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(Circulation. 1997;96:1173-1179.)
© 1997 American Heart Association, Inc.

Articles

Effects of Chronic ACE Inhibition on Sympathetic Nerve Traffic and Baroreflex Control of Circulation in Heart Failure

Guido Grassi, MD; Bianca M. Cattaneo, MD; Gino Seravalle, MD; Antonio Lanfranchi, MD; Massimo Pozzi, MD; Alberto Morganti, MD; Stefano Carugo, MD; ; Giuseppe Mancia, MD

From the Cattedra di Medicina Interna, Università di Milano, Ospedale S. Gerardo, Monza (G.G., M.P., S.C., G.M.); Centro di Fisiologia Clinica e Ipertensione, Università di Milano e Ospedale Maggiore, Milano (G.G., B.M.C., A.L., A.M., G.M.); and Centro Auxologico Italiano, Milano (B.M.C., G.S., G.M.), Italy.

Correspondence to Professor Giuseppe Mancia, I Divisione di Medicina, Cattedra di Medicina Interna, Ospedale S. Gerardo dei Tintori, Via Donizetti 106, 20052 Monza, Italy.

	Abstract

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Background In congestive heart failure ACE inhibitors chronically reduce plasma norepinephrine. No information exists, however, on whether and to what extent this reduction reflects a true chronic inhibition of sympathetic outflow and which mechanisms may be responsible.

Methods and Results In 24 patients aged 60.3±2.0 years (mean±SEM) affected by congestive heart failure (New York Heart Association class II) and treated with diuretics and digitalis, we measured mean arterial pressure (Finapres), plasma renin activity and angiotensin II levels (radioimmunoassay), plasma norepinephrine (high-performance liquid chromatography), and muscle sympathetic nerve activity (microneurography at a peroneal nerve) at rest and during baroreceptor stimulation and deactivation caused by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. In 12 patients measurements were repeated after a 2-month addition of the ACE inhibitor benazepril (10 mg/d PO), while in the remaining 12 patients they were performed again after 2 months without any treatment modifications. Benazepril did not alter mean arterial pressure, markedly increased plasma renin activity, reduced plasma angiotensin II, and caused a nonsignificant reduction in plasma norepinephrine. In contrast, muscle sympathetic nerve traffic was significantly reduced (-30.5±5.3%, P<.01). This reduction was accompanied by no change in the sympathoexcitatory responses to baroreceptor deactivation but by a marked enhancement of the sympathoinhibitory responses to baroreceptor stimulation (103.5±3.4%).

Conclusions These results provide the first direct evidence that in congestive heart failure chronic ACE inhibitor treatment is accompanied by a marked reduction in central sympathetic outflow. This reduction may depend on a persistent restoration of baroreflex restraint on the sympathetic neural drive.

Key Words: heart failure • reflex • nervous system • baroreceptors • renin • angiotensin

	Introduction

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Congestive heart failure is characterized by an increase in sympathetic activity.^{1 2 3 4 5} This increase was long seen as a mechanism compensating for the weakening of the myocardium and preserving, through systemic vasoconstriction, BP and vital organ perfusion.⁶ However, cardiac function, vascular function, and survival of patients with CHF have been shown to be adversely affected by sympathetic activation,^{7 8 9} which is now regarded as a negative rather than a favorable hallmark of this condition.^{10 11}

In the past few years evidence has been obtained that ACE inhibitors improve the survival rate of CHF patients.^{12 13 14 15 16 17} Evidence has also been obtained that in these patients ACE inhibitors chronically reduce plasma NE concentrations,^{18 19 20} thereby generating the hypothesis that prolonged survival might originate from the reversal of sympathetic activation. A reduction in plasma NE during chronic treatment of CHF may also depend, however, on an improved tissue clearance of the neurotransmitter due to a treatment-induced increase in blood flow, and whether prolonged ACE inhibitor treatment reduces central sympathetic neural outflow in CHF has thus not been conclusively demonstrated. Indeed, a single intravenous administration of the ACE inhibitor enalaprilat in patients with New York Heart Association class II and III CHF has been shown to significantly but only slightly reduce sympathetic nerve activity.²¹

In the present study of patients with CHF we addressed this issue by directly recording sympathetic nerve traffic through microneurography before and after 2 months of ACE inhibitor administration. We also investigated the effect of ACE inhibition on baroreceptor modulation of sympathetic nerve activity. This is a key issue because in CHF the sympathetic activation is paralleled and possibly triggered by a baroreflex impairment.^{22 23} Studying cardiovascular baroreflex modulation before and after chronic administration of ACE inhibitors may also allow an investigation of the mechanisms responsible for their possible neurohumoral effects.

