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Original Article

TITLE: CARDIOVAGAL AND VASOSYMPATHETIC BAROREFLEX LATENCIES MEASURED DURING ACTIVE STANDING IN NORMAL SUBJECTS

Authors: 1 Estañol Bruno, Delgado Guillermo R, Malamud Kessler Caroline, Macías Gallardo Julio, 2 Fossion Ruben, Rivera Ana Leonor, Frank A.lejandro

Affiliations: 1 From the Clinical Neurophysiology Laboratory, Department of Neurology and Psychiatry of the National Institute of Medical Sciences and Nutrition Salvador Zubirán, 2 Institute of Complexity Sciences.

Corresponding Address: Bruno Estañol, M.D. National Institute of Medical Sciences and Nutrition Salvador Zubiran, Vasco de Quiroga 15, Tlalpan, Mexico City, 10700.

Tels. 55-55683450 E-mail: bestanol@hotmail.com

Abstract

Introduction

Cardiovagal and vasosympathetic latencies were measured during the immediate fall of blood pressure (BP) that is seen during active standing (AS). The fall during AS is profound and after its nadir is followed by a gradual recovery. The heart rate (HR) increases to a peak and gradually decreases. The BP stabilizes in about 20-25 s and the HR between 25-30 s.

Subjects and methods

We studied 29 healthy control subjects during AS. The subjects were recumbent for 6 minutes and then were asked to sit up and immediately assume the upright position. The upright position was maintained during 5 minutes. The BP and interbeat intervals (IBI) were continuously monitored using the non invasive finger pressure Finapres® device during the entire maneuver.

Results

There was an initial peak of rise of systolic blood pressure of 22 mmHg followed by an abrupt fall of 25-40 mmHg that gradually recovered. The cardiovagal reflex was measured from the trough of the SBP and the initial rise of recovery of the IBI and was found to be 2.8 with CI between 0.81-3.63 s . The vasosympathetic vasoconstrictive latency was measured from the basal BP (immediate SBP before standing) to the trough or nadir of the fall of BP and was found to be 7 ± 1.8 s.

Discussion

There is a complex sequence of physiological events during AS. The immediate profound fall of BP is seen only during AS and is not seen during passive tilt. The relationship between the changes of BP and HR are clearly seen during active standing, and this allowed us to measure the cardiovagal and vasosympathetic vasoconstrictive latencies. We obtained slightly longer cardiovagal latencies than those reported previously. This may be due to the

previous profound fall of BP before its rise and was slightly different in each subject. The vasosympathetic vasoconstrictive latencies were very consistent at 7 s with a time constant of 4.2 s. Vasosympathetic vasoconstrictive latencies have been difficult to measure previously. These data may be useful to study patients with different disorders such as neurally mediated syncope, orthostatic hypotension and POTS.

Key words: active standing (AS), fall of SBP, cardiovagal latency, vasosympathetic latency.

Running title: Cardiovagal and cardiosympathetic latencies during active standing

Introduction

Blood pressure autoregulation is a fundamental mechanism that corrects the perturbations of BP that occur during the activities of daily life (1,2) On a short term basis is performed by a complex negative feedback mechanism termed the baroreceptor reflex (13). The baroreflex has at least two afferent entries: 1) the high pressure, and 2) the low pressure baroreceptors, and at least three effector arms: 1) the cardiovagal reflex; 2) the cardiosympathetic reflex, and 3) the vasosympathetic or vascular reflex. It has a central integration network located at the nucleus tractus solitarii, the nucleus ambiguous, the ventrolateral medulla and the intermediolateral column of the spinal cord (3,4). It is a polysynaptic reflex that (is) activates under the (influences) effects of several supranuclear influences mostly from the hypothalamus, the limbic system and the insular cortex (2,5,6). The supranuclear modulation is poorly understood but is mainly related to perturbations of BP given by central mechanisms or central commands and (is) are associated to emotions, cognitive activities and voluntary muscle contractions (1,5,6). The purpose of (the) this reflex, which is altered by the multiple internal and external disturbances, to which it is constantly exposed, is to stabilize the BP (from) the multiple internal and external disturbances to which is constantly exposed (1). The two main external disturbances are the gravitational stress and the respiratory movements, both, induce well known hemodynamic changes (3,7,8). (Se puede poner el gráfico que realizamos)

