Does pulsatile and sustained neck pressure or neck suction produce differential cardiovascular and sympathetic responses in humans?

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1 Does pulsatile and sustained neck pressure or neck suction produce differential cardiovascular and sympathetic responses in humans? Shigehiko Ogoh *, Paul J. Fadel, Janelle M. Hardisty, Wendy L. Wasmund, David M. Keller, Peter B. Raven and Michael L. Smith Department of Integrative Physiology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA (Manuscript received 7 April 2003; accepted 30 June 2003) Although square-wave sustained and R wave-triggered pulsatile stimuli have been used to assess carotid baroreflex (CBR) function in humans, it remains unclear whether these different stimulus protocols elicit comparable responses and whether CBR responses adapt during prolonged stimulation. Thus, we measured muscle sympathetic nerve activity (MSNA), heart rate (HR) and mean arterial pressure (MAP) in response to +30 Torr neck pressure (NP) and _30 Torr neck suction (NS) delivered for 20 s either as a sustained or pulsatile stimulus. CBR-mediated changes in MSNA, HR and MAP were similar with sustained and pulsatile stimuli. The time course of MSNA and HR responses identified that significant changes occurred during the initial 5 s and were better maintained over 20 s with NP than with NS. Changes in MAP exhibited a slower onset with the peak increase during NP occurring at 10 s (sustained, 7 ± 1 mmhg; pulsatile, 7 ± 1 mmhg; P > 0.05) and the nadir during NS occurring at 20 s (sustained, _7 ± 1 mmhg; pulsatile, _9 ± 2 mmhg; P > 0.05). These data demonstrate that sustained and pulsatile NP and NS produce comparable CBR-mediated responses. Furthermore, despite MSNA and HR returning towards baseline during NS, CBR-mediated changes in MAP are well maintained over 20 s of NS and NP. Experimental Physiology (2003) 88.5, Carotid baroreflex (CBR) function has been extensively studied in humans by the application of neck pressure (NP) and neck suction (NS) to the carotid sinus using the variable pressure neck chamber (Eckberg, 1977b; Mancia et al. 1978, 1985; Wallin & Eckberg, 1982; Strange et al. 1990; Potts et al. 1993; Papelier et al. 1994; Sundblad & Linnarsson, 1996; Fadel et al. 2001a; Ogoh et al. 2002). While this technique has provided important information regarding CBR control, questions remain as to the extent to which CBR adaptation may occur with the use of NP and NS. Eckberg (1977b) has previously reported that in humans constant-intensity stimulation resulted in significant adaptation of the CBR-mediated heart rate (HR) response. Other investigations (Eckberg, 1977a; Potts et al. 1993; Potts & Raven, 1995; Ogoh et al. 2002) have also indicated that alterations in R R interval or HR are transient with the application of NS for 5 s during a held expiration. These findings have lead to the speculation that alterations in afferent nerve traffic from the carotid baroreceptors are not maintained during sustained stimuli (Eckberg & Sleight, 1992). However, Mancia et al. (1978, 1985) have reported that HR responses were well maintained during 2 min of NP and over the first 15 s of NS. In addition, Wallin & Eckberg (1982) reported that cardiac responses to 5 s of NP and NS were well maintained until the stimulus was terminated; however, muscle sympathetic nerve activity (MSNA) responses were only transitory. These disparate findings have been difficult to reconcile and they continually raise the question as to whether or not baroreceptor adaptation occurs with NP and NS. The application of NP and NS during held expiration, a common manoeuvre to limit respiratory-related fluctuations in HR (Potts et al. 1993), limits the time period during which CBR responses can be assessed. Therefore, even though the greatest changes in HR and MSNA occur early in response to NP and NS, possibly even before the stimulus is terminated, it may be that extension of the stimulus for a longer period (i.e. without a breath hold) may maintain CBR-mediated responses. Alternatively, considering that animal investigations have shown that baroreflex responses Present address: Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX , USA. Publication of The Physiological Society * Corresponding author: sogoh@hsc.unt.edu 2586