	Methods

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Population
Our study was performed in 24 patients (23 men and 1 woman) with CHF. In 12 of these patients (age, 60.5±3.0 years, mean±SEM) benazepril was added to their current treatment (see below). In the remaining 12 patients (age, 60.1±2.8 years) current treatment was left unchanged in order to use them as control subjects. Patients were sequentially assigned to the benazepril or control group. All patients had mild CHF (New York Heart Association class II) caused by either coronary heart disease (n=17) or idiopathic dilated cardiomyopathy (n=7). Mild CHF was selected because it shares with more severe heart failure both sympathetic activation and baroreflex impairment.²³

All patients included in the study were normotensive and in sinus rhythm. Body mass index was <25 kg/m², the "radiographic" cardiothoracic ratio was >0.55, and the "echocardiographic" LVEDD was >55 mm. No patient had a history of myocardial infarction in the 6 months preceding the study or clinical or laboratory evidence of valvular heart disease, renal insufficiency, diabetes mellitus, or any other condition known to affect the autonomic nervous system.²⁴ All 24 patients were treated with furosemide (40 to 80 mg/d PO), while digoxin (0.125 or 0.250 mg/d) was part of the chronic drug treatment for 6 patients of the former group and 5 patients of the latter group, respectively.

The study protocol was approved by the ethics committee of our institution. All patients agreed to participate after being informed of the nature and purpose of the study.

Measurements
BP was measured with a mercury sphygmomanometer; patients were placed in the supine position and the 1st and 5th Korotkoff sounds were taken to identify systolic and diastolic values, respectively. BP was also measured by using a finger photoplethysmographic device (Finapres, Ohmeda 2300) capable of providing accurate and reproducible beat-to-beat systolic and diastolic values.²⁵ In 7 patients from each group CVP was measured by using a catheter placed in the right atrium from an antecubital vein of the right arm and connected with a transducer (model P23XL, Gould Instruments) positioned at the midchest level. The respiration rate was monitored by using a strain-gauge pneumograph also positioned at the midchest level. HR was continuously monitored by a cardiotachometer triggered by the R wave of an ECG lead. LVEDD was obtained from an echocardiogram performed in M mode after selection of the measurement section by a B-mode scan. The echocardiographic data, which were also used to calculate the LVEF,²⁶ were collected by a single operator. The within-operator coefficient of variation for two LVEDD measurements obtained at a 2-day interval under standardized conditions was 6%.

Multiunit recordings of efferent MSNA were obtained through a tungsten microelectrode inserted into the right or left peroneal nerve.^{22 23 27} The nerve signal was amplified (x70 000), fed through a bandpass filter (700 to 2000 Hz), and integrated with a custom nerve-traffic analysis system (Bioengineering Department, University of Iowa). Integrated nerve activity was monitored by a loudspeaker; displayed on a storage oscilloscope (model 511A, Tektronix); and recorded with BP, HR, CVP, and respiration rate on thermic paper by using an ink polygraph (Gould 3800, Gould Instruments). MSNA was assessed according to published criteria,^{22 23 27} and the recording was accepted only if the signal-to-noise ratio exceeded the value of 3. Under baseline conditions MSNA was quantified as bursts per minute and as bursts per 100 heartbeats, ie, by parameters that our group and others have shown to be highly reproducible on both a short- and long-term basis.^{22 23}

Plasma NE concentrations were measured by using high-performance liquid chromatography,²⁸ and PRA and plasma AngII concentrations were measured by using a radioimmunoassay.^{29 30} The measurements were obtained from a blood sample drawn from a cannula placed in an antecubital vein of the arm contralateral to that used for finger BP measurements.

