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(Hypertension. 1995;25:1270-1275.)
© 1995 American Heart Association, Inc.

Articles

Modulation of Cardiac Autonomic Control in Humans by Angiotensin II

Jonathan N. Townend; Muzahim Al-Ani; John N. West; William A. Littler; John H. Coote

From the University of Birmingham Departments of Cardiovascular Medicine (J.N.T., J.N.W., W.A.L.) and Physiology (M.A.-A., J.H.C.), Queen Elizabeth Hospital, Edgbaston, Birmingham, UK.

Correspondence to J.N. Townend, Department of Cardiovascular Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK.

	Abstract

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Abstract Angiotensin II (Ang II) exerts an inhibitory action on vagal activity in animals and may also facilitate sympathetic activity. The object of this study was to compare autonomic activity resulting from equivalent steady-state baroreflex activation during intravenous Ang II infusion with that resulting from a control infusion of phenylephrine. Eight healthy subjects aged 22 to 34 years were studied in a single-blind, randomized, prospective crossover study. Autonomic activity was determined by computer analysis of RR interval variability in the time and frequency domains. Despite equal experimental hypertension with Ang II and phenylephrine infusion, at peak infusion rates the mean RR interval was significantly shorter with Ang II (983±179 milliseconds; mean±SD) than with phenylephrine (1265±187 milliseconds, P<.01). The variability of RR intervals was not significantly different, but the variability (median interquartile difference) of RR interval successive differences was significantly lower with Ang II (66 milliseconds) than with phenylephrine (104 milliseconds, P<.02). Power spectral analysis revealed the power of the 0.25-Hz component in normalized units to be significantly smaller during Ang II infusion (20.5±12.7 U) than during phenylephrine (38.2±14.7 U, P<.05), whereas the power of the 0.1-Hz component was significantly greater during Ang II infusion (67.8±17.1 U) than phenylephrine (38.8±20.3 U, P<.05). Measures of vagal modulation of heart rate were significantly attenuated, and sympathetic modulation appeared to be increased during Ang II infusion compared with control phenylephrine infusions. These observations may underlie reports of increased vagal activity during angiotensin-converting enzyme inhibitor therapy.

Key Words: angiotensin II • autonomic nervous system • spectrum analysis • heart rate

	Introduction

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Evidence obtained largely from animal experiments suggests that circulating angiotensin II (Ang II) has important interactions with both limbs of the autonomic nervous system. With the use of direct neural recording techniques, inhibition of both central and peripheral cardiac vagal activities has been described in animal experiments^{1 2} in addition to facilitation of sympathetic tone.³ No such direct evidence is available in healthy humans. However, in disease states such as congestive heart failure, angiotensin-converting enzyme (ACE) inhibitors appear to attenuate the associated elevation of sympathetic tone^{4 5} and may also increase vagal activity.^{6 7} Such actions would be consistent with reduced circulating concentrations of Ang II, but it is difficult to dissociate these effects from the secondary hemodynamic effects of these agents.

To determine the effect of Ang II on autonomic activity in healthy subjects, we used analysis of heart rate variability in both the time and frequency domains during steady-state intravenous infusion of Ang II. Heart rate variability in the time domain reflects modulation of sinus node activity by the autonomic nervous system. Analysis in the frequency domain allows determination of the frequency and power of the component oscillations. To control for the pressor response associated with Ang II and the associated baroreflex activation, we used an equivalent pressor infusion of phenylephrine in each experiment.

	Methods

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Eight male subjects (mean age, 26±8 years; range, 22 to 34 years) were studied in a single-blind crossover study. All subjects were volunteers from staff and students at our institution, all were in good health with no history of cardiovascular or other disease, and all were normotensive (casual supine blood pressure <140/90 mm Hg during an initial screening visit). No subject was taking any medication. The study was approved by the Ethics Committee of the South Birmingham Health Authority.

Subjects were randomly assigned to receive intravenous Ang II or a control infusion of phenylephrine during the first of two studies; the other agent was given during a second study 7 to 14 days later.

