Journal of the Autonomic Nervous System, 11 (1984) 115-124 115 Elsevier

JAN 00379

Arterial baroreceptor control of blood pressure in man

G i u s e p p e Manc ia , G u i d o Grass i , G i o v a n n i Bertinieri , A l b e r t o Fer ra r i and A l b e r t o Zanche t t i

lstituto di Clinica Medica IV, Universiti~ di Milano and Centro di Fisiologia Clinica e Ipertensione, Ospedale Maggtore, Milano (Italy)

(Received May 10th, 1984) (Accepted May 20th, 1984)

Key words: aortic baroreceptors - carotid baroreceptors - heart rate - ageing - blood pressure variability - hypertension

Abstract

Information on arterial baroreceptor control of circulation is much more re- stricted in man than in animals, largely because of the limitations in the techniques available in humans for this type of study. However, recent utilization of the neck chamber technique that addresses the primary function of an arterial baroreflex, i.e. blood pressure control, has provided a significant amount of information. This paper describes baroreceptor control of blood pressure as derived from neck chamber studies in normal people and discusses its modifications by exercise and ageing, and its participation in a phenomenon such as spontaneous blood pressure variability. The description given here is focused on aspects of this baroreceptor control that have changed the concept of the overall arterial baroreceptor function developed by means of techniques for studying only baroreceptor influences on heart rate.

Introduction

Since the discovery of the aortic nerves by de Cyon and Ludwig [5] and of the carotid sinus nerves by Hering [11], the control of circulation exerted by the arterial

Correspondence: G. Mancia, Clinica Medica IV, Policlinico, Via F. Sforza 35, 20122 Milano, Italy.

0165-1838/84/$03.00 © 1984 Elsevier Science Publishers B.V.

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baroreceptors has been one of the major fields pursued in cardiovascular research. Studies performed in both anesthetized and unanesthetized animals have shown

that (1) this control is vital for insuring blood pressure homeostasis in daily life, (2) it involves to an important degree baroreceptors located in the carotid, aortic and subclavian portion of the arterial tree, (3) it is not similar for these different reflexogenic areas nor does it similarly involve all cardiovascular targets and (4) it is altered in a complex fashion during development of several cardiovascular diseases, the alterations being also different according to the different reflex involved [7,13].

Information on arterial baroreceptor control of circulation is much more re- stricted in man, largely because of the limitations in the techniques available for this type of study. Techniques such as carotid sinus massage or carotid sinus nerve electrical ~timulation and anesthesia cannot quantify the stimulus applied to the baroreceptor afferent fibers, or quantify it by means of grossly invasive procedures that pose ethical problems [24]. However, other techniques have also drawbacks that range from the inability to limit the stimulus exclusively to the arterial baroreceptors (the Valsalva manoeuver) to the assessment of their influences only on the heart or on few vascular districts (the vaso-active drugs technique, the lower body suction) with no evaluation of the overall function of the arterial baroreflex, i.e. blood pressure control [24].

Presently, the only technique that permits study of blood pressure control exerted by arterial baroreceptors, is the variable pressure neck chamber, by means of which the increases and reductions in arterial blood pressure that accompany quantifiable stimulations and deactivations of carotid baroreceptors can be easily studied [17,21,22]. This technique has provided a considerable number of new data, some of which have altered the former concept of the overall arterial baroreflex function in normal and abnormal conditions.

This paper will focus on these data, and discuss them in the light of the differences from the results obtained by other techniques.

Non-linear properties of the carotid baroreceptor control of blood pressure By use of the neck chamber, Thron et al. [34] first observed that the blood

pressure fall that accompanied carotid baroreceptor stimulation was less than the blood pressure rise that accompanied carotid baroreceptor deactivation below the level of activity tonically determined by the existing blood pressure. This was confirmed by Stegemann et al. [32] and more recently by us. Fig. 1, which is taken from a study we made in 11 normotensive subjects [21], shows the mean arterial pressure rises and falls that occurred in response to application of positive and negative neck chamber pressures which reduced and increased, respectively, carotid transmural pressure. The slope of the rise in mean arterial pressure that was observed when carotid transmural pressure was reduced, was greater than the slope of the mean arterial pressure fall that was observed when carotid transmural pressure was increased. The difference between the two reflex responses was not only statistically significant in the group as a whole, but also in nearly all individual subjects.