Arterial Baroreflex Testing
Baroreceptor modulation of MSNA and HR was assessed by the technique based on intravenous infusion of vasoactive drugs.²⁴ Briefly, PE was incrementally infused through the cannula placed in an antecubital vein at 0.4, 0.8, and 1.1 µg·kg^-1·min^-1 to progressively increase MAP (diastolic BP plus one third of pulse pressure) and thus progressively stimulate arterial baroreceptors. NP was also incrementally infused into an antecubital vein at 0.4, 0.8, and 1.2 µg·kg^-1·min^-1 to progressively reduce MAP and thus progressively deactivate arterial baroreceptors. Both infusions were maintained for 15 minutes, each incremental step lasting 5 minutes. The drug initially infused was followed by the second one after a recovery time of 45 minutes. MAP, MSNA, and HR were averaged for 10 baseline minutes before infusion and for the 5 minutes of each incremental step. Baroreceptor modulation of MSNA was estimated by calculating absolute changes in sympathetic bursts per minute and percent changes in the sympathetic burst amplitude (integrated activity) associated with changes in MAP induced by each dose of PE and NP. It was also estimated by calculating absolute changes in HR associated with changes in MAP induced by each vasoactive drug dose.

The average ratio between MSNA or HR changes and MAP changes was also separately calculated for the infusion of PE and NP. This was taken as the measure of baroreflex sensitivity during baroreceptor stimulation and deactivation.

Protocol and Data Analysis
All patients were hospitalized 4 days before the first study. They were taken to the laboratory in the morning after a light breakfast, placed in the supine position, and subjected to echocardiographic examination. They were then fitted with the intravenous cannulas, the ECG lead, the finger BP recording device, and the microelectrodes for MSNA recording. After a 30-minute interval, a blood sample was drawn, and BP was then measured three times by using a mercury sphygmomanometer; the three values were averaged. BP, HR, CVP, MSNA, and respiration rate were measured continuously during an initial 10-minute baseline condition, the stepwise infusion of one vasoactive drug, a second 10-minute baseline condition, and the stepwise infusion of the second vasoactive drug. PE was infused first in half the patients; NP was infused first in the remaining half. The patients were then dismissed from the hospital and asked either to keep their drug treatment unchanged (control group) or to add benazepril (10 mg/d PO) to their ongoing therapeutic schedule. No dietary or lifestyle changes were advised for either group. After 2 months (during which the patients were seen twice in the outpatient clinic) they were hospitalized again for 4 days to be restudied according to the procedure adopted for the first study. Adherence to treatment was verified both by pill counting and by the results of humoral measurements (see below). The second study was performed about 3 hours after ingestion of the last dose of benazepril.

Data were calculated by a single investigator unaware of the experimental design. Values from individual subjects were averaged for the groups with and without ACE inhibitor treatment and are expressed as mean±SEM. The significance of the differences in mean values was assessed by using a two-way ANOVA. The two-tailed t test for paired observations was used to locate the difference between resting conditions and baroreceptor stimulation or deactivation using Bonferroni's correction for multiple comparisons.³¹ A probability value of <.05 was considered significant.

	Results

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Treatment with benazepril for 8 weeks caused nonsignificant reductions in MAP, HR, CVP, and LVEDD. LVEF was slightly but significantly increased by the drug, which caused a marked and significant increase in PRA and a marked and significant reduction in AngII (Fig 1). Benazepril did not significantly reduce NE, but it did cause significant reductions in MSNA values of -30.5±5.3% (bursts/min) and -24.2±6.8% (bursts/100 heartbeats) (Fig 2). This was in striking contrast to the pattern observed in the control group, which showed no substantial alteration in any variables over the 8-week period except for a slight but nonsignificant increase in MSNA (Figs 1 and 2).

View larger version (35K): [in this window] [in a new window]   Figure 1. Bar graphs showing MAP (sphygmomanometric and Finapres evaluation), HR, CVP, LVEDD, LVEF, PRA, and plasma AngII (Ag II) values before (B, open bars) and after 8 weeks of benazepril treatment (hatched bars) and before (B, open bars) and after an 8-week observational period (shaded bars). Data are mean±SEM; n=12 for each group with the exception of CVP values, for which n=7 for each group. *P<.05.

