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(Hypertension. 1995;25:1167-1171.)
© 1995 American Heart Association, Inc.

Articles

Influence of Atrial Natriuretic Factor on Spontaneous Baroreflex Sensitivity for Heart Rate in Humans

Gary C. Butler; Beverley L. Senn; John S. Floras

From the Division of Cardiology, Toronto Hospital and Centre for Cardiovascular Research, University of Toronto (Canada).

Correspondence to Dr John S. Floras, Division of Cardiology, Mount Sinai Hospital, Suite 1615, 600 University Ave, Toronto, Ontario M5G 1X5, Canada.

	Abstract

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Abstract Our objective in these experiments was to evaluate the effects of atrial natriuretic factor on the gain of the spontaneous baroreceptor–heart rate reflex in humans. On two separate study days, we gave either atrial natriuretic factor during supine rest (16 nmol over 3 minutes, then 16 pmol/kg per minute) or saline (as vehicle) to nine healthy men (age, 23±1 years; mean±SEM) according to a random, double-blind design. Beat-by-beat RR interval and systolic pressure were recorded noninvasively. Sequences during which systolic pressure and the RR interval of the following beat changed in parallel (either increasing [Up] or decreasing [Down]) over at least three consecutive beats were identified and classified as baroreceptor–heart rate reflex sequences. Regression lines relating RR interval to the preceding systolic pressure were derived for each individual sequence. The mean value of the slopes of these regression lines was calculated to obtain the mean spontaneous baroreflex sensitivity for heart rate for each subject. Saline infusion did not change RR interval, systolic pressure, or number of baroreflex sequences nor the slope of the mean spontaneous baroreflex sensitivity for heart rate or slopes of Up or Down sequences. Atrial natriuretic factor, at a dose that lowers central venous pressure, did not affect systolic pressure, respiratory rate, or the number of baroreflex sequences but reduced RR interval from 952±35 to 930±40 ms (P<.04) and the mean slope of spontaneous baroreflex sensitivity for heart rate from 32.7±4.8 to 23.1±2.8 ms · mm Hg^-1 (P<.04). Baroreflex sensitivity during Up sequences decreased during atrial natriuretic factor infusion, from 32.9±5.5 to 24.2±3.3 ms · mm Hg^-1 (P<.05). The slope of Down sequences did not change (from 27.9±4.2 to 23.0±3.2 ms · mm Hg^-1) compared with baseline values, but when compared with the slope during saline infusion (35.0±5.2 ms · mm Hg^-1), this effect of atrial natriuretic factor on baroreflex sensitivity during Down sequences was significant (P<.05). These data indicate that atrial natriuretic factor reduces the vagal component of the arterial baroreflex control of heart rate in healthy humans. The cardioacceleration observed in humans during atrial natriuretic factor infusion may be in part due to diminished parasympathetic modulation of heart rate.

Key Words: pressoreceptors • blood pressure • heart rate • peptides, atrial natriuretic

	Introduction

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There is now substantial experimental evidence that atrial natriuretic factor (ANF) has neuromodulatory effects that may facilitate its known diuretic and natriuretic actions.^{1 2 3 4 5} However, the therapeutic application of this peptide may be limited by the abrupt and unpredictable onset of paradoxical bradycardia that some subjects have experienced during prolonged ANF infusion.^{6 7 8} The specific influence of ANF on the neural control of heart rate and vascular resistance appears to differ from species to species, and experiments in which baroreceptor reflexes in humans have been perturbed either pharmacologically, by vasoactive drugs, or mechanically, by the application and withdrawal of carotid sinus or lower body negative pressure, have not yielded consistent results.^{1 4 9 10 11} However, these methods are invasive or obtrusive and can be used only on an intermittent basis.¹² Consequently, there has been considerable interest in alternative methods of estimating the sensitivity or gain of baroreceptor–heart rate reflex.

