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Clinical Science (1992) 83, 535-s-iO (Printed in Great Britain) 535 Carotid arterial haemodynamics after mild degrees of lower-body negative pressure in man P. J. LACOLLEY, B. M. PANNIER, M. A. SLAMA, J. L. CUCHE, A. P. G. HOEKS, S. LAURENT, G. M. LONDON and M. E. SAFAR Department of Internal Medicine, Hypertension Research Centre and INSERM (U 337), 8roussais Hospital, Paris, France (Received 3 Februaryj26 May 1992; accepted 16 June 1992) 1. Pulsatile changes in the diamettlr of the common carotid artery were studied transcutaneously using an echo-tracking technique in 15 normal subjects: eight subjects b,fote and during application of graded lower-bodyntlgative prtlSsurefrom - 5 to -15 mmHg, and seven subjects before and during weightbearing hea.d-up tilt at 30 and 60 degrees. 2. In concomitant studies of changes. in forearm vascular resistance, it was seen that mild lower-body negative pressure produced deactivathm of cardiopulmonary receptors without changes in systemic blood pressure or heart rate. 3. After lower-body negative pressure, a significant decrease in carotid arterial diastolic diameter [from 0.662tO.028 to 0.624tO.033cm (lower-body negative prtlSsure -10mmHg) and 0.640t 0.030em lowerbody negative pressure -15 mmHg), P< 0.001 and < 0.05] was obstlrvoo. 4. After head-up tilt, carotid arterial diameter was also significantly decreased at 30 and 60 degrees, where.as a significa.nt increase il1 heart rate occll....ed only at 60 degrees and mean blood pressure did not change. 5. 'the study provides evidenee that the geometry of the arterial wall is substantially modified by noninvasivemanoeuvrtlS such ashtlad-up tilting .and lower-body ntlgative pressure. The latttlr is assumed to selectively deactivate human cardiopulmonary recepto.rs, but the present data suggest that local chapges may also intlutlnctl carotid baroreceptors. INTRODUCTION Lower-body negative pressure (LBNP) is widely used to study the role of cardiopulmonary receptors in the low-pressure system in humans [1-3]. Graded LBNP from -5 to -20mmHg produces a progressive decrease in central blood volume and central venous pressure and an increase in forearm vascular resistance in the absence of significant changes in systemic blood pressure (BP) and heart rate. In this situation, it is considered that there is no activation of baroreeeptors in the high-pressure system. However, with LBNP exceeding -20mmHg, the heart rate increases and BP tends to decrease, indicating that this degree of LBNP inhibits both cardiopulmonary and arterial baroreeeptors.. Finally, the basic premise is thought to be that a change in systemic BPis the principal stimulus producing stretch in arterial baroreoeptors, Many experimental studies on high-pressure system baroreeeptors have shown that the reflex stimulus is the deformation of the arterial wall rather than the level of BP [1-3]. With the application of LBNP, only changes in systemic BPplay a part in the activation of baroreceptors, assuming a passive response of the carotid artery to changes in the BP distending the vessel. However, recent studies in man have Shown that these arteries do not simply behave passively [4, 5], but, rather,respond actively to neurohumoral stimuli, in particular to those arising from baroreceptors in the low- and the high-pressure systems [5]. In this regard, Ultrasonic echo-tracking techniques have been developed in the last few years for the transcutaneous evaluation of the geometry of large arterial vessels [6-10]. The most suitable artery for investigation is the common carotid artery, a superficial and straight large artery, in which it is possible to satisfactorily evaluate deformation of the arterial wall, very close to the carotid baroreceptors [6-lOJ. The purpose of the present study was to determine changes in carotid arterial diameter after LBNP and head-up tilting, two manoeuvres which cause changes in the activation of mechanoreceptors in the low-pressure system. METHODS Subjects Fifteen normal male subjects Were included in the study. They were aged between 22 and 39 years. Their mean age was 29 ± 7 years (± SD) and their height and weight Were respectively 173± 7emand 65±7 kg. BPwas measured with a mercury key W!lrds: baroreflex mechanisms. common carotid artery, echo-tracking techniques, lower-body negative pressure•. tilting. Abbreviations: BP, blood pressure, LBNP, lower-body negative pressure. C!ltrespondence: Professor Michel Safar. Medecine Interne (M I), Hopital Broussais, 96 rue Didot, 75014 Paris. France. 