View larger version (18K): [in this window] [in a new window]   Figure 2. Bar graphs showing MSNA expressed as bursts per minute (left) and bursts per 100 heartbeats (hb; middle) and plasma NE (right) values before (B, open bars) and after 8 weeks of benazepril treatment (hatched bars) and before (B, open bars) and after an 8-week observational period (shaded bars). Data are mean±SEM; n=12 for each group. *P<.05, **P<.01.

Fig 3 (left) shows the results obtained by baroreceptor stimulation and deactivation through the vasoactive drug infusion. Before administration of benazepril, HR and MSNA were slightly and progressively reduced by progressively increasing MAP via PE and progressively and somewhat more markedly increased by progressively reducing MAP via NP. After administration of benazepril, the bradycardic and sympathoinhibitory responses to baroreceptor stimulation were all significantly and markedly increased, with a >100% increase in the calculated baroreflex sensitivities compared with the values before benazepril administration (Table 1). In contrast, the tachycardic responses, the sympathoexcitatory responses, and the calculated baroreflex sensitivities to baroreceptor deactivation were not significantly affected. The baroreceptor-MSNA and baroreceptor-HR reflexes were not significantly affected in the control group (Fig 3 and Table 1). PE and NP infusions caused small increases and reductions in CVP, respectively. The changes were significant only at the highest doses of the vasoactive drugs, and in both the control and benazepril groups they were similar in the two sessions performed at an 8-week interval (Table 2).

View larger version (21K): [in this window] [in a new window]   Figure 3. Plots showing changes in HR (expressed as bpm [b/min]) and MSNA (expressed as bursts per minute [bs/min] and percent integrated activity [% i.a.]) accompanying stepwise reductions and increases in MAP induced by intravenous infusions of NP and PE, respectively. Solid lines refer to HR and MSNA changes observed under baseline conditions; dashed and dotted lines refer to HR and MSNA changes observed after 8 weeks of either benazepril treatment or an observational period, respectively. Data are mean±SEM; n=12 for each group. *P<.05, **P<.01.

View this table: [in this window] [in a new window]   Table 1. Sensitivity of Baroreceptor-HR and Baroreceptor-MSNA Reflexes for PE and NP Before and After 8 Weeks of Benazepril

View this table: [in this window] [in a new window]   Table 2. Changes in CVP Induced by Intravenous Stepwise Infusions of PE and NP

	Discussion

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In our CHF patients a 2-month administration of an ACE inhibitor at a dose that effectively interfered with the renin-angiotensin system (ie, marked increase in PRA and reduction in AngII) and improved left ventricular function (ie, increase in LVEF) was accompanied by a slight and nonsignificant reduction in plasma NE. MSNA, however, was markedly reduced, regardless of how its quantification was obtained. Thus, prolonged ACE inhibitor treatment truly deactivates sympathetic neural drive in CHF. This deactivation is much more pronounced than the one shown after acute blockade of the renin-angiotensin system by a single-dose ACE inhibitor,²¹ indicating that this is a distinct feature of chronic treatment with this class of drugs.

Our study also provides new information on the mechanisms responsible for the sympathoinhibitory effect of ACE inhibition in CHF. The increase in sympathetic activity characterizing this condition has been ascribed to an excitatory effect of increased plasma levels of AngII at the level of the brain,³² on ganglionic transmission of the sympathetic stimuli,³³ and/or on release of NE from adrenergic nerve terminals.³⁴ However, data from our group²³ and others²² have documented that in CHF the baroreceptor ability to restrain not only HR but also sympathetic nerve traffic is markedly impaired and that the impairment is related to the increase in sympathetic burst frequency. The hypothesis can thus be made that sympathetic activation in CHF may have, among others, a baroreflex origin. This is supported by our present findings that ACE inhibitor treatment caused both a reduction in sympathetic nerve traffic and an improved baroreceptor restraint on sympathetic drive. The present findings also suggest that restoration of this restraint might represent a mechanism through which ACE inhibition corrects the sympathetic abnormality typical of CHF. This may occur in conjunction with a removal of the sympathoexcitatory effect of increased AngII levels and with an enhancement of the sympathoinhibitory effect of bradykinins,^{33 35} the levels of which are increased by ACE inhibition.³⁶