Among the seemingly random variations in heart rate and blood pressure that occur at rest in conscious animals¹³ and humans,^{12 14 15 16 17 18} one can identify by invasive or noninvasive methods sequences of three or more beats in which systolic pressure and pulse intervals change in parallel, either increasing (Up sequences) or decreasing (Down sequences).^{12 16 17 18} Calculation of the slope of the regression equation relating RR interval to the preceding level of systolic pressure during these sequences yields an estimate of the gain of the spontaneous baroreceptor–heart rate reflex (or baroreflex sensitivity, BRS) (in milliseconds per millimeter of mercury [ms · mm Hg^-1]) quantitatively similar to that obtained in response to bolus administration of vasoactive drugs by the ramp method.^{16 17} These brisk sinus node responses to ramp increases and decreases in arterial pressure are mediated by vagal cholinergic activation or withdrawal, respectively,¹⁹ and tend to be greater when blood pressure rises than when it falls.²⁰

Recently, using spectral analysis of heart rate variability, we have documented a reduction in both total power and high-frequency spectral power (absolute units) during ANF infusion.²¹ The implication of this decrease in total spectral power is that ANF reduces spontaneous variations in heart rate in humans. Because power in the high-frequency component of the heart rate variability spectrum was attenuated in these studies, the mechanism responsible for this decreased spontaneous variation would appear to be a reduction in the vagal modulation of heart rate.²² We reasoned that if ANF interfered with the vagal modulation of heart rate, it should attenuate chronotropic responses to ramp increases and decreases in arterial pressure. Therefore, the aim of the present experiment was to test the hypothesis that ANF reduces the spontaneous BRS for heart rate in humans.

	Methods

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Subjects
We studied nine healthy men (age, 23±1 years; mean±SEM). Medical history, physical examination, and laboratory investigations excluded hypertension, concurrent illness, and use of medication. Subjects were nonsmokers; they avoided caffeine on the day of study and alcohol 24 hours before the study. Each subject signed a consent form approved by the Human Subjects Review Committee of the University of Toronto.

Procedures
All studies occurred at the same time of day. Subjects lay supine in a quiet, motionless, and awake, eye-opened state. An intravenous catheter was placed in a left forearm vein for infusions. A finger cuff was placed on the left index finger for continuous noninvasive beat-by-beat recording of blood pressure²³ (Ohmeda 2300 Finapres). Respiratory movements were detected by a pneumobelt coupled to a P23 1D transducer (Gould Inc). Lead II of the electrocardiogram was recorded continuously and inscribed by an ink recorder onto paper, along with mean heart rate, the blood pressure waveform, and breathing frequency.

Protocol
Each subject was studied on 2 separate days and received either human ANF (99-126, IAF Biochem) or vehicle (isotonic saline) allocated at random and in a double-blind manner. After a 15-minute baseline period, ANF was administered as in our previous protocols,^{1 21} first as a bolus of 16 nmol (50 µg) in 10 mL over 3 minutes and then at a rate of 16 pmol/kg per minute (50 ng/kg per minute) at 0.8 mL/min. The principal hemodynamic effects of this dose, which increases plasma concentrations to approximately 160 pmol/L (500 pg/mL),¹ are reductions in central venous pressure and diastolic pressure.¹ Saline was given as a bolus of 10 mL over 3 minutes and then at a rate of 0.8 mL/min.