2 596 S. Ogoh and others Exp Physiol 88.5 rapidly adapted to static pressures but were maintained with pulsatile stimuli (James & Daly, 1970; Mendelowitz & Scher, 1988, 1990), perhaps a more pulsatile stimulus delivered to the carotid sinus at the same intensity maintains CBR-mediated responses to a greater extent than the traditional static sustained stimulus. Although attempts have been made to avoid any potential adaptive effects on the CBR by using pulsatile NS (Strange et al. 1990; Sundblad & Linnarsson, 1996) and NP (Papelier et al. 1994), no direct comparisons between pulsatile and static NS or NP stimuli have been made. This is an important consideration since the use of sinusoidal NS has been shown to better maintain cardiovascular responses when compared to more static stimuli (Bath et al. 1981). Therefore, the purpose of this investigation was to determine whether the method of carotid baroreceptor stimulation, pulsatile or sustained, influences CBR-mediated responses and to examine the time course of CBRmediated changes in MSNA, HR and mean arterial pressure (MAP) to 20 s pulsatile and sustained NP and NS. We tested the hypothesis that pulsatile and sustained NP and NS would cause similar responses and that the CBRmediated responses would be well preserved over 20 s of NP and NS. METHODS Subjects Fourteen subjects (11 men; 3 women) were recruited for voluntary participation in the present study. The mean age, height and weight were 24 ± 1 years, 178 ± 3 cm and 74 ± 4 kg, respectively. Eight subjects participated in the neck pressure protocol (6 men; 2 women), while seven subjects completed the neck suction protocol (5 men; 2 women). One subject participated in both protocols. All subjects were free of any known cardiovascular or pulmonary disorders, were normotensive non-smokers and were not using prescribed or over the counter medications. Written informed consent was obtained from all subjects, and the study protocol was approved by the University of North Texas Health Science Center Institutional Review Board for the use of human subjects. On experimental days, subjects were asked to abstain from caffeinated beverages for a minimum of 12 h and from strenuous physical activity for 24 h prior to arriving at the laboratory. Experimental measurements Cardiovascular variables were monitored beat-to-beat and recorded on a personal computer equipped with customized software. Heart rate (HR) was monitored using a standard lead II electrocardiogram (ECG). The ECG signal output was connected to an ECG monitor (Hewlett-Packard 78342A, Andover, MA, USA) interfaced with the personal computer. Arterial blood pressure was measured non-invasively on a continuous basis Figure 1 Outline of the experimental protocol. Left-hand panel, protocols 1 and 2 performed at end-expiration; right-hand panel, protocols 3 and 4 performed at end-inspiration. There were no significant differences in the carotid baroreflex-mediated responses between the end-expiration and end-inspiration protocols. NP, neck pressure; NS, neck suction; ChP, neck chamber pressure; Resp, respiration.

3 Exp Physiol 88.5 Responses to carotid baroreceptor stimulation 597 using finger photoplethysmography (Finapres, Ohmeda, Madison, WI, USA). The Finapres was placed on the middle finger of the right hand and was supported on the arm of a chair that was adjusted to position the finger cuff at heart level. Before data collection was started the Finapres was calibrated to match the diastolic blood pressure obtained by brachial auscultation. A respiratory band was placed around the thorax to monitor the subject s respiratory cycle, which assisted in timing the delivery of the 20 s NP and NS stimuli at end-expiration and endinspiration. Standard microneurographic techniques were used to obtain post-ganglionic MSNA recordings from the peroneal nerve near the popliteal fossa or fibular head of the right leg, as described previously (Vallbo et al. 1979). The MSNA responses were identified according to their appearance and timing in relation to the preceding R wave of the ECG and calculated as burst frequency and total activity (burst frequency times mean burst amplitude) which is expressed in arbitrary units. Experimental protocol Each subject was seated in a reclining chair with one leg supported in an extended position for ease of obtaining MSNA recordings. After being instrumented for the collection of HR, MAP and MSNA measurements, the subjects were fitted with a malleable lead neck collar for the application of +30 Torr NP or _30 Torr NS. Our laboratory has previously reported anatomical variation in the location of the carotid sinus bifurcation amongst individuals (Querry et al. 2001). To account for these findings, all subjects underwent a familiarization protocol before the experimental day, which included a visualization of the carotid sinus bifurcation (n = 8) using ultrasound technology (Model RT6800, General Electric) and an assessment of the heart rate responses to NP and NS (n = 14). The rationale for using HR responses being that a minimal HR response would primarily be due to the collar not covering the carotid sinus bifurcation. After adjusting collar sizes for each subject, any subject who was lacking a HR response or had a visually detected high or low anatomical locus of the carotid sinus bifurcation were excluded from this investigation. Subjects were randomly allocated to either a NP or NS protocol (Fig. 1). Both protocols were performed in a similar manner with the only difference being the application of pressure or suction. Subjects received 20 s pulses of NP or NS