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Cardiopulmonary baroreflex inhibition of sympathetic nerve activity is preserved with age in healthy humans

Hirofumi Tanaka *, Kevin P. Davy * and Douglas R. Seals *¹

MS 8688 Received 3 September 1998; accepted after revision 4 November 1998.

	ABSTRACT

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1. We tested the hypothesis that the ability of the cardiopulmonary baroreflex to produce sympathoinhibition is reduced with age in humans. Eleven young (23 ± 1 years, mean ± s.e.m.) and ten older (64 ± 1) healthy adult males were studied under supine conditions (control) and in response to cardiopulmonary baroreflex stimulation evoked by acute central circulatory hypervolaemia (10 deg head-down tilt). The two groups were normotensive and free of overt cardiovascular disease.

2. Supine baseline (control) levels of efferent muscle sympathetic nerve activity (MSNA) burst frequency were twice as high in the older men (41 ± 2 vs. 21 ± 2 bursts min^-1, P < 0·05). In both groups in response to head-down tilt arterial blood pressure and heart rate were unchanged, peripheral venous pressure (PVP) increased (P < 0·05), MSNA total activity decreased (P < 0·05), antecubital venous plasma noradrenaline concentrations did not change significantly, and forearm blood flow and vascular conductance increased (vascular resistance decreased) (all P < 0·05). The mean absolute MSNA/PVP was similar in the young and older men, although the higher control levels of MSNA in the older men resulted in a smaller percentage MSNA/PVP (P < 0·05). Per PVP, the reduction in forearm vascular resistance was smaller in the older men, but there were no age group differences when expressed as increases in forearm vascular conductance.

3. These results indicate that the ability of the cardiopulmonary baroreflex to inhibit MSNA is well preserved with age in healthy adult humans. As such, these findings are not consistent with the concept that this mechanism plays a role in the age-associated elevation in basal MSNA.

	INTRODUCTION

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Basal (resting) muscle sympathetic nerve activity (MSNA) increases markedly with advancing age, even in healthy humans (Sundlof & Wallin, 1978; Ebert et al. 1992; Ng et al. 1993). The mechanism(s) underlying this age-related elevation in MSNA, however, are unknown. The cardiopulmonary baroreflex exerts a strong tonic inhibitory influence on MSNA in humans (Mark & Mancia, 1983). Thus, it is possible that the age-related elevation in resting levels is associated with a reduction in the ability of the cardiopulmonary baroreflex to suppress MSNA.

Based in part on an earlier finding that the reflex reduction in forearm vascular resistance in response to acute central circulatory hypervolaemia (induced by leg raising) was smaller in older than in young and middle-aged subjects (Cleroux et al. 1989), currently it is believed that cardiopulmonary baroreflex inhibition of SNA is impaired with age in humans. However, these limb vasomotor responses represent only an indirect measure of MSNA. This hypothesis has not been directly tested in humans using intraneural measurements of MSNA during cardiopulmonary baroreflex stimulation. Accordingly, in the present investigation we did so by measuring MSNA via microneurography during supine resting control conditions and in response to 10 deg head-down tilt in healthy young and older adult humans. To confirm previous observations, we also measured limb blood flow and arterial blood pressure, allowing the calculation of limb vascular resistance (and conductance), during these conditions in the same subjects.

	METHODS

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Subjects

Eleven young (23 ± 1 years, mean ± S.E.M.) and ten older (64 ± 1 years) healthy non-obese men participated in the present study. All subjects were normotensive and free from overt cardiovascular disease as assessed from casual blood pressure measurements and a medical history. Older subjects were further evaluated for clinical evidence of cardiopulmonary disease with a physical examination and resting and maximal exercise electrocardiograms. All subjects were non-smokers, and none took medication that could affect autonomic-circulatory function. Prior to participation a verbal and written explanation of the procedures and potential risks was provided. All subjects gave their written informed consent to participate. This study was reviewed and approved by the Human Research Committee of the University of Colorado at Boulder and conforms with the Declaration of Helsinki.

