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.
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 α1-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.
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.
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: where I and NI represent measured blood flows in the infused and noninfused arm, respectively, during periods of NE administration and preceding placebo or perindoprilat (P) administration. This method is essentially that used by Greenfield and Patterson17 to minimize the effects of variation in blood flow caused by minor external factors. The percentage change in FABF during LBNP was calculated as a direct percentage of preceding placebo or perindoprilat FABF. Results are expressed as mean (SEM). Comparison of blood flow changes was made by repeated-measures ANOVA, and data from individual time points were compared with the use of Student’s paired t test, with P being corrected for the total number of comparisons using Bonferroni’s correction; P<.05 is taken as statistically significant.
All volunteers gave informed written consent. The study was approved by the Ethics Committee of King’s College Hospital.
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 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).
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 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).
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 (α1) 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 α1-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 α1-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 α-adrenergic antagonist phentolamine and by the α1-adrenergic antagonists prazosin and terazosin. It was not inhibited by propranolol or by the α2-adrenergic antagonist yohimbine.31 Thus, NE-stimulated hypertrophy of cultured rat myocardial cells is an α1-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.
Selected Abbreviations and Acronyms
|Ang II||=||Angiotensin II|
|FABP||=||Forearm blood flow|
|LBNP||=||Lower body negative pressure|
- Received September 23, 1996.
- Revision received March 3, 1997.
- Accepted March 7, 1997.
- Copyright © 1997 by American Heart Association
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