Subjects were seated semisupine in a chair, and a venous cannula was inserted into a forearm vein for drug administration. Skin electrodes were applied to the chest wall for electrocardiographic monitoring. The electrocardiographic signal was amplified, processed, and digitized at 125 Hz for each channel with an analog-to-digital convertor board (National Instruments NB/M10/16H/9). R waves were detected by individually adjusted thresholds and a maximum-to-minimum voltage difference within five samples (0.04 second) of greater than 0.5 V. The signal was displayed on the screen of a personal computer (Apple Macintosh IIci running LAB VIEW software, National Instruments), and selected periods were stored on a disk. Blood pressure was continuously monitored from the index finger with the Finapres (Ohmeda 2300) device and from intermittent conventional sphygmomanometry.

After a minimum of 30 minutes of rest to achieve a stable heart rate (mean rate over two 30-second recordings 5 minutes apart varying by <10%), the baseline electrocardiographic recording consisting of at least 512 consecutive RR intervals was made. Ang II or phenylephrine infusion was then begun. Ang II analogue (Hypertensin, CIBA-Geigy Pharmaceuticals) was infused in 5% dextrose at rates of 5 to 20 ng/kg per minute. Phenylephrine was infused at rates of 0.7 to 2.8 ng/kg per minute. Infusion rates were increased incrementally as above until a maximum rise in mean blood pressure of 20 mm Hg was achieved. At each infusion rate, a 10-minute equilibration period was allowed followed by a recording period sufficient to record at least 512 consecutive RR intervals. For each subject, data were recorded during at least three infusion rates for each pressor agent.

The variability of RR intervals has been assessed in a number of different ways. The standard deviation of the values is commonly used, but this value is influenced by intervals at extreme ends of the frequency distribution, necessitating careful examination of the recording to exclude artifact and ectopic activity. We have previously reported the use of the interquartile difference (75th to 25th percentiles) of the frequency distribution of the total number of RR intervals as an index of heart rate variability.⁶ This simple index excludes possible artifactual values at each end of the frequency distribution.

The variability of RR intervals is determined primarily by the degree of sinus arrhythmia, which is primarily a reflection of vagal tone although there are also sympathetic influences.^{8 9 10} The variability of successive differences between RR intervals is thought to be determined almost exclusively by vagal activity.¹¹ Thus, the interquartile difference of the frequency distribution of successive RR interval differences can be used as an index of vagal tone.

In addition to analysis of RR intervals in the time domain, we also analyzed the recordings in the frequency domain to determine the power of the underlying component oscillations. Stationarity of the time series was tested by calculation of the mean and variance of the first and last 256 beats of each recording period to verify a difference of less than 10% in the values for each time series. Power spectral analysis was performed with the use of the Burg algorithm.¹² The model order was chosen by Akaike information criterion.¹³ The autoregressive spectrum characteristically provides three major nonrandom components; a very-low-frequency peak between 0 and 0.03 Hz, a component centered at approximately 0.1 Hz, and a component centered at the respiratory frequency, which is usually in the region of 0.25 Hz. Quantification of the power of each underlying frequency was performed by decomposing the total variability signal applying the method of Zetterberg.¹⁴ Because total power varies greatly among individual subjects, power was expressed in both absolute units and as normalized values. The power in normalized units was calculated by dividing the absolute power of a given component (area under the component curve) by the total variance minus the DC component.

Considerable evidence suggests that the power of the 0.1-Hz component is determined by sympathetic activity with vagal modulation, whereas the 0.25-Hz component corresponds to respiratory sinus arrhythmia and reflects the cardiac vagal activity.^{15 16}

The parameters of RR interval variability were not normally distributed. These data are presented as medians; the significance of differences between groups was determined using the Wilcoxon signed rank test. Paired data for heart rate and blood pressure and data produced by power spectral analysis were normally distributed and compared using Student's t test.

	Results

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Mean blood pressure and RR interval at baseline were not significantly different when subjects received Ang II or phenylephrine (Table 1). At low infusion rates (Table 2), mean blood pressure increased by similar amounts, and there was a trend toward a shorter RR interval during Ang II infusion. The variability of RR intervals was not significantly different, but the variability of successive differences between RR intervals was significantly lower during Ang II infusion. Power spectral analysis using normalized units showed that the power of the respiratory (0.25 Hz) component was significantly lower with Ang II than with phenylephrine; conversely, the power of the 0.1-Hz component was significantly higher with Ang II than with phenylephrine (Table 2).