536 P. J. Lacolley et al. sphygmomanometer with the subjects in the supine position after 15min of rest. The BP was measured on 3 separate days before the haemodynamic study. The systolic BP was consistently less than 140mmHg and the diastolic BP was less than 90 mmHg. Cardiovascular status (on physical examination), chest X-ray and electrokymograph were normal in all subjects. The sodium intake was taken to be between 60 and 120mmo1/24h, as measured by 24h excretion. The study was approved by the CNES (Centre National &Etudes Spatiales, Paris) and by the Ethics Committee of INSERM (Institut National de la Santk et de la Recherche Mtdicale, Paris). All subjects freely consented to the investigation after a detailed description of the procedure had been given. Subject familiarization included tours of the laboratory and Clinical Research Centre before entry into the study. The haemodynamic study was performed during 1 day of hospitalization in a room with a controlled temperature (21°C). The investigation began at 08.00 hours after a standard breakfast, with the subject in the supine position. Mean, systolic and diastolic BPs and heart rate were measured automatically in the left arm every 2min during each period of the investigation, with a Dinamap Type 845 oscillometric BP recorder [S]. After 20min rest in the supine position, haemodynamic determinations were performed up to 10.30 hours. Forearm and carotid haemodynamic responses were studied before and after the following two different manoeuvres: in eight subjects, application of LBNP, and in seven subjects the effect of head-up tilting from the supine position. Samples for the determination of plasma catecholamine and dopamine levels were taken before and after the application of LBNP and were analysed as described by Cuche et al. [ll]. A small catheter was inserted into an antecubital vein at 08.00 hours, about 30 min before the first blood sample was taken. Determination of forearm haemodynamics Forearm blood flow was determined in the supine position by venous occlusion plethysmography using a mercury strain gauge plethysmograph as described previously [123. The forearm was placed in 90" adduction, 5-10cm above the heart level. An adjustable arm rest ensured that the forearm remained in the same position relative to the heart. A mercury strain gauge was applied to the arm 6cm distal to the lateral epicondyle of the humerus and was then calibrated. The position of the gauge was marked with a reference mark. A pneumatic cuff was placed around the arm for venous occlusion. For the determination of blood flow, wrist occlusion was used and venous occlusion was achieved by cuff inflation to 50mmHg at a constant rate of 5 mmHg/s. Several consecutive flow curves were recorded every 30s, the mean value being taken as characteristic for each subject. Forearm vascular 0.0 J, 0 I 1 3 4 5 Time (s) Fig. 1. Example of the displacement waveform of the anterior and posterior walls of the common carotid artery. The lower part represents the pulsatile change at each beat (6). resistance was calculated as the ratio of mean arterial BP to forearm blood flow. Reproducibility and normal values for forearm vascular resistance have been published in detail elsewhere [l2]. Carotid arterial parameters Wall movement of the right common carotid artery was measured using an original pulsed ultrasound echo-tracking system based on the principle of Doppler shift. Two conditions were studied before and during application of LBNP, and before and during a tilt test. The details of the method have been given elsewhere [7]. Briefly, this transcutaneous method allows the assessment of the displacement of arterial walls during the cardiac cycle and, hence, time-dependent changes in arterial diameter relative to initial diameter at the start of the cardiac cycle. Based on the two-dimensional B-mode image, a M-line perpendicular to the artery was selected exactly lcm below the carotid bifurcation. The radio-frequency signal of 4-8 cardiac cycles was recorded, digitized and temporarily stored in the computer memory. Two sample volumes, selected under cursor