative pressure of
20 cm H2O, as used in these experiments, produces
sympathetic vasoconstriction of the resistance vessels in the forearm
muscles through unloading of low-pressure cardiopulmonary
baroceptors.29 This degree of LBNP has been shown to
reduce FABF without producing a change in heart rate or a sustained
effect on arterial pressure.28 Higher degrees
of LBNP with negative pressure of 
40 cm H2O are, however,
associated with systemic hemodynamic and hormonal
changes.30
The sympatholytic action of ACE inhibitors may have a
number of clinically important consequences, such as contributing,
along with other mechanisms, to their ability to cause regression of
left ventricular hypertrophy.
Simpson31 demonstrated that NE stimulates muscle cell
hypertrophy in primary cultures from the neonatal rat
ventricle and that this stimulation was inhibited by the nonselective
-adrenergic antagonist phentolamine and by the
1-adrenergic antagonists prazosin and
terazosin. It was not inhibited by propranolol or by the
2-adrenergic antagonist
yohimbine.31 Thus, NE-stimulated hypertrophy
of cultured rat myocardial cells is an 1-adrenergic
response and therefore likely to be attenuated by ACE inhibition.
In the peripheral vasculature, ACE inhibition prevents the development of vascular smooth muscle polyploidy in vivo, either by reducing the direct effects of Ang II on the cells or indirectly by reducing sympathetic discharges as defined in this study.32
The sympathetically mediated action of Ang II may explain the reduction in sympathetic tone, as measured by plasma concentrations of NE, that accompanies the use of ACE inhibitors in cardiac failure.7 8 The removal of Ang II–initiated sympathetic vasoconstriction may also explain why ACE inhibition attenuates sympathetic coronary vasoconstriction in patients with coronary artery disease.33 Finally, the favorable effect of converting enzyme inhibition on heart rate variability after myocardial infarction may be contributed to by this sympatholytic effect of ACE inhibitors.34
In conclusion, in this study we suggest that ACE inhibition produces a significant sympatholytic effect in the forearm circulation and that this effect is mediated at a postsynaptic level. These findings give further support for a major neuromodulatory role for this class of drug.
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Selected Abbreviations and Acronyms |
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Received September 23, 1996; revision received March 3, 1997; accepted March 7, 1997.
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References |
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