Measurements

All experimental protocols were performed in the morning following a 12 h overnight fast with proper hydration. MSNA, heart rate and arterial blood pressure were measured continuously during 10 min of baseline control and 10 min of 10 deg head-down tilt with subjects positioned supine. Venous blood samples for subsequent determination of plasma noradrenaline were obtained during the last minute of the control and head-down tilt period. Plasma noradrenaline was determined using the single-isotope radioenzymatic technique (Peuler & Johnson, 1977). Recordings of multi-unit MSNA were obtained from the right peroneal nerve using the microneurographic technique (Hagbarth & Vallbo, 1968). The neural activity was amplified, filtered (700-2000 Hz), full-wave rectified and integrated (time constant = 0·1 s) (Nerve Traffic Analyser, model 662c-3, University of Iowa Bioengineering, Iowa City, IA, USA). Neurograms were considered acceptable as recordings of efferent MSNA according to previously published criteria (Wallin, 1988; Ng et al. 1993). MSNA was analysed by a single investigator blinded to subject and condition identity. MSNA was expressed both as bursts of integrated activity per minute (burst frequency) and as total minute activity (arbitrary units) as quantified by computer measurements of area under each burst of neural activity. Heart rate was measured from the lead of an electrocardiogram, which produced the highest R-wave amplitude. Respiratory excursions were measured by a pneumobelt placed around the upper abdomen. Beat-to-beat arterial blood pressure was measured with finger photoplethysmography (Finapres model 2300, Ohmeda, Austell, GA, USA). Forearm blood flow was measured in the right arm using venous occlusion plethysmography (Siggaard-Andersen, 1970).

On a separate day, peripheral venous pressure (PVP), heart rate, and arterial blood pressure were measured continuously during supine baseline control and head-down tilt conditions identical to those of the MSNA recording session. Subjects were in the right lateral decubitus position with the right arm extended downward. PVP (Statham model P23, Gould Instruments, Valley View, OH, USA) was measured using the method of Gauer & Sieker (1956). Under these conditions, changes in PVP recorded from a catheter placed in a large antecubital vein of the dependent arm accurately reflect changes in central venous pressure (r = 0·96) (Gauer & Sieker, 1956). The arterial blood pressure and heart rate responses to head-down tilt were not different during this protocol from that observed in the MSNA protocol. All the analyses were performed by the same investigator, who was blinded to the identity of the subjects.

Percentage body fat was estimated from skinfold measurements using a Lange caliper (Beta Technology, Cambridge, MD, USA) (Jackson & Pollock, 1978). Waist circumference was measured at the umbilicus using a non-elastic tape (Lafayette Instruments, Lafayette, IN, USA) and was used as a measure of abdominal (central) adiposity as described previously (Bonora et al. 1995).

Statistical analysis

Repeated measures analysis of variance (ANOVA) was used to assess the effects for group and time for each dependent variable. In the case of a significant interaction effect, a post hoc test using the Newman-Keuls procedure was used to identify significant differences among mean values. Data on physical characteristics (e.g. age, height) were analysed using a one-way ANOVA. Analysis of covariance (ANCOVA) was used as a complimentary approach to the ratio method for examining possible group differences in the MSNA/PVP response to head-down tilt. Univariate correlations were performed to examine relations of interest. The probability level of statistical significance was set a priori at P < 0·05 in all comparisons. Descriptive statistics were expressed as means ± S.E.M.

	RESULTS

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Subject group characteristics

There was an 40-year age difference between the young and older subjects (P < 0·05) (Table 1). However, no significant differences in height, body mass, or body mass index were observed between the groups. Body fat percentage and waist circumference were greater in the older men (P < 0·01). Although well within the normotensive range, resting brachial artery systolic blood pressure was higher in the older than in the younger men (P < 0·05). The two groups did not differ significantly in resting brachial artery diastolic blood pressure.

Table 1. Subject characteristics

Supine baseline control levels

Finger systolic and pulse pressures were higher in the older subjects (P < 0·05), but mean and diastolic pressures, heart rate, and PVP were not significantly different in the two age groups (Table 2). MSNA burst frequency and total activity were 90-100 % higher in the older men (both P < 0·05), but antecubital venous PNE concentrations were not significantly different across age. Forearm blood flow, vascular resistance and vascular conductance were not significantly different in the two groups.