control, were positioned on the anterior and posterior arterial walls. To avoid the possibility that nearby structures producing prominent echoes might temporarily encroach on the selected sample volumes, thus obscuring the vessel wall signal, a system was developed which allowed the sample volumes to track the vessel walls. The displacement of the arterial wall was then determined by processing the Doppler signals originating from the two selected sample volumes. This procedure gives high spatial resolution ( < 30 pm for internal diameter and l p m for pulsatile change). A typical displacement waveform of the anterior and posterior walls of the common carotid artery is shown in Fig. 1: the five successive values of the stroke change in diameter during systole (D,-Dd), the end-diastolic diameter (Dd) and the relative stroke change in diameter [(D,- Dd)/Dd] were computed from the recording; however, only mean Carotid haemdynamics afrer lower-body negative pressure 0.9 1 I 10 I 1 1 1 I 20 30 40 50 60 Time (min) Fig.2. Carotid arterial diastolic diameter (D,,) during a Mmin observation period in five subjects. Measurements were made by the 537 level of the antero-superior iliac crests. After a rest period of 15min, the baseline recording was performed. The pressure within the box was then reduced to levels of -5, -10 and -15mmHg by using a domestic vacuum cleaner. These three levels of negative pressure are known to not affect BP or heart rate and therefore to ‘selectively’ deactivate cardiopulmonary receptors, whereas a greater negative pressure (-40mmHg) is known to reduce systemic BP and to involve arterial baroreceptors in the reflex response [l]. Each stimulus of - 5 , -10 and -15mmHg was maintained for 5min in a stepwise fashion. BP, heart rate, carotid arterial parameters, forearm blood flow and vascular resistance were measured before and during each - 5 , - 10 and - 15mmHg stimulus. Arterial parameters were measured at the third minute. Blood sampling was carried out before LBNP and at the end of the - 15mmHg stimulus period. same observer. Response to tilt test values were considered for the purposes of the present study. The side on which measurements were made did not influence the arterial dimensions. Indeed, in 17 other normotensive subjects (not included in the present study), no significant difference was observed between measurements performed on the left and the right common carotid artery C7.0f1.0 versus 7.0 f0.8 mm, 0.45 f 0.12 versus 0.44 f0.09 mm and 6.6f2.2 versus 6.4f 1.5% for D,, D,-D, and (D,-Dd)/Dd, respectively]. Thus all arterial dimensional data given in the present study were from the right common carotid artery. The reproducibility of the method was studied in five normotensive subjects. The coefficient of variation (SD expressed as a percentage of the mean of several successive measurements) was used for this purpose. Reproducibility was first assessed during the recording of 4-8 successive cardiac cycles. The mean coefficient of variation determined under these conditions was 1f0.6 and 6+2% for Dd and D,-D,, respectively. Secondly, reproducibility was assessed during 12 measurements performed by each of two observers during a 90min period in the same five subjects. Under these conditions, the mean intra-observer coefficient of variation was 3 f 1 (Fig. 2) and 8 f1% for D , and D,- D,, respectively. The inter-observer reproducibility was 5 f 2 and 9 f 2% for D , and D, -D,, respectively. The reproducibility of all these parameters has been published in detail elsewhere [13]. Response to LBNP To achieve deactivation of cardiopulmonary receptors, the eight subjects were placed in the ne position, with their legs and lower abdomen osed in a polyvinyl chloride box sealed at the In seven subjects, BP, heart rate and carotid parameters were measured with the subject in the supine position and during 3 and 5min of 30 and 60 degrees, weight-bearing, head-up tilt. Particular care was taken to ensure accurate BP determinations by keeping the subject’s arm exten that the pressure device and tubing were con at atrial level. All tilt tests were performed at least twice with a 5min interval between tests. The first tilt was performed to provide a period of familiarization before the second tilt, during which the determinations were made. The BP response to the first tilt was not