Calculation of Spontaneous BRS
The analog output of the electrocardiographic meter was discriminated to yield a train of rectangular impulses corresponding to the QRS spikes. The impulse train was processed on a real-time basis with a microcomputer at a sampling frequency of 1000 Hz and stored sequentially for data analysis. Immediately after detecting an R wave, the computer algorithm tracked the pressure channel and identified the systolic and diastolic pressures as the highest and lowest values occurring before the next R wave. Over the last 7 minutes of each baseline period, and from 16 to 23 minutes into the respective infusions, sequences of three or more beats in which the systolic pressure and the RR interval of the immediately following beat changed in the same direction (either increasing [Up] or decreasing [Down]) were identified and classified as baroreflex sequences. As reported by others,^{16 17 18} most of these were three-beat sequences, but some were four-, five-, or six-beat sequences. The direction of each sequence (Up or Down) was identified, and a linear regression, relating RR interval to the systolic pressure of the antecedent cardiac cycle, was derived for each individual sequence. For each time period (baseline or infusion), the mean value of the slope of spontaneous BRS was calculated for each subject, and the number of sequences per minute per subject was also recorded. Sequences were not accepted for analysis if the correlation coefficient between systolic pressure and the subsequent RR interval was less than .85. The number of baroreflex sequences obtained for each subject was expressed as the number of sequences per minute per heart rate. Because of possible hysteresis in blood pressure–heart rate relationships,²⁰ the spontaneous BRS for Up and Down sequences for each subject were determined separately.

Statistical Analysis
Means and their standard errors are reported throughout. A two-way ANOVA was used to test for significant differences between mean baseline or preinfusion values for each subject, as well as values obtained during the respective ANF or saline infusions, and to compare values obtained during the ANF infusion with values obtained during the saline infusion. The Student-Newman-Keuls test was used for post hoc comparison of intervention effects over time against initial values and for comparison of interaction effects. Statistical significance was accepted at a value of P<.05.

	Results

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There were no significant differences in baseline preinfusion values between the ANF or saline day for systolic pressure, respiratory rate, number of baroreflex sequences per minute per heart rate, mean spontaneous BRS, or spontaneous BRS during either Up or Down sequences (Tables 1 through 3). In addition, there were no significant differences in the number of Up or Down sequences per minute per heart rate during the preinfusion baseline (Table 2).

View this table: [in this window] [in a new window]   Table 1. Effects of Atrial Natriuretic Factor and Vehicle Infusions on Systolic and Diastolic Blood Pressures, RR Interval, and Respiratory Rate

View this table: [in this window] [in a new window]   Table 2. Effect of Atrial Natriuretic Factor and Vehicle on Total, Up, or Down Number of Baroreflex Sequences

View this table: [in this window] [in a new window]   Table 3. Effect of Atrial Natriuretic Factor and Vehicle on Spontaneous Baroreflex Sensitivity for Heart Rate

Systolic pressure and respiratory rate did not change during either infusion (Table 1). Saline did not change the mean RR interval (Table 1), whereas ANF infusion decreased mean RR interval from 952±35 to 930±40 ms (P<.04). There was a significant between-group effect of ANF infusion (P<.04) on RR interval: ie, heart rate was greater during ANF infusion than during saline.

Tables 2 and 3 summarize group means of spontaneous baroreflex data obtained during saline and ANF infusions. The number of baroreflex sequences (total, Up, or Down) did not change during either infusion. Mean slopes of the spontaneous BRS for heart rate (BRS) for Up and Down sequences assessed separately and together were stable during the saline infusion. In contrast, ANF lowered the mean BRS slope for all sequences from 32.7±4.8 to 23.1±2.8 ms · mm Hg^-1 (P<.04) (Fig 1). Spontaneous BRS for Up sequences decreased from 32.9±5.5 to 24.2±3.3 ms · mm Hg^-1 (P<.05). There was no change in the baroreflex slope for Down sequences compared with baseline values before ANF infusion (from 27.9±4.2 to 23.0±3.2 ms · mm Hg^-1 [P>.05]) (Fig 2). However, there was a significant ANF-saline interaction for the slope of these Down sequences (F=6.9, P<.05); ie, the slope for Down sequences was significantly shallower during ANF infusion than during saline (35.0±5.2 ms · mm Hg^-1).

View larger version (18K): [in this window] [in a new window]   Figure 1. Plots of Up (broken lines) and Down (solid lines) baroreflex sequences for one subject during supine rest baseline (top) and atrial natriuretic factor infusion (bottom) show the magnitude of spontaneous blood pressure (BP) and heart rate changes during these sequences. The longest line represents the mean slope of the spontaneous baroreflex sensitivity for heart rate in this subject during each condition.