Table 2. Cardiovascular and sympathetic nervous system data during supine baseline control and in response to 10 deg head-down tilt in the young and older healthy adult men

	Young men (n = 11)			Older men (n = 10)
Variable	Control	HDT		Control	HDT
Systolic BP (mmHg)	117 ± 3	120 ± 3	3 ± 1	130 ± 4	133 ± 4	2 ± 1
Mean BP (mmHg)	84 ± 3	85 ± 3	2 ± 1	89 ± 3	90 ± 2	1 ± 1
Diastolic BP (mmHg)	67 ± 3	68 ± 3	1 ± 1	68 ± 3	69 ± 3	1 ± 1
Pulse pressure (mmHg)	51 ± 2	53 ± 2	2 ± 1	62 ± 4	64 ± 4	2 ± 1
Heart rate (beats min-1)	63 ± 3	62 ± 2	-1 ± 1	58 ± 2	58 ± 2	0 ± 1
PVP (mmHg)	4·1 ± 0·4	5·4 ± 0·5	1·3 ± 0·2*	3·4 ± 0·7	5·8 ± 0·7	2·4 ± 0·3 *
MSNA (bursts min-1)	21 ± 2	18 ± 2	-3 ± 1	41 ± 2	39 ± 2	-3 ± 1
MSNA (U min-1)	1005 ± 186	810 ± 190	-195 ± 56 *	1883 ± 115	1597 ± 120	-286 ± 61 *
PNA (pg ml-1)	375 ± 36	328 ± 34	-47 ± 23	411 ± 58	351 ± 42	-60 ± 39
FBF (ml (100 ml)-1 min-1)	2·6 ± 0·3	3·0 ± 0·4	0·4 ± 0·2 *	3·2 ± 0·4	3·9 ± 0·5	0·7 ± 0·2 *
FVR (U)	32 ± 4	28 ± 3	-4·4 ± 1·3 *	28 ± 4	24 ± 3	-4·7 ± 0·8 *
FVC (U)	0·031 ± 0·004	0·035 ± 0·004	0·004 ± 0·001 *	0·037 ± 0·005	0·044 ± 0·006	0·007 ± 0·001 *

Cardiovascular and MSNA responses to head-down tilt

Arterial blood pressure and heart rate did not change significantly from supine baseline levels in response to head-down tilt in either group (Table 2). PVP increased (P < 0·05) during head-down tilt in both groups; the increase was greater in the older men (P < 0·05). MSNA burst frequency was not significantly changed, but MSNA total activity decreased (P < 0·05) in response to head-down tilt in both groups (P < 0·05). The mean absolute unit decrease in MSNA total activity tended to be greater in the older than in the young subjects, but the differences were not statistically significant (P = 0·2). The mean percentage decrease in MSNA total activity was not significantly different in the young (-20 ± 3) and older (-15 ± 4) subjects. PNE did not change significantly from supine baseline levels in response to head-down tilt in either age group. Forearm blood flow and vascular conductance increased, and vascular resistance decreased (all P < 0·05) in both groups in response to head-down tilt; the increases in blood flow and vascular conductance were greater (P < 0·05) in the older men. The PVP, MSNA and forearm vasomotor responses to head-down tilt were directionally consistent among the individual subjects. Only one individual (an older subject) failed to demonstrate responses directionally consistent with the mean group responses. Exclusion of this subject's data from the analysis did not influence the results.

Cardiopulmonary baroreflex MSNA responsiveness during head-down tilt

Figure 1 illustrates the mean absolute reductions in MSNA per millimetre of mercury increase in PVP during head-down tilt. The mean MSNA/PVP was similar in the young and older men. ANCOVA with PVP as the covariate confirmed that the absolute unit MSNA response to head-down tilt was similar in the two age groups (P = 0·55). Because of their markedly higher baseline level of MSNA, the percentage MSNA/PVP was smaller in the older men (0·36 ± 0·14 vs. 0·83 ± 0·20 %; P < 0·05).

		View larger version [in this window] [in a new window]
Figure 1 Reflex inhibition of muscle sympathetic nerve activity (MSNA; total activity) expressed as a function of changes in the hypervolaemic stimulus (increases in peripheral venous pressure, PVP) in response to 10 deg head-down tilt in young and older healthy adult men. Values are expressed as means ± S.E.M.

Forearm vascular responses to head-down tilt

The forearm vascular resistance (FVR) and conductance (FVC) responses to head-down tilt per millimetre of mercury increase in PVP are presented in Fig. 2. The mean FVR/PVP was smaller (P < 0·05) in the older than in the young subjects (Fig. 2A). However, the mean FVC/PVP was similar in the two age groups (Fig. 2B). ANCOVA with PVP as a covariate confirmed these relations across subject age. The mean values for FVR/MSNA and FVC/MSNA were (arbitrary units) 49 ± 26 and 33 ± 10 (P = 0·61), respectively, in the young men and 36 ± 15 and 51 ± 16 (P = 0·45) in the older men.