significantly different from that observed in response to the second tilt. Statistical evaluation [141 Results were expressed as means f SD. A two-way repeated analysis of variance test was performed on the haemodynamic changes after LBNP. A P value of less than 0.05 was considered significant. RESULTS Table 1 shows that there was no significant change in heart rate, mean arterial, systolic and diastolic BP and consequently pulse pressure during LBNP. Forearm vascular resistance increased significantly (P<O.Ol). During LBNP, carotid arterial diastolic diameter decreased significantly (P<0.01) (Fig. 3). The percentage change in pulsatile diameter was unaltered. No significant correlation was observed between the changes in forearm vascular resistance or between BP and the changes in carotid arterial diastolic diameter. Plasma catecholamine and dopamine levels did not change after LBNP at - 15mmHg. Adrenaline, noradrenaline and dopamine levels were, respecti- P. J. Lacolley et al. 538 Table 1. Haemodynamic changes after LBNP. Values are means fSD. Statistical significance: *P <O.OS, **P <0.01, ***P <0.001 versus baseline. Abbreviations: SABP, systolic arterial B P DABP, diastolic arterial B P MABP, mean arterial B P HR, heart rate; FBF, forearm blood flow; FR, forearm vascular resistance; D, carotid arterial diastolic diameter; D,, carotid relative stroke change in diameter; NS. not significant. Baseline 116+9 65f7 82+7 62+8 7.62+ 3.05 12.8f6.2 0.662f0.028 8.48f2.3I SABP (mmHg) DABP (mmHg) MABP (mmHg) HR (beatslmin) FBF (ml min-1 IW-lml) FR (mmHg ml-lmin 100-lml) D (cml D, (%I ** 0.70 F value LBNP - IOmmHg -5mmHg 113k9 62f 19 80f9 62f9 5.25 f2.52*** 18.2f lo*** 0.638 0.028* 8.39 f3.06 + I14+ 10 64+10 78+ 10 63+9 5.22 f2.33*** 19*OfII** 0.624 f0.033*** 8.25 f 2.06 - 15mmHg I12f I2 61+10 79f I2 64f 10 4.78 I.64*** 20.5f 10.6*** 0.640 0.030* 8.21 2.43 + + + NS NS NS NS 0.00I 0.001 0.01 NS x E 3 8 Y L .-5 0.65 W .s s 4 0.70 .5 = ._ -u 0.65 - c- .-R ",0.60 - U 0 s Y 0.60 L s E 0.55 - E Y K g Y U 0.55 Baseline -5mmHg " 0.50 4 -1OmmHg Baseline -1SmmHg J Y Fig. 3. Carotid arterial diastolic diameter after LBNP in eight subjects. The heavy line and bars represent mean values. Statistical significance: *P<0.05, **P <0.001 compared with baseline. Table 2 Haemodynamic changes after tilting. Values are means+so. Statistical significance: *P<0.05, **P<O.OI, ***P<O.001 versus baseline. Abbreviations: SABP, systolic arterial BP; DABP. diastolic arterial BP; MABP, mean arterial B P HR, heart rate; D, carotid arterial diastolic diameter; D,, carotid relative stroke change in diameter; NS, not significant. Tilting 30 degrees SABP (mmHg) DABP (mmHg) MABP (mmHg) HR (beatslmin) D (cm) D" (%) 120+8 68+5 85+5 62+6 0.664k0.033 8.03 2.02 + 118+7 69k6 86+5 62+5 0.631 L-0.042 7.61 1.56 + F value 60 denrees 118+7 ' 30 degrees 60 degrees Tilting LBNP Baseline - 70+7 86+7 69+3 0.624+0.053 7.29f 1.64 NS NS NS <0.002 <0.01 NS vely, 45 +40, 164+ 55 and 33 f45 pg/ml before and 37f25, 161f98 and 29+3Opg/ml after LBNP at - 15mmHg. BP did not change during the 30 and 60 degrees tilt tests. Heart rate increased significantly (P<O.OOl) only at 60 degrees (Table 2). Table 2 Fig. 4. Carotid arterial diastolic diameter after tilting in seven subjects. The heavy line and bars represent mean values. Statistical significance: *P<0.05, **P<O.Ol compared with baseline. shows that the carotid arterial diastolic diameter decreased significantly (P<0.01) (Fig. 4) at 30 and 60 degrees without any alteration in the percentage change in diameter. DISCUSS10N LBNP is a widely accepted method used to achieve selective deactivation of cardiopulmonary receptors of the low-pressure system in humans 11, 15-18]. Zoller et aZ. [19] have shown that, with LBNP levels of - 5 and - lOmmHg, central venous pressure decreased and forearm vascular resistance increased in the absence of significant changes in mean arterial BP, arterial pulse pressure and heart rate. A beat-to-beat analysis of systemic arterial BP recorded at high gain did not show any transient decrease in systolic BP that might have inhibited arterial baroreceptors. In contrast, significant changes in BP and heart rate occur when LBNP is applied at levels more negative than -20mmHg, which therefore simulate passive tilting [l, 15-18]. Carotid haemdynamics after lower-body negative pressure Such