initiated at either endexpiration or end-inspiration while the subjects breathed to a metronome at a rate of 12 breaths min _1. The application of NP and NS was computer-controlled with the pulses being presented as either a sustained or pulsatile stimulus. The sustained stimuli were delivered to the neck precisely 50 ms after the R wave of the ECG and maintained for the full 20 s period. On the other hand, the pulsatile stimuli consisted of pulsed pressures of 500 ms duration delivered to the neck precisely 50 ms after the initiation of each R wave during the 20 s period. Between each pulse the neck chamber was vented to atmospheric pressure by computer control thereby creating the pulsatile stimulus. The generated neck collar pressure applied to the carotid sinus region was measured by a pressure transducer (model DP45, Validyne Engineering, Northridge, CA, USA). Data analysis All subjects underwent a minimum of three sustained and three pulsatile trials for each respiratory protocol (i.e. end-expiration and end-inspiration; Fig. 1). Baseline pre-stimulus values were obtained by taking a 10 s average for MSNA, HR and MAP just prior to the change in neck tissue pressure. The responses to NP and NS were averaged for each 5 s period of stimulation and Table 1. Baseline subject characteristics NP protocol NS protocol (n =8) (n =7) HR (bpm) 64 ± 4 58 ± 2 MAP (mmhg) 81 ± 4 87 ± 5 MSNA Total activity (units min _1 ) 674 ± ± 117 Burst frequency (bursts min _1 ) 23±2 17±2 No significant differences were noted between subjects undergoing the NP and the NS protocols. HR, heart rate (beats per minute); MAP, mean arterial pressure; MSNA, muscle sympathetic nerve activity. Data are presented as means ± S.E.M. compared to the pre-stimulus value. No significant differences were found in MSNA, HR and MAP responses between the endexpiration and end-inspiration protocols and therefore these data were combined and mean responses are reported. Statistical analysis A two-way repeated measures analysis of variance was used to compare responses between 20 s pulsatile and sustained NP and NS stimuli (stimulus w time). A Student Newman Keuls test was employed post hoc when main effects were significant. Statistical significance was set at P < Analyses were conducted using Sigma Stat for Windows (Jandel Scientific Software, SPSS Inc. Chicago, IL, USA). RESULTS The baseline characteristics for the subjects participating in the NP and the NS protocols are summarized in Table 1. There were no significant differences in resting HR, MAP or MSNA between the two groups. CBR-mediated responses to 20 s pulsatile and sustained NP Heart rate, MAP and MSNA responses to 20 s of sustained and pulsatile NP are presented in Fig. 2. The application of +30 Torr NP caused significant CBR-mediated increases in HR within 5 s for both pulsatile and sustained NP (sustained, 6 ± 1 beats min _1 ; pulsatile, 6 ± 1 beats min _1 ; P > 0.05). Although this response was well maintained over the 20 s time period with a mean increase in HR of 4 ± 1 beats min _1 at 20 s for both the pulsatile and sustained stimuli (Fig. 2A), the pulsatile stimulus was more effective overall in maintaining the HR response (P < 0.03 vs. sustained). This was most apparent at the 10 s and 15 s time points where the increases in HR were significantly greater during the pulsatile stimulus compared to the sustained stimulus. MSNA also increased significantly during the initial 5 s for both the pulsatile and sustained NP (sustained, 40 ± 18 %; pulsatile, 23 ± 17 %; P > 0.05). The MSNA responses remained elevated throughout the 20 s time period with the greatest increases being observed at the 20 s time point for the sustained stimulus (61 ± 25 %) and at the 10 s time point for the pulsatile stimulus (39 ± 10 %) (Fig. 2B). Carotid baroreflex-mediated increases in MAP exhibited a slower onset with a peak increase occurring at 10 s

4 598 S. Ogoh and others Exp Physiol 88.5 (sustained, 7 ± 1 mmhg; pulsatile, 7 ± 1 mmhg; P > 0.05) that was also well maintained throughout the stimulus (at 20 s: sustained, 6 ± 1 mmhg; pulsatile, 4 ± 1 mmhg; P > 0.05; Fig. 2C). CBR-mediated responses to 20 s pulsatile and sustained NS The HR, MAP and MSNA responses to the application of sustained and pulsatile NS at _30 Torr are also presented in Fig. 2. The peak decrease in HR in response to NS occurred within the first 5 s (sustained, _5 ± 1 beats min _1 ; pulsatile, _4 ± 1 beats min _1 ; P > 0.05) and gradually returned towards baseline throughout the 20 s stimulus (Fig. 2A). No significant differences in HR responses were found between the sustained and pulsatile stimuli. The decreases in MSNA elicited by _30 Torr NS were very profound over the initial 5 s period (sustained, _73 ± 10 %; pulsatile, _77 ± 10 %; P > 0.05) and gradually returned towards baseline during both the sustained and pulsatile stimuli (Fig. 2B). Mean arterial pressure also exhibited a rapid decrease at the onset of NS (at 5 s: sustained, _3 ± 1 