View larger version (9K): [in this window] [in a new window]   Figure 2. Line graph shows mean values of the relationship between change in RR interval and change in systolic blood pressure (SBP) for nine healthy men on the atrial natriuretic factor (ANF) study day. Upper right quadrant illustrates the significant (asterisk) reduction in Up baroreflex sensitivity with ANF (P<.05) (solid line) compared with preinfusion baseline (dotted line). Lower left quadrant depicts Down baroreflex responses for ANF during the preinfusion baseline and ANF infusion time periods.

	Discussion

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In previous experiments in healthy subjects we have shown that ANF has a relative inhibitory effect on sympathetic nerve traffic to muscle¹ and reduces heart rate variability in the frequency domain.²¹ This reduction in total spectral power suggested that ANF attenuates sinoatrial responsiveness to neural input.²⁴ Decreased reflex responsiveness to arterial baroreceptor reflex input could be one mechanism by which prolonged infusion of ANF might predispose some subjects to paradoxical bradycardia, hypotension, and presyncope.^{6 7 8 25 26} There were two components to this reduction: an inhibitory influence of ANF on the sympathetic neural regulation of heart rate (which in and of itself may not be sufficient to account for these reports of paradoxical bradycardia) and a reduction in absolute power in the high-frequency component of the heart rate variability spectrum, which suggested that ANF might also decrease the parasympathetic control of heart rate.²² We designed the present experiment to determine the influence of ANF on the gain of the vagal component of the arterial baroreflex control of heart rate. This was derived noninvasively by relating spontaneous beat-to-beat changes in RR interval to corresponding changes in systolic pressure.¹⁸ Responses to ramp changes in arterial pressure occur too rapidly to be caused by sympathetic neuroeffector mechanisms²⁷ and appear to be mediated entirely by vagal cholinergic mechanisms.¹⁹ In addition, because previous investigations have observed qualitatively different (ie, opposite) effects of ANF on heart rate response to rises and falls in arterial pressure in both rats^{28 29} and humans,^{1 4 9 30} we analyzed separately the effect of ANF on the spontaneous baroreflex for Up and Down sequences.

The spontaneous baroreflex method applied in the present experiments has a number of advantages over other methods for estimating the arterial baroreflex control of heart rate. The neck chamber device, for example, is cumbersome, provokes some anxiety, and requires breath holding by the subject to characterize the slope of the heart rate response and perturbs only one afferent component of the reflex under study.¹⁹ Consequently, any responses to carotid baroreceptor stimulation are countered by the activity of aortic baroreceptor afferents.^{9 19} More importantly, heart rate responses to selective carotid activation and deactivation are less than those observed when both sets of arterial baroreceptors act in concert. For example, Ebert and Cowley⁹ recorded baroreflex slopes of 2 to 4 ms · mm Hg^-1 in healthy subjects compared with resting values of 25 ms · mm Hg^-1 in the present study or slopes of 15 to 40 ms · mm Hg^-1 that would be anticipated from responses to bolus injection of phenylephrine.^{3 4 19 31} Consequently, the neck collar method has less likelihood of detecting a significant influence of potential modulatory interventions in the baroreceptor–heart rate reflex, as might be elicited by ANF, even if these were present.