		View larger version [in this window] [in a new window]
Figure 2 Reflex reductions in forearm vascular resistance (FVR; A) and increases in forearm vascular conductance (FVC; B) expressed as a function of changes in the hypervolaemic stimulus (increases in peripheral venous pressure; PVP) in response to 10 deg head-down tilt in young and older healthy adult men. Values are expressed as means ± S.E.M. *P < 0·05 vs. young men.

Univariate correlations

The only significant correlation found in the pooled subject population was between adiposity and supine baseline MSNA. Both total body fat (r = 0·48, P < 0·05) and waist circumference (r = 0·49, P < 0·05) were positively related to MSNA burst frequency. Supine baseline levels of MSNA were not significantly related to any of the following indices of cardiopulmonary baroreflex-MSNA inhibitory responsiveness: (a) MSNA/PVP (r = 0·22, P = 0·33); (b) FVR/PVP (r = 0·34, P = 0·12); and (c) FVC/PVP (r = 0·02, P = 0·93).

	DISCUSSION

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The primary new finding of the present study is that the absolute reflex reduction in MSNA in response to acute central circulatory hypervolaemia was similar in young and older adults. Therefore, our results do not support the hypothesis that the ability of the cardiopulmonary baroreflex to inhibit central sympathetic outflow is reduced with age in healthy adult humans. Moreover, our results demonstrate that basal levels of MSNA were not related to any measure of cardiopulmonary baroreflex MSNA inhibitory responsiveness. Although these findings do not directly address the question of whether impaired tonic cardiopulmonary baroreflex sympathoinhibition contributes to age-related elevations in basal MSNA, they certainly do not support such a role.

The present results concerning cardiopulmonary baroreflex inhibition of MSNA are consistent with our recent findings that arterial baroreflex suppression of MSNA is not obviously affected by age in healthy adults (Davy et al. 1998b). Moreover, we recently demonstrated that cardiopulmonary and integrative (cardiopulmonary + arterial) baroreflex control of MSNA during graded central hypovolaemia is, if anything, augmented with age (Davy et al. 1998a). Taken together, the results of these recent investigations by our laboratory support the view that baroreflex regulation of MSNA is well preserved with advancing age in healthy adult humans.

The present findings in humans differ from an earlier report of reduced cardiopulmonary baroreflex suppression of renal SNA with age in beagles (Hajduczok et al. 1991). The differences in the results of the two studies may be due to a number of factors including species differences, and/or the use of anaesthesia, measurement of renal SNA (compared with MSNA), and the method of cardiopulmonary baroreflex stimulation (graded volume expansion) in this previous study in the dog.

It is important to emphasize that our conclusion that cardiopulmonary baroreflex inhibition of MSNA is not impaired with age is based on the reflex reductions in absolute levels of MSNA. Because of the higher baseline (control) MSNA in the older men, expression of the inhibitory responses as percentage change resulted in a smaller reflex adjustment in this age group. Certainly the issue of whether absolute or percentage change is the more appropriate remains open to debate. However, as we have argued previously (Ng et al. 1993; Davy et al. 1998b), we believe that it is the absolute, rather than the percentage, change in MSNA that has the greatest influence on target organ responses and, therefore, is the most physiologically significant expression. The fact that we have shown previously in young and older adult humans that absolute unit changes in MSNA total activity are strongly related to the corresponding changes in plasma noradrenaline concentrations (Seals et al. 1988b), limb vasoconstriction (Seals, 1989), and changes in arterial blood pressure (Victor et al. 1987; Seals et al. 1988a; Seals, 1990) is consistent with this contention. Nevertheless, the reader should carefully consider this issue in the interpretation of the present findings.