studies, including the present one, might suggest that mild LBNP is a safe method with which to investigate the role of cardiopulmonary receptors alone in humans. However, previous studies have not evaluated the changes in the geometry of the carotid artery after LBNP. In recent years, several devices have been utilized to measure arterial diameter and wall motion transcutaneously by tracking echo signals from both the anterior and posterior arterial walls [&lo]. Earlier models [6] used an amplitude tracking method, which had several drawbacks. Superimposed echoes from the tissue surrounding the artery, as well as imperfect alignment of the ultrasonic beam perpendicular to the arterial wall, caused significant and unpredictable amplitude changes in the echo waveform. Newer devices have a high spatial resolution with a better linearity, dynamic range and tracking speed, even in the presence of a low original signalto-noise ratio. The present apparatus was substantially improved by the additional use of measurement of the Doppler shift, thus allowing a high degree of reproducibility to be achieved [7]. Indeed, during LBNP or tilt testing one can be certain that the point of measurement in the vessel is not dislocated in the longitudinal and transverse directions, and repeated evaluations of two-dimensional B-made imaging are required for this. In the present work, this possibility of dislocation does not fit with our two principal results after LBNP and tilting at the site of the common carotid artery, lcm just below the carotid bifurcation: a decrease in carotid arterial diastolic diameter, but no alteration in the ge change in pulsatile diameter. r LBNP and tilting, we did not find any modification of the percentage change in pulsatile arterial diameter. Since brachial pressure was also found to be unchanged, it can be suggested that no significant modification of carotid arterial distensibility occurred [20, 211. However, this possibility should be considered very cautiously. First, a slight tendency towards a reduced pulse pressure when measured indirectly was noted, and it may be that lower negative suction might have modestly reduced stroke volume [16], which would per se slightly reduce the pulsatile diameter changes. Secondly, the oscillometric apparatus used (Dinamap) is optimized for mean arterial BP measurements and may be less reliable for systolic and diastolic BP. Thirdly, pulse pressure difYers physiologically at the site of the carotid and the brachial arteries, due to the amplification of pressure pulse from central to peripheral arteries [20], and pressure wave transmission may have been modified after LBNP or tilting. For all these reasons, the present commehts will be focused exclusively on the substantial changes in the geometry of the arterial wall that we observed, namely a significant decrease in carotid arterial diastolic diameter. In other words, the dominant finding of this study was that mild LBNP and head-up tilting were associated with a lower degree of stretch of the 539 carotid arterial wall, due to a reduction in vessel diameter without any change in mean systemic BP. At this point, it should be stressed that the mechanism of the decrease in arterial diameter may differ after LBNP or tilting. In the latter case, the intra-carotid BP will change due to a hydrostatic pressure difference from the atrial reference level [1, 2, 201. In contrast, after LBNP, the role of passive modification in arterial diameter caused by BP changes may be excluded, suggesting several other hypotheses. Deactivation of cardiopulmonary receptors has recently been shown to be associated not only with an increase in forearm vascular resistance (i.e. arteriolo-constriction), but also with a reduction in brachial artery diameter [5]. Reduction in brachial artery diameter has been shown to be due either to neurogenic factors or to a flow-dependent mechanism [5]. It is thus possible that deactivation of cardiopulmonary receptors may also be associated with a reduction in carotid arterial diameter. There are, however, several arguments against this hypothesis. First, cardiopulmonary baroreceptor mechanisms have a predominant role in skeletal muscle (as in the forearm) and no reports of an effect on the large arteries exist, particularly at the site of the carotid circulation [l]. Secondly, in our