Beat-by-beat estimates of total peripheral resistance (TPR) can be obtained from continuous measurements of cardiac output by using Doppler ultrasound and noninvasive mean arterial blood pressure (MAP). We employed transfer function analysis to study the heart rate (HR) and vascular response to spontaneous changes in blood pressure from the relationships of systolic blood pressure (SBP) to HR (SBP→HR), MAP to total peripheral resistance (TPR) and cerebrovascular resistance index (CVRi) (MAP→TPR and MAP→CVRi), as well as stroke volume (SV) to TPR in nine healthy subjects in supine and 45° head-up tilt positions. The gain of the SBP→HR transfer function was reduced with tilt in both the low- (0.03–0.15 Hz) and high-frequency (0.15–0.35 Hz) regions. In contrast, MAP→TPR transfer function gain was not affected by head-up tilt, but it did increase from low- to high-frequency regions. The phase relationships between MAP→TPR were unaffected by head-up tilt, but, consistent with an autoregulatory system, changes in MAP were followed by directionally similar changes in TPR, just as observed for the MAP→CVRi. The SV→TPR had high coherence with a constant phase of 150–160°. Together, these data that showed changes in MAP preceded changes in TPR, as well as a possible link between SV and TPR, are consistent with complex interactions between the vascular component of the arterial and cardiopulmonary baroreflexes and intrinsic properties such as the myogenic response of the resistance arteries.
- power spectral analysis
- Doppler ultrasound
- cardiac output
mean arterial blood pressure (MAP) is normally tightly regulated around a desired set point by modulation of cardiac output [Q̇ = heart rate (HR) × stroke volume (SV)] and total peripheral vascular resistance (TPR) (35). The dynamic nature of blood pressure regulation has been extensively characterized through investigations of the HR component of the arterial baroreflex (25, 45, 49, 50, 56, 59). The interaction between MAP and TPR has been examined in conditions of relative steady state, such as during head-up tilt (HUT) (8) or application of neck chamber pressure (33, 41). As well, changes in muscle sympathetic nerve activity have been recorded as an index of the vascular response during drug-induced changes in MAP (11) or neck chamber pressure (15). Spontaneous fluctuations in MAP have been studied extensively (2, 44), but there are few investigations in humans of spontaneous variability in TPR (14).
Cross-spectral analysis of data from the areflexic, conscious rat revealed that, in the absence of intact feedback loops, both systemic and regional vascular conductances lagged ∼1 s behind MAP, suggesting that myogenic mechanisms accentuated spontaneous short-term variability in MAP (32). In contrast, in rats with intact reflexes, there was reduced coherence between MAP and vascular conductance (32), an observation consistent with the poor relationship often found between muscle sympathetic nerve activity and MAP in humans under resting conditions (16, 39, 57), although these latter experiments did not measure vascular conductance or resistance. Whereas it is well established that induced changes in arterial blood pressure activate the arterial baroreflex causing reflex modulation of TPR to regulate MAP (35), there is evidence that arterial blood pressure might also be influenced by whole body autoregulation (3, 4, 22). Certainly autoregulation acts within individual vascular beds, such as the brain (23, 58), kidney (28), and other regions (5, 21, 30, 47). For the cerebral circulation, autoregulation acts to maintain relatively constant blood flow in the face of changes in arterial pressure, at least in the lower frequency range below ∼0.1 Hz (23, 58). In contrast, other vascular beds, such as skeletal muscle, are not as dependent on constant flow, so it is not known if autoregulation in these other regions reflects a similar “constant flow” mechanism or an intrinsic response of vascular smooth muscle to changes in arterial pressure.
Continuous estimation of