mmhg; pulsatile, _3 ± 1 mmhg; P > 0.05); however, MAP continued to decline progressively throughout the first 15 s of NS reaching a stable decrease between 15 and 20 s of the stimulus (at 20 s: sustained, _7 ± 1 mmhg; pulsatile, _9 ± 2 mmhg; P > 0.05; Fig. 2C). Figure 3 shows original records of the MSNA and arterial blood pressure responses to sustained and pulsatile NP (Fig. 3A) and NS (Fig. 3B). Figure 2 Carotid baroreflex-mediated changes in heart rate (DHR, beats per minute; A), muscle sympathetic nerve activity (DMSNA; B) and mean arterial pressure (DMAP; C) elicited by the application of sustained and pulsatile neck pressure (NP) and neck suction (NS). MSNA is expressed as total activity (TA) and presented as a percentage change from baseline. * Significant difference between pulsatile and sustained stimuli (P < 0.05); significant difference from baseline, both pulsatile and sustained stimuli (P < 0.05); 2 significant difference from 5th second (P < 0.05); 3 significant difference from 10th second (P < 0.05). Data are presented as means ± S.E.M. DISCUSSION Previously, the results from several human investigations have suggested that constant-intensity stimulation of the carotid baroreceptors with NP or NS results in significant adaptation (Eckberg & Sleight, 1992). As a result several investigations have used the variable-pressure neck chamber to produce pulsatile changes in carotid sinus transmural pressure, rather than using sustained static changes, with the expectation that the pulsatile stimulation would avoid any baroreceptor adaptation (Strange et al. 1990; Papelier et al. 1994; Sundblad & Linnarsson, 1996). The data of the present investigation indicate that the mode of presentation of NP and NS to the carotid sinus, pulsatile or sustained, does not affect the CBR-mediated changes in MSNA, HR and MAP. Thus, CBR function can be equally estimated by using either sustained or pulsatile stimulus protocols. Furthermore, during both NP and NS significant changes in MSNA and HR consistently occurred during the initial 5 s of the stimulus; however, responses were better maintained over 20 s of NP than NS. Nevertheless, CBR-mediated changes in MAP were well maintained over 20 s of NP and NS suggesting that significant carotid baroreceptor adaptation does not occur within 20 s. In fact, with NS there was a progressive decrease in MAP throughout the first 15 s of the stimulus after which a stable reduction was maintained until the NS was terminated.

5 Exp Physiol 88.5 Responses to carotid baroreceptor stimulation 599 Pulsatile vs. sustained stimuli In the present investigation, sustained and pulsatile NP and NS produced comparable cardiovascular and sympathetic responses. In previous human studies, others (Strange et al. 1990; Papelier et al. 1994; Sundblad & Linnarsson, 1996) have used pulsatile R wave-triggered pulses instead of the more typical sustained static square-wave pressure delivery to the carotid sinus. This methodological approach was based on results from human investigations suggesting that CBR adaptation occurs with sustained NP/NS (Eckberg & Sleight, 1992) in combination with animal investigations (James & Daly, 1970; Mendelowitz & Scher, 1988, 1990) indicating that the baroreflex rapidly adapts with static pressures but maintains responses with more pulsatile stimuli. However, until now, responses to sustained and pulsatile stimulation of the carotid baroreceptors have not been directly compared in human studies. In contrast to the findings from animal investigations (James & Daly, 1970; Mendelowitz & Scher, 1988, 1990), we have demonstrated that the mode of pressure delivery does not alter CBRmediated responses. A likely explanation for the differences between our findings and those of animal studies may be that the application of a sustained external NP or NS only alters the transmural pressure and because of the underlying arterial pressure waveform, the carotid baroreceptors are still presented with a pulsatile pressure. In contrast in animal studies (Brunner et al. 1984; Geerdes et al. 1993), the sustained carotid sinus pressure is accomplished by raising intraluminal pressure without pulsation; hence, the baroreceptors are exposed to a sustained change in mean pressure without pulsations of pressure within the vessel (i.e. a true square-wave static pressure). Considering that the baroreceptors naturally respond to fluctuations in blood pressure on a beat-to-beat basis, any fixed pressure creates a stimulus that is not typically present under normal physiological conditions. This constant-pressure stimulus may explain the adaptation of the baroreceptors that is seen under such experimental conditions. Figure 3 Original records of muscle sympathetic nerve activity (MSNA) and arterial blood pressure (ABP) responses to the application of +30 Torr neck pressure (A) and _30 Torr neck suction (B) during 20 s sustained and pulsatile stimuli. ChP, neck chamber pressure; Resp, respiration.