study, there was no correlation between changes in forearm vascular resistance and changes in carotid arterial diastolic diameter. On the other hand, humoral changes associated with decreased cardiopulmonary blood volume and filling pressure of the heart after LBNP might also contribute to the constriction of the carotid artery. However, LBNP at levels of -5, -10 and -15mmHg is known to produce little change in plasma renin activity and plasma vasopressin concentration [11 and no substantial modification of plasma catecholamine or dopamine levels occurred in the present study, as in others [l]. The method of applying LBNP itself might contribute to the carotid response observed. During LBNP a subatmospheric pressure is applied to vessels and viscera in the pelvis and abd possibility that reflexes originating in sen tors in these areas may contribute to circulatory and humoral modifications during LBNP must be taken into account [l]. Another possibility is that mild LBNP produces slight changes in cardiac output with resulting changes in arterial diameter through the mechanism of flow-dilatation (or constriction) [22]. Howeve rmacologically induced changes in carotid bl shown to be unusually associated with concomitant changes in carotid arterial diameter [23]. The last hypothesis is that positional manoeuvres causing a change in cardiopulmonary blood volume and filling pressure might modify per se the size of the heart and vessels [24], resulting in a change in the longitudinal stretch of the carotid artery. Our findings of decreased carotid arterial diameter after tilt might partly favour this possibility. With this pro- 540 P. 1. Larnlley et al. cedure, a decrease in carotid arterial diameter was already observed at 30 degrees of tilt, before any increase in heart rate was observed. At 60 degrees of tilt, heart rate increased, indicating a significant activation of baroreceptors in the high-pressure system. At the end of this discussion, it is important to notice the complexity of the physiological situation, as results from the classical analysis of the baroreflex mechanisms [2]. The arterial baroreceptors contain both adventitial stretch receptors with myeh a t e d afferents, functioning as if coupled ‘in parallel’ with other wall elements (being thus unloaded by arterial constriction), and unmyelinated stretch afferents more or less infiltrating the media (as if coupled ‘in series’ with the muscle cells) which may rather become activated during reflex constriction of the carotid artery. Thus, these two sets of bar0 (stretch) afferents might tend to balance each other out with respect to their potential secondary contribution to the overall reflex effects of volume receptor unloading. In conclusion, the present study has shown that, with graded application of mild LBNP, deactivation of cardiopulmonary receptors is associated with a significant reduction in carotid arterial diameter, lcm below the carotid bulb. The possibility that this phenomenon could produce a lower level of stretch at the site of arterial carotid receptors should be considered as a factor which might affect the habitual interpretation of interactions between baroreceptors in the high- and low-pressure systems in humans. Further studies are needed on this important problem. 3. 4. 5. 6. 7. 8. 9. 10. II. 12. 13. 14. 15. 16. 17. ACKNOWLEDGMENTS This study was performed with the aid of grants from the Institut National de la SantC et de la Recherche Midicale (INSERM-U337), the Centre National &Etudes Spatiales (CNES), Dassault Electronique (B. Daugny) and the Comit6 de Recherche Clinique de l’Assistance Publique, Paris. We thank Mrs Sylvie Minne for her excellent technical assistance. 18. 19. 20. 21. 22. REFERENCES I. Mark, A.L. & Mancia. G. Cardiopulmonary baroreflexes in humans. In: Shepherd, J.T. & Abboud, F.M., eds. Handbook of physiology. The cardiovascular system. Section 2. Bethesda, MD: American Physiological Society, 1983 vol. 111, part 2, chapter 21, 79543. 2. Mancia, G. & Mark, A.L. Arterial baroreflexes in humans. In: Shepherd, J.T. & 23. 24. Abboud, F.M., eds. Handbook of physiology. The cardiovascular system. Section 2. Bethesda, MD: American Physiological Society, 1983 vol. 111, part 2, chapter 20, 755-93. Cleroux, I.,Giannattasio, C., Giambattista, 8. et al. 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