These limitations may explain why results of previous experiments with the use of invasive or obtrusive methods of testing the arterial baroreflex control of heart rate have been inconsistent. Volpe et al⁴ reported that ANF (50 ng/kg per minute, or approximately 16 pmol/kg per minute) augmented the reflex bradycardic response to phenylephrine and attenuated the tachycardic response to nitroglycerin in young healthy volunteers, but this neural interaction with ANF, similar to that observed in rats,²⁹ was abolished by pretreatment with the angiotensin-converting enzyme inhibitor enalapril. The reflex increase in heart rate elicited by +20 mm Hg neck pressure was also attenuated by ANF (at a lower dose than in this study: 15 to 25 ng/kg per minute, or approximately 5 to 8 pmol/kg per minute), but the peptide did not affect the reflex bradycardic response to -40 mm Hg of neck suction nor the magnitude of spontaneous respiratory sinus arrhythmia.⁹ Moreover, attenuated tachycardia was not observed by Volpe et al, who applied more intense neck pressure (+60 mm Hg) during a higher dose of ANF (approximately 160 pmol/kg followed by 16 pmol/kg per minute).³⁰ Also, in our previous experiments, ANF (at the same dose as in the present study) augmented the reflex increase in heart rate in response to hypotensive lower body negative pressure (-40 mm Hg),¹ an intervention that also lowers central venous pressure.

ANF reduced the magnitude of the vagally mediated heart rate responses to spontaneous rises and falls in arterial pressure. The bradycardic response to rises in blood pressure fell from 32.9±5.4 to 24.3±3.3 ms · mm Hg^-1. Compared with preinfusion baseline, the effect of ANF on the tachycardic response to spontaneous decreases in blood pressure was less striking (from 27.9±4.2 to 23.0±3.2 ms · mm Hg^-1).

Because the principal interaction appeared to be with responses to parasympathetic activation rather than withdrawal, ANF might act on vagal cholinergic neuroeffector mechanisms, ie, by inhibiting the release or postjunctional action of acetylcholine. However, when compared with saline, ANF infusion also reduced the slope of the spontaneous BRS for heart rate in response to falls in blood pressure (P<.05), suggesting an additional, perhaps central, effect of ANF on this reflex. Atchison et al^{28 32 33} have shown that ANF augments the parasympathetic regulation of heart rate in rats through a prejunctional mechanism analogous to ₁ antagonism but has no direct effect on the rate of sinoatrial action potential discharge. Our observations do not establish any evidence for a similar action by ANF in humans. However, the presence of immunoreactive ANF receptors for this peptide in and near brain sites involved in cardiovascular regulation^{34 35 36} provides the opportunity for ANF to influence the neural control of heart rate and vascular resistance via a central effect. For example, in Wistar rats microinjection of exogenous ANF into the caudal nucleus tractus solitarius increases the firing rates of nucleus tractus solitarius neurons,³⁴ reduces arterial blood pressure,³⁴ and blunts the baroreceptor control of heart rate.³⁵

The ANF dose given in the present study increases plasma concentrations beyond the normal physiological range in young adults, to levels observed in healthy elderly subjects and in conditions such as congestive heart failure.^{37 38} However, replication of our previous infusions allows us to interpret our present observations within the framework of the hemodynamic and neuromodulatory effects of ANF documented in previous experiments.^{1 21} Systolic pressure was unaffected, indicating that the ANF dose administered in these experiments did not alter the set point of the arterial baroreflex. In addition, as the mean slopes of chronotropic responses to increases and decreases in arterial blood pressure were similar under both saline and ANF conditions (Fig 2, Table 1), our observations relate to the gain of this reflex across the linear portion of its operating curve. Finally, these effects of ANF, on either heart rate variability or spontaneous BRS, cannot be attributed to changes in breathing frequency, as this variable did not alter.

These observations allow us to conclude that, in addition to inhibiting sympathetic outflow to muscle¹ and the sinoatrial node,²¹ this ANF dose attenuates the spontaneous baroreflex regulation of heart rate by the parasympathetic nervous system. The latter likely contributes to the mild positive chronotropic effects of ANF infusion in humans.^{1 10 11 21}

	Acknowledgments

 
This work was supported by operating grant MT 9721 from the Medical Research Council of Canada. Dr Butler is a Fellow of the Medical Research Council of Canada. Dr Floras is the recipient of a Career Scientist Award from the Ministry of Health of the Province of Ontario.

Received July 8, 1994; first decision November 22, 1994; accepted February 6, 1995.

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