Active standing (AS) induces an immediate fall of BP with subsequent recovery, that has three phases: 1) an initial peak that is characterized by a parallel rise of BP and

HR that is induced when the person is changing the position from supine to sitting; 2) a fall of BP with an associated tachychardia (9,10) ; the tachycardia has been ascribed to reflex withdrawal of vagal influences and the entrance of cardiosympathetic activity (9,10); the fall of BP has been attributed to the pooling of blood in the abdomen and lower extremities due to the action of the gravitational acceleration vector, although a reflex inhibition due to activation of the cardiopulmonary reflexes or arterial baroreflex vasosympathetic inhibition by the previous rise of BP, has also been suggested (7,11,12); the drop of BP is followed by a recovery phase, and finally 3) a second rise of BP that ends in a second peak that appears to be a sympathetic overcompensation or overshoot similar to that seen in the fourth phase of the Valsalva maneuver (7,9,1115). (Figure 1)

We attemped to measure the latencies of the three effector arms of the reflex as we considered AS an excellent physiological window to measure these latencies, as the fiducial or sample points can be very well defined, and because the immediate profound fall of BP when assuming the upright position is solely seen during AS and is not observed with passive tilt (7,8,11,12,15). The baroreflex vasosympathetic inhibitory component, following the initial BP peak, induces mainly vasodilation and is partly responsible of for the fall of BP (8,15). In any event the abrupt fall of BP successively activates the cardiosympathetic and the vasoympathetic reflexes, and during the gradual increase of the recovery phase of BP, the cardiovagal reflex is activated. The latencies and duration of these influences can thus, be clearly defined.

SUBJECTS, MATERIAL AND METHODS

Study Population. We enrolled twenty eight healthy subjects, aged 19 to 35 years of age, without a history of diabetes, hypertension, cardiac or neurological diseases, or history of syncope; subjects were nonsmokers and were on no medications. They all had, as part of the previous evaluation, BP measurements in supine, sitting and standing positions. BP measurement was performed using standard sphygmomanometry. In all subjects, BP was 120/80 mmHg or less. The BP measurements were done by two subjects that were blind to each other findings. Blood sugar levels were below 95 mgs/dl, and the body mass index was below 26. They also underwent a neurological examination and had normal pupils, normal myotatic reflexes and no Romberg sign. The study was approved by the Ethical Committee of the National Institute of Medical Sciences and Nutrition and an informed written consent was obtained from all participants.

Protocol. All evaluations were performed in the morning. Participants were instructed to avoid alcohol, caffeinated beverages and over-the-counter medications

after 22:00 on the night before the evaluation. Finger arterial pressure (FAP) was non-invasively and continuously (beat-to-beat) monitored using the volume-clamp

method by Peňáz and the Physiocal (physiological calibration) criteria by

Wesseling. 12 SBP, DBP and mean BP (MBP) were then reconstructed from FAP; and heart rate (HR) was meanwhile computed as the inverse of the interbeat interval (Finometer® PRO, Finapres Medical Systems, Amsterdam). Measurements were made at supine rest before AS (5 min), and during AS. Hemodynamic parameters

were extracted with BeatScope for Windows® (v.1.1a, Finapres Medical Systems).

Description of the maneuver. The subjects stayed resting in a supine position breathing normally for 10 minutes and thereafter they were asked to sit and stand up immediately after they sat up. We recorded the beat to beat changes in basal

SBP and HR while supine, during the time the subject moved from supine to the sitting position, and during the period of active standing. We also recorded the SBP and HR for five minutes after the subject stood up.