Given the fact that the present data do not obviously support a role for reduced cardiopulmonary baroreflex inhibition of MSNA with age, what alternative mechanisms may be involved in the age-associated increases in basal MSNA? Recent reports from our laboratory (Jones et al. 1997a,b) indicate that age-related elevations in whole-body and abdominal adiposity can explain up to 60 % of the variance in basal MSNA with age in healthy adult humans. The relation between body fat and MSNA is observed in both young and older adult populations (Jones et al. 1997b). In the present study, although BMI was not significantly different in the two age groups, both total body fatness and abdominal adiposity were greater in the older subjects and were directly related to baseline levels of MSNA. Preliminary data from our laboratory (Monroe et al. 1998) indicate that circulating concentrations of leptin are related to both adiposity and MSNA. Thus, age-associated elevations in total and abdominal adiposity may be mechanistically linked to increases in MSNA, at least in part, via elevations in leptin levels.

Preliminary data from Dr Murray Esler's laboratory suggest that increased central sympathetic noradrenergic neuronal activity (i.e. increased CNS 'drive') also may play a role in age-related elevations in MSNA. Specifically, healthy older adult males demonstrate higher rates of subcortical noradrenaline spillover than young adult controls (M. Esler & D. Seals, unpublished observations). Esler and colleagues had previously shown that the spillover of noradrenaline from subcortical brain regions is strongly and positively related to basal MSNA in young healthy subjects (r = 0·81) (Lambert et al. 1997) and is elevated in pathophysiological states that are characterized by higher basal MSNA (e.g. hypertension) (Ferrier et al. 1992, 1993). However, data from Fagius et al. (1985) are not consistent with the idea of an increase in central sympathetic drive with age. Specifically, they observed what appeared to be 'maximal' levels of MSNA in two subjects aged 36 and 44 years following temporary blockade of the glossopharyngeal and vagus nerves in the neck (i.e. blockade of both arterial and cardiopulmonary baroreceptor afferents). Thus, these latter observations suggest that unopposed central sympathetic drive is already 'maximal' in young and early middle-aged healthy humans.

In the present study, we confirmed previous observations of a lower FVR/CVP in older than in young adult subjects (Cleroux et al. 1989). However, our neurophysiological data demonstrate that such indirect measures cannot be used as evidence for impaired sympathetic baroreflex inhibition of MSNA with age. Parenthetically, the smaller FVR/PVP in the older subjects may be an artifact of the use of vascular 'resistance' rather than evidence for impaired peripheral vasodilatory responsiveness per se (Lautt, 1989; O'Leary, 1991; D'Almeida & Lautt, 1992). The fact that no age-related differences in forearm vasodilatation in response to head-down tilt were observed when the data were expressed as changes in vascular 'conductance' supports this idea. The latter expression is deemed the more appropriate under conditions in which blood flow is changing more than arterial pressure (Lautt, 1989; O'Leary, 1991; D'Almeida & Lautt, 1992), as is the case during head-down tilt.

We should emphasize that acute perturbations in central blood volume can produce changes in carotid artery haemodynamics and, therefore, possibly the stimulus for the carotid sinus baroreceptors (Pannier et al. 1995; Taylor et al. 1995). Thus, we cannot rule out the possibility that the head-down tilt manoeuvre employed in the present study resulted in carotid sinus baroreflex activation which may have contributed to the reductions in MSNA. We think this unlikely, however, because activation of these arterial baroreceptors would be expected to produce a reflex bradycardia, and no changes in heart rate were observed in response to head-down tilt. Alternatively, it is possible that other reflex inputs to the CNS, e.g. vestibular reflexes (Ray & Hume, 1998), may have been altered during head-down tilt and modulated the MSNA responses.

In conclusion, the present results indicate that the ability of the cardiopulmonary baroreflex to inhibit MSNA is well preserved with age in healthy adult humans. Taken together with our recent findings of robust reflex increases in MSNA in response to non-hypotensive central hypovolaemia in older adults (Davy et al. 1998), these experimental observations do not support the idea that reduced tonic cardiopulmonary baroreflex suppression is an important mechanism in the age-related elevation in basal MSNA.

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Acknowledgements

This work was supported by National Institute of Health RO1 grants HL-39966, AG-06537 and AG-13038 (D. R. S.), F32 grants AG-05717 (H. T.) and AG-08834 (K. P. D.), and KO1 grants AG-00847 (H. T.) and AG-00687 (K. P. D.). We gratefully acknowledge the technical assistance of David Johnson, MD, for the determination of plasma noradrenaline concentrations, and Mary Jo Reiling.

Corresponding author

H. Tanaka: Department of Kinesiology and Applied Physiology, University of Colorado at Boulder, Campus Box 354, Boulder, CO 80309-0354, USA.

Email: tanakah{at}colorado.edu

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