View this table: [in this window] [in a new window]   Table 1. Baseline Parameters

View this table: [in this window] [in a new window]   Table 2. Parameters During Low-Dose Angiotensin II Infusion and Control Phenylephrine Infusion

At peak infusion rates, although the mean level of induced hypertension was equal with both agents, the pulse interval responses were widely divergent, with significantly less increase in the mean RR interval with Ang II than with phenylephrine (Table 3). This discrepant RR interval response is also illustrated in Fig 1. The shift to the right of the frequency distribution curve of RR intervals is seen to be smaller in response to Ang II than to phenylephrine. The RR interval variability tended to increase more in response to phenylephrine than to Ang II (Fig 1), but the difference in the median interquartile difference of RR intervals was not significant (Table 3). The variability of successive differences between RR intervals was significantly lower during Ang II than during phenylephrine infusion (Table 3 and Fig 3). Power spectral analysis revealed the power of the component centered on 0.25 Hz expressed in both absolute and normalized units to be significantly lower during Ang II infusion than during phenylephrine (Table 2). Once again, the power of the low-frequency 0.1-Hz component expressed in normalized units was significantly smaller during phenylephrine than Ang II infusion (Table 3). An example of power spectra taken from one individual at the peak infusion rates of Ang II and phenylephrine is shown in Fig 3. The power of the 0.25-Hz component was markedly attenuated during Ang II infusion compared with a phenylephrine infusion causing a similar rise in blood pressure.

View this table: [in this window] [in a new window]   Table 3. Parameters During High-Dose Angiotensin II Infusion and Control Phenylephrine Infusion

View larger version (22K): [in this window] [in a new window]   Figure 1. Graphs show frequency distributions of RR intervals recorded from one subject during phenylephrine and angiotensin II infusions. The increase in RR interval variability seen during phenylephrine infusion is attenuated during angiotensin II infusion.

View larger version (13K): [in this window] [in a new window]   Figure 3. Graphs show power spectra from one subject during infusion of angiotensin II and phenylephrine. Although mean blood pressure was similar during each infusion (102 and 104 mm Hg, respectively) the spectra show marked differences. The power of the 0.25-Hz component is markedly lower with angiotensin than with phenylephrine, whereas the power of the 0.1-Hz component is greater with angiotensin II.

The ratio of low-frequency (0.1-Hz) to high-frequency (0.25-Hz) components (in normalized units) was significantly greater with Ang II than with phenylephrine infusion at both low and high drug infusion levels (Tables 2 and 3).

	Discussion

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This study confirms an observation first described in 1969 when transient increases in blood pressure after bolus doses of Ang II were noted to be associated with significantly less baroreflex-mediated bradycardia than equal increases in blood pressure produced by phenylephrine.¹⁷ Subsequently, a similar effect was noted during steady-state infusions of the two pressor agents.¹⁸ The discrepant effects of Ang II and phenylephrine on the baroreflex control of heart rate were ascribed to an increase in sympathetic outflow¹⁷ or inhibition of vagal efferent activity¹⁸ by Ang II although direct evidence for either mechanism was lacking.

The vagus nerve is not accessible to recording techniques in humans, so measurement of cardiac vagal efferent activity is necessarily indirect. Methods of investigating vagal activity have involved measurement of either the increase in heart rate caused by atropine or the magnitude of respiratory sinus arrhythmia.⁸ The latter approach can be performed using analysis of heart rate variability in either the time or frequency domains. As respiratory sinus arrhythmia is the principal determinant of beat-to-beat variability, measurement of the variability of successive intervals between RR intervals provides an index of vagal activity. Analysis of heart rate variability in the frequency domain allows determination of the power and frequency of component oscillations. The amount of respiratory modulation of heart rate can be measured by determining the power of the component that is synchronous with respiration; this usually produces a distinct peak at approximately 0.25 Hz. Neither power spectral analysis nor analysis of heart rate variability in the time domain provides an absolute measure of vagal (or indeed sympathetic) nervous activity. However, these measurements do reflect the degree of neural modulation of heart rate. Assuming that the heart responds normally to neural modulation during the experiment, it seems reasonable to equate the magnitude of neural modulation with neural activity.