6 600 S. Ogoh and others Exp Physiol 88.5 In agreement with our findings, Smith et al. (2000) demonstrated that the HR and MAP responses to 12 consecutive pulses of NP/NS (in the range +40 to _80 Torr) of 500 ms duration were not different from sustained 5 s pulses of NP and NS over the same range of pressures. It is important to note that our data extend these observations to a period of 20 s and include direct recordings of sympathetic nerve activity. Thus we contend that in humans, sustained and pulsatile 20 s NP and NS produce comparable responses indicating that CBR function can be equally estimated by using either stimulus protocol. Temporal changes induced by NP and NS Examining the time course of the MSNA and HR responses to NP and NS showed that significant changes consistently occurred during the initial 5 s and were better maintained over 20 s with NP than with NS. In agreement with these findings, Mancia et al. (1978, 1985) demonstrated that carotid sinus deactivation with NP for 2 min elicited a sustained increase in HR; however, the bradycardic response to NS was more transient and not different from baseline at 2 min despite a persistent reflex-induced hypotension. In addition, Wallin & Eckberg (1982) suggested that MSNA was only transiently inhibited during NS. It is interesting that, similar to Mancia et al. (1978, 1985), we also noted that MAP decreased progressively throughout the NS stimulus reaching a fairly stable level between the 15 and 20 s time points. In fact, the persistence of a CBR-mediated MAP response was consistent for both NS and NP. We believe that the maintenance of an increase and decrease in MAP during NP and NS, respectively, suggests that adaptation of the carotid baroreceptors probably does not occur over 20 s. If adaptation was to occur it would be expected that any CBR-mediated changes would reach a peak and return towards baseline over the duration of the stimulus as afferent neural firing would diminish. We propose a hypothesis for the different time course of the MSNA and HR responses between NP and NS. One possibility is to assume that the reflex reduction of arterial pressure induced by NS is sensed and opposed by aortic receptors to a greater extent than the reflex increase of arterial pressure induced by NP. In agreement, Smith et al. (2000) reported that at rest the operating-point arterial pressure is higher than the centring-point arterial pressure of the aortic HR baroreflex function curve in humans, suggesting that the aortic HR baroreflex is more sensitive to hypotension than hypertension. Furthermore, the profound effects of hypotension on aortic baroreceptormediated increases in MSNA and HR have been repeatedly documented in healthy subjects (Sanders et al. 1989; Fadel et al. 2001b). However, this may not fully explain our findings as it has also been shown that the aortic baroreceptors cause a large decrease in MSNA (Sanders et al. 1988) and HR (Ferguson et al. 1985) during hypertensive challenges, which should have resulted in a counteraction in response to the increase in MAP during NP. The complexity of examining differences in aortic and carotid baroreceptor responses in humans makes definitive conclusions difficult and although our inference of aortic baroreceptor counteraction may not fully explain our findings we suggest this to be the most plausible explanation given the inherent limitations of human integrative physiological investigations. Accordingly, we recognize that we have relied on CBRmediated responses to examine carotid baroreceptor adaptation without any direct measure of afferent nerve activity. However, this approach is justified given the impossibility of attaining such recordings in humans. Furthermore, cardiac, sympathetic and blood pressure responses are the main end-points used to assess the baroreflex function and as such, any conclusions on baroreceptor function should be based on these efferent responses. A potential limitation in the design and interpretation of the present investigation is that only one level of neck pressure and suction was used. It is possible that other levels of neck pressure or suction may cause different results in terms of the range and sensitivity of the carotid baroreflex. However, we chose to use stimuli that have been shown to consistently elicit responses close to the threshold (NP, +30 Torr) and saturation (NS, _30 Torr) of the CBR stimulus response curve for MSNA (Fadel et al. 2001a) and HR (Potts et al. 1993; Norton et al. 1999; Smith et al. 2000) under resting conditions. Thus, these representative stimuli should provide the ideal range of responses to test for noticeable alterations in CBR-mediated responses due to the different stimulus protocols. In summary, we have demonstrated that the different modes of pressure delivery (sustained vs. pulsatile) do not influence CBR-mediated responses during the application of both NP and NS. Thus, CBR function can be equally estimated by using either sustained or pulsatile stimulus protocols. In addition, the time course of the MSNA and HR responses to NP and NS identified that significant changes occurred during the initial 5 s and were better maintained over 20 s with NP than with NS. 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