To explain such difference in magnitude between the blood pressure responses to

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ca ro t id ba ro recep to r s t imula t ion and deact iva t ion , several possibi l i t ies were consid- ered. One, it was thought that this a symmet ry might d e p e n d on an a symmet ry in the ca ro t id ba ro recep to r engagement by the posi t ive and negat ive neck c ha mbe r pres- sures. This poss ib i l i ty was ruled out by measur ing pressure t ransmiss ion th rough the neck tissues and calcula t ing the magn i tude of the neck chamber - induced posi t ive and negat ive pressure changes outs ide the caro t id sinuses ra ther than outs ide the neck [17]. Two, it was thought that the posi t ive neck chamber pressure might s t imula te caro t id chemorecep to r s or cause t rans ient cerebra l i schemia by increas ing neck venous pressure and reducing b lood flow through the caro t id bodies or the bra in . Tiffs was also ruled out by observing that (1) prevent ion of caro t id ba ro recep- tor s t imula t ion by pure oxygen b rea th ing d id not reduce the neck chamber - induced b lood pressure rise and (2) dur ing the posi t ive neck chamber appl ica t ion , venous b lood f rom the b ra in d id not show any oxygen desa tu ra t ion as c o m p a r e d to the cont ro l condi t ion . F ina l ly , it was argued that the a symmet ry in the b lood pressure responses could or ig inate from a greater buffer ing ac t ion of the aor t ic ba ro recep to r s on the b lood pressure falls as c o m p a r e d to the b lood pressure rises induced by the ca ro t id barorecep tors . This poss ib i l i ty could not be exper imenta l ly cont ro l led as there is no me thod in man to d i rec t ly s tudy reflexes s t emming selectively f rom the aor t ic ref lexogenic areas. However , there are repor ts that at no rma l b lood pressure, aor t ic ba ro recep to r s do not exert a subs tan t ia l b lood pressure inf luence in man [10] and, that in animals , bo th their mye l ina ted and non-mye l ina ted c o m p o n e n t is usal ly ba re ly at threshold [26,33]. This should favour their buffer ing ac t ion on b lood

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Fig. 1. Changes in mean arterial pressure induced by changes in carotid transmurat pressure in 11 normotensive subjects. Data are means :i: S.E. of individual regression coefficients relating the carotid transmural pressure alterations to the late or steady-state mean arterial pressure responses. Alterations in carotid transmural pressure were calculated by the algebraic sum of the mean arterial pressure and the positive and negative pressure changes induced by a neck chamber device outside the carotid sinuses (from Mancia et al. [21], redrawn from Circulation Research, by permission).

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pressure rises and oppose rather than originate the asymmetry observed with the neck chamber studies.

The most likely explanation is therefore that the asymmetric blood pressure responses to carotid baroreceptor stimulation and deactivation depend on the inherent properties of the carotid baroreflex, namely on the location of its set-point towards the saturation limit of the curve relating the carotid baroreceptor stimulus to the blood pressure effect. Although this eccentrical set-point may depend on several mechanisms, it is possible that one factor responsible is a high basal activity of the carotid sinus mechanoreceptors because of their sensitivity to pulsatile as well as mean blood pressure stimuli [2] and of their location in a thin, elastic and distensible vascular wall [27]. Regardless of the mechanism, however, this set-point should make the carotid baroreflex system of normal human beings physiologically more effective for buffering a reduction rather than an increase in blood pressure.

A discussion of the normal set-point of the human carotid baroreflex must include the results of Eckberg [6], who has observed in normotensive subjects large bradycardic and slight tachycardic responses to neck chamber-induced carotid baroreceptor stimulation and deactivation respectively. It is difficult to reconcile our conclusions with these observations, which suggest that the normal set-point position does not approach the reflex saturation but rather the reflex threshold. However, such position does not account for the large pressor and tachycardic responses that have been reported in normotensive man following anesthesia of the carotid sinus nerves (Fig. 2, Ref. 12), and occlusion of the common carotid arteries (Fig. 3, Ref. 29). These studies suggest that carotid baroreceptors have a large tonic influence on both blood pressure and heart rate, and that therefore the set-point of this reflex is normally well above threshold.

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The carotid baroreflex during exercise and ageing The arterial baroreceptor control of heart rate has been studied under a variety of

behaviors and found to be often increased and reduced as compared to that measured at rest [3,4,31]. Fig. 4 shows the bradycardia induced by an arterial baroreceptor s t imulat ion obta ined through an i.v. bolus of phenylephr ine injected at rest and dur ing dynamic exercise [3]. The slope, relating the magni tude of the R - R

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lengthening to the phenylephrine-induced blood pressure rise became progressively less and finally reached zero as the exercise intensity progressed indicating that this behavior markedly impaired the sensitivity of the baroreceptor-heart rate control.

Reductions in this control have been observed not only during behaviors that depart from rest, but also during a physiological event, such as ageing [9,14]. Fig. 5 shows the results of a study performed by Gribbin et al. [9] on a large number of normotensive and hypertensive subjects whose age ranged from 20 to 60 years. In both cases, the sensitivity of the arterial baroreceptor-heart rate reflex (measured by the same technique employed by Bristow et al. [3]), was maximal and minimal in the 20- and in the 60-year old subjects, respectively, with a steady reduction of about 10% every 10 years. These findings highlight the fact that, in each subject, the effectiveness of reflex homeostatic mechanisms undergo large short- and long-term variations. Thus, this function (as any biological function) must not be represented by a single but rather by a spectrum of values.