Data Analysis and Statistics. The investigation was focused on SBP and HR changes in the initial hemodynamic response to AS and was carried out utilizing BeatScope software. Supine values of SBP and HR were calculated as the corresponding arithmetic means of the 5 min supine rest, and afterwards SBP response was determined at the time of the initial peak of SBPa (tSBPa), time at valley or trough of the fall of SBPb (tSBPb), and at the SBP overshoot (tSBPos). The selection of sample points was prompted by the results of previous studies (79,1113,16). Statistical analysis was performed with STATISTICA for Windows® (v.5.1). Prior to group analyses, individual data were tested for normality (Shapiro-Wilk test). The calculation of latencies was performed by either using Student's t-test or Mann- Whitney U test. A p-value below 0.05 (p < 0.05) was considered significant. All results are expressed as mean ± SD or median (interquartile range).

RESULTS

  • 1. AS is a relatively simple method to measure cardiovagal latencies during a step stimulus? It can be measured directly from the point of the onset of recovery of SBP to the time of the first increase of the IBI. In normal subjects it had a mean latency of 2.8 s with C.I. between 0.81-3.63 s. The latencies did not have a normal distribution but the measurements were precise as the onset of the recovery of the SBP was clearly seen in all subjects and the onset of the lengthening of the IBI was also well defined (Figure 2).

  • 2. The vasosympathetic latency was measured from the first peak of the SBP to the valley or trough of the fall of the BP. We found similar latencies to those reported by Wieling with a mean of 7 ± 1.8 s (7,8). (Figure 3)

  • 3. The fall of the SBP was measured from the basal SBP, while the subject was supine, to the trough or valley and was 29.6 ± 15 mmHg. This is more pronounced than that found by Wieling that had a mean of 20 mmHg (7,8). When we made the calculations from the first peak to the trough it was 52.3 ± 16.5 mmHg. We carefully repeated the calculations and found both of them were o to be accurate.

  • 4. The time of recovery recovery time of the SBP was measured from the point of onset of the ascending arm (which indicated the onset of recovery) to the second peak of the SBP. The measured time was 9.6 s with C.I. between 7.8-11.4 s.

  • 5. We attempted to measure the latency of the cardiosympathetic reflex but could not find reliable fiducial points. The initial shortening of the IBI at the onset of the fall of SBP could be attributed to withdrawal of vagal influences and it was difficult or impossible to recognize the point where the sympathetic influences began. We also attempted to measure the cardiosympathetic latency from the onset of the fall from the second peak, to the onset of tachycardia but could not find clear fiducial points. DISCUSSION AS is probably one of the simplest maneuver to calculate cardiovagal latencies as they can be measured directly from the time of the onset of

recovery of SBP to the time of the initial lengthening of the IBI (Figure 2). AS is one of the routine maneuvers that are performed in the autonomic laboratory and therefore most researchers can do this calculation easily. We found cardiovagal latencies longer than those reported with other methods 8 . One of the reasons may be the very profound fall of SBP of approximately 30 mmHg and the slight magnitude of the initial recovery of the SBP after this profound fall. Therefore, the stimulus (∆SBP) may take longer to act. It may also reflect the dynamic nature of the cardiovagal reflexes having a slight time difference under different conditions (17). The intersubject variability is also compatible with a polysynaptic reflex that is constantly modulated by supranuclear influences. Polysynaptic reflexes have variable latencies in general. The variability of latencies may also be related to the timing of respiratory movement (3,17).

The vasosympathetic reflex had latencies similar to those reported previously by others with a mean of 7 s (7,15). The vasosympathetic or vascular latency is most likely the longest of the three effector arms of the baroreceptor reflex (1). This is to be expected as it has a long central processing time at various successive sites including the nucleus solitarii, the ventrolateral medulla ,the intermediolateral columns of the spinal cord, the slow conduction velocities of the C fibers that innervate resistant blood vessels, the slow release of noradrenaline at the neuroeffector junction, and the proper time constant of the arteriolar constriction (1).