The variability of successive differences between RR intervals during experimental hypertension produced by Ang II infusion was significantly less than that resulting from an equal rise in arterial pressure caused by phenylephrine infusion. Similarly, power spectral analysis demonstrated that respiratory modulation of heart rate—the power of the high-frequency 0.25-Hz component—was significantly lower during Ang II infusion than during phenylephrine infusion. These observations would suggest that at least part of the attenuated bradycardia seen during Ang II infusion was caused by inhibition of cardiac parasympathetic activity. In an animal experiment, the increase in directly recorded vagal efferent activity seen with increases in blood pressure produced by phenylephrine or an aortic balloon was absent or severely attenuated when Ang II was used to raise blood pressure.¹ The site of this central inhibition of vagal activity may be the area postrema in the medulla, which is accessible to circulating factors, including Ang II. The integrity of this site appears to be central to the cardiovascular response to intravertebral or intravenous Ang II.^{19 20} In addition, Ang II also reduces the decrease in heart rate seen with peripheral vagal stimulation.² Our results help to confirm that Ang II also inhibits vagal efferent activity in humans, but we were unable to distinguish whether this effect occurred at a central or peripheral level.

The low-frequency 0.1-Hz component of the power spectrum has been used as an index of sympathetic activity at rest although there is undoubtedly also a vagal influence on this oscillation.^{15 16} The power of the 0.1-Hz component during Ang II infusion at both infusion levels was significantly greater than that associated with phenylephrine infusion. Interpretation of this result is difficult because of the dual influences on the 0.1-Hz component, but it may reflect diminished vagal modulation and possibly facilitation of sympathetic nervous activity. However, although sympathetic facilitation by Ang II has been demonstrated in animals,^{3 21} it has been harder to show in humans. Radiolabeled norepinephrine kinetic studies have found no effect of infused Ang II at subpressor doses on sympathetic activity in either healthy subjects²² or patients with chronic heart failure.²³ In a study that used direct neural recording techniques to measure muscle sympathetic activity in humans, no evidence was found to support a facilitatory effect of Ang II when pressor effects were controlled.²⁴ Finally, during equipressor Ang II and phenylephrine infusions, Goldsmith and Hasking²⁵ also showed a clear difference in heart rate responses but no difference in sympathetic activity as reflected in systemic norepinephrine spillover.

Our observations may have important clinical significance. Reduced vagal tone (reflected in reduced heart rate variability and reduced baroreceptor sensitivity) is a potent adverse prognostic indicator in survivors of myocardial infarction^{26 27} and is also a feature of congestive heart failure, a condition associated with a high incidence of sudden death.²⁸ Animal work has shown that vagal stimulation exerts an antiarrhythmic effect by increasing the fibrillatory threshold of ischemic myocardium.²⁹ Treatment with ACE inhibitors appears to increase cardiac parasympathetic activity. A variety of reflex effects, including an absence of reflex tachycardia^{30 31 32} and an increase in baroreflex sensitivity⁷ and heart rate variability⁶ in heart failure, have been reported with ACE inhibitor treatment. The use of ACE inhibitors after myocardial infarction and in heart failure has been shown to reduce total mortality.^{33 34} More specifically, a reduction in sudden (presumed arrhythmic) death has been reported in two studies comparing ACE inhibitors with direct-acting vasodilators in heart failure.^{35 36} We suggest that ACE inhibitors cause an improvement in "sympathovagal balance," which may reduce the incidence of malignant arrhythmias as a direct result of a reduction in circulating Ang II. Further studies will be needed in patients with heart failure to elucidate whether it is this reduction in Ang II or some other effect of ACE inhibitors, such as their action on bradykinin-prostaglandin metabolism, that accounts for their autonomic modulation.

View larger version (24K): [in this window] [in a new window]   Figure 2. Graphs show frequency distributions of successive differences between RR intervals recorded from one subject during phenylephrine and angiotensin II infusions. The increase in RR interval variability differences seen during phenylephrine infusion is severely attenuated during angiotensin II infusion.

	Acknowledgments

 
This study was supported by the British Heart Foundation. The angiotensin II analogue (Hypertensin) was kindly supplied by CIBA Laboratories, UK.

Received August 8, 1994; first decision September 21, 1994; accepted January 18, 1995.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Townend, J. N. Articles by Coote, J. H. Search for Related Content PubMed PubMed Citation Articles by Townend, J. N. Articles by Coote, J. H.