Our study does not clarify the mechanisms by which ACE inhibition restores baroreflex restraint on sympathetic drive. We have previously shown, however, that arterial compliance and distensibility are reduced in CHF³⁷ ; that this reduction correlates with the baroreflex impairment, presumably by reducing the ability of stretch sensors such as baroreceptors to respond to the inside pressure³⁸ ; and that both the compliance and the distensibility alterations are reversed by ACE inhibitor administration, presumably because under these circumstances a reduction in AngII levels and sympathetic deactivation reduce vascular smooth muscle contraction, which is a major determinant of arterial wall stiffness.³⁹ ACE inhibition might thus improve baroreflex function by increasing baroreceptor responsiveness to physiological stimuli, thus acting on the initial portion of the reflex arch. This may not be the only factor involved, however, because a surprising finding of our study was that while ACE inhibitor administration markedly enhanced the responses to baroreceptor stimulation by PE infusion, it did not affect or even reduced the responses to baroreceptor unloading by NP infusion. Based on animal data, it can be speculated that this originates from a complex influence of AngII on the central integration of the arterial baroreceptor signal, ie, on the fact that in the brain this substance may have an opposite effect on the cardiovascular responses to arterial baroreceptor stimulation and unloading,⁴⁰ making the effect of its removal by ACE inhibition different for these two components of the reflex stimulus-response curve.

Several other results of our study deserve to be mentioned. First, in the patients treated with benazepril the marked increase in the reflex sympathoinhibitory responses to baroreceptor stimulation was paralleled by a similar marked increase in the concomitant reflex bradycardic responses. This finding (which is in line with data on the HR responses to carotid baroreceptor stimulation by a neck chamber device^{41 42} ) indicates that correction of the baroreflex impairment typical of CHF by ACE inhibitors involves both the vascular and sinus node modulation exerted by the baroreflex. Because sinus node modulation is predominantly mediated through the vagus,²⁴ this finding also means that not only the sympathoinhibitory but also the vagal excitatory influences of the baroreflex are restored by this therapeutic intervention. Second, CVP increased during the PE-induced increase in BP, suggesting a participation of both arterial baroreceptors and cardiac stretch receptors in the reflex responses.⁴³ However, the changes in CVP induced by PE infusion were small and similar before and after ACE inhibitor administration. Furthermore, the sympathoinhibitory and bradycardic responses to the infusion were significantly greater after than before ACE inhibition even at the smallest infusion dose, when no significant change in CVP occurred. Thus, although our results might in theory be accounted for by an ACE inhibitor–dependent potentiation of both the arterial baroreflex and the cardiogenic reflex (which has been shown to be potentiated by acute enalaprilat administration²¹ ), it is more likely that they reflect the ability of this treatment to restore arterial baroreflex control. Third, in our patients the decrease in MSNA induced by ACE inhibition was much greater and more consistent than the concomitant change in NE. In theory this could reflect a greater effect of ACE inhibition on sympathetic nerve traffic and traffic modulation in muscle than in other vascular tissues. However, similar results have been obtained in a variety of diseases and conditions in which sympathetic activity is increased or reduced,^{44 45 46 47 48 49} which makes it more likely that MSNA is a better marker of alterations in sympathetic activity than NE, probably because of its greater reproducibility over time.⁵⁰

It is generally believed that in CHF the adrenergic activation has an adverse prognostic significance^{7 8 9 10 11} and that its removal by treatment represents a favorable therapeutic effect.^{12 13 14 15 16 17 19 20} Thus, the demonstration that ACE inhibitor treatment is accompanied by a marked reduction in central sympathetic outflow has clinical implications. At present this demonstration has only been provided for digitalis⁵¹ and, to a very minor extent, for enalaprilat.²¹ In both instances, however, studies were restricted to acute administration, with no evidence as to the chronic persistency of the effect, which is the variable relevant to long-term prognosis.

	Selected Abbreviations and Acronyms

 

Ang II = angiotensin II BP = blood pressure CHF = congestive heart failure CVP = central venous pressure HR = heart rate LVEDD = left ventricular end-diastolic diameter LVEF = left ventricular ejection fraction MAP = mean arterial pressure MSNA = muscle sympathetic nerve activity NE = norepinephrine NP = nitroprusside PE = phenylephrine PRA = plasma renin activity

Received December 16, 1996; revision received March 14, 1997; accepted March 18, 1997.

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