The time course of the response of the resistant blood vessels, which are a widely distributed and rather large system, also has to be taken into account. The duration

of the vasosympathetic response (time of recovery of SBP) to the second peak was found to be 9.6 s with a C.I. between 7.8-11.4 s. This indicates that the duration of the vasosympathetic response has a mean of 10 s during in which there is gradual increasing vasoconstriction until the complete recovery of the basal SBP. The time constant (TC) of the recovery is thus ~6 s. This is also compatible with the anatomophysiological characteristics of the central and peripheral sympathetic networks that innervate the resistant blood vessels. The vasosympathetic latency and duration are both important characteristics in the understanding and the evaluation of the autoregulation of BP. The cardiovagal response has been evaluated thoroughly through the different types of baroreflex sensitivity indices (BRS) but the vasosympathetic response has been more elusive because its measurement is done indirectly through the changes of BP, as the peripheral resistance is difficult to measure with direct means (5,8). Hence, the measurement of its latency and duration, during active standing, are feasible and also relatively easy to perform.

The measure of the latency and duration of the vasosympathetic response are both important in the evaluation of different pathologies that produce orthostatic hypotension (4,7,14,1824). The work of Wieling that has characterized various types of initial or immediate orthostatic hypotension using AS as a research tool has been very important in focusing attention to this relatively simple maneuver (7,8). We think that not only the amount of the fall of SBP during active standing is of fundamental importance, but also: 1) the time of duration of the fall, and, 2) the time of recovery after the initial physiological orthostatic hypotension are of interest for the understanding and evaluation of the latency and duration of the arterial baroreflex vasoconstricting response.

The small initial peak, observed during the time of position change from supine to sitting, is most likely induced by the contraction of the abdominal and limb muscles during the time from sitting to the recumbent position (712). At the point of increased venous return to the right heart cavities and the pulmonary circulation there may be activation of the low pressure cardiopulmonary receptors. The parallel tachycardia seems to be due to reflex vagal withdrawal (10). The activation of the low pressure pulmonary receptors and the increase of BP immediately before the fall may enhance the fall of SBP at the time of standing by activation of arterial baroreceptors (7,11,12).

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CAPTIONS FOR FIGURES

  • 1. Healthy subject 30 years old. Two positive peaks of BP are seen during active standing. The first peak is observed when the subject changes position from supine to sitting position. The negative peak is the valley of the fall of the BP at the moment of standing. The second positive peak is seen at the end of the recovery of the BP while the subject is still standing.

  • 2. Measurement of cardiovagal latencies: time from the valley of the fall of SBP immediately after standing to the onset of the lengthening of the IBI. The two fiducial points were clearly observed in all subjects.

  • 3. Measurement of the vasosympathetic latency: time from the onset of the fall of the BP from the first peak to the valle. The two points were clearly observed in all subjects.

  • 4. Measurement of the duration of the vasosympathetic response: time from the valley of the fall of SBP to the highest point of the second peak of SBP.

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4 Cambios posturales respiración contracción muscular Red de integración central Perturbaciones externas Control neural: Barorreflejo
Cambios posturales respiración contracción muscular Red de integración central Perturbaciones externas Control neural: Barorreflejo Sistema simpático
Cambios posturales
respiración
contracción muscular
Red de integración central
Perturbaciones
externas
Control neural:
Barorreflejo
Sistema simpático
Reflejo cardiosimpático
PAS 2
Sistema parasimpático
PAS 1
Reflejo vasosimpático
Receptores locales de presión arterial
Alta presión
Baja presión

Figura 1

Flujograma del control de la presión arterial: la PAS 1 indica la PAS inicial, PAS 2 se refiere a la PAS

posterior al control del barorreflejo y PAS nal se refiere a la PAS nal posterior al mecanismo de retroalimentación.