Without challenging the truth of the previously mentioned concept, it must be emphasized that studies employing the neck chamber technique have found the carotid baroreceptor-blood pressure reflex to be much less variable over short-term and long-term time bases. Fig. 6 shows the results we obtained by studying the bradycardic and the hypotensive response to carotid baroreceptor stimulation at rest and during an isometric exercise (hand-grip) in a population of 19 essential hyper- tensive subjects [23]. In line with the data described previously, during exercise, the lengthening in R - R interval, induced by the baroreceptor stimulation, was markedly reduced as compared to that obtained at rest. Calculation of the reflex response as heart rate rather than R - R interval, also showed a reduction during exercise. In contrast, the hypotensive response to baroreceptor stimulation was similar at rest

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and during exercise, this being the case either in a mild normotensive (n = 10) and a more severe hypertensive ( n - - 9 ) group separately analyzed. Similar findings had been reported in an earlier study limited to normotensive people [16]. This leaves no doubt upon the fact that the exercise-induced impairment of arterial baroreflexes may be largely limited to their heart rate component , the ability of this mechanism to control blood pressure being substantially preserved in this condition.

In our experience this appears to be the case also as far as ageing is concerned. Fig. 7 shows the pressor and the depressor responses to neck chamber- induced carotid baroreceptor deactivation and stimulation in 4 groups of subjects with similar blood pressure values but progressively increasing age. When the pressor response was calculated early (i.e. within 15 s) after the alteration in the barorecep- tor stimulus, its magni tude was indeed progressively less with the increasing age. However, when the pressor response was calculated during the late or steady-state phase of the stimulus alteration, its magni tude was not significantly affected by the age factor. This was the case also for both the early and the late or steady-state depressor responses to baroreceptor stimulation. Thus, ageing impairs the speed of the baroreceptor-dependent blood pressure homeostasis against hypotensive dis- turbances, which may account for the larger prevalence of orthostatic hypotension in elderly people. This condition, however, does not reduce other baroreceptor in- fluences on blood pressure, for example those which help blood pressure homeosta- sis against pressor disturbances. This is in contrast with the overall reduct ion of baroreceptor-heart rate control that has been described with ageing.

Does the contrast between preservation of ba ro recep to r -b lood pressure control extend to other condit ions? In addit ion to exercise and age, also pr imary and secondary hypertension are associated with a clearcut reduction of arterial barore-

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ceptor influences on heart rate [30]; those on blood pressure and vasomotor targets being largely unaffected [1,19,20,22,24,28,35]. However, no information is available on the baroreceptor-blood pressure reflex in other physiological and pathophysio- logical conditions which are associated with a reduction (mental stress, anesthesia, heart disease) or an enhancement (sleep) of the baroreceptor-heart rate reflex. No information is also available on the mechanisms responsible for the difference in the attenuation of these two components of the baroreflex. During ageing, these phe- nomena might reflect an impairment of the effector responses to neural stimuli (reduction in number and sensitivity of sympathetic and vagal receptors) mainly limited to the heart [15]. During exercise (and possibly during hypertension), however, it may reflect engagement of hypothalamic or other central influences which selectively reduce the sensitivity of the vagal but not of sympathetic baroreflex modulation [25]. Knowledge of this issue might lead to understanding of key mechanisms in cardiovascular control under normal and abnormal conditions.

Blood pressure variability and arterial baroreflexes The participation of arterial baroreflexes in blood pressure control has so far been

inferred by studies and tests designed and performed within the laboratory environ- ment. However, the ability to measure intra-arterial blood pressure in ambulant subjects has recently opened a new important approach to this field of investigation. We have employed this approach to determine whether arterial baroreflexes in

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MAP responses after 90-120 s after the NTP change (from Mancia et al. [20]. by permission).

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normal human life have the stabilizing effect on blood pressure that has been inferred by countless laboratory evidence. To this aim, we recorded intra-arterial blood pressure in 62 subjects (Oxford technique, [8]) and analyzed the blood pressure trace beat-to-beat by a computer which provided a series of standard deviations reflecting different blood pressure variabilities (variability during day-time, variability during night sleep, ' short- term' or within half hours variability, ' long-term' or among half hours variability, [18]). In the same subjects, arterial baroreceptor control of heart rate was assessed by the vasoactive drug techniques (phenylephrine and trinitroglycerine, i.v. boluses) and carotid baroreceptor control of blood pressure by the neck chamber technique. Correlations between mean arterial pressure varia- bilities and baroreflex sensitivity were usually statistically significant, with r-values ranging from 0.35 to 0.49; the correlation coefficients always showing a negative value. This indicated that, in our population, a greater baroreflex sensitivity was accompanied by a tendency of blood pressure to show smaller spontaneous varia- tions, and that this was the case regardless of their occurrence during the awake or the sleep time.

These results suggest that baroreflexes do exert an anti-oscillatory effect on blood pressure in humans. It should be emphasized, however, that the r-values, though statistically significant, were low enough to indicate that other factors are im- portantly involved in determining the size of human blood pressure variabilities. According to our data, these factors should consist of influences originating within the central nervous system and acting consensually on the heart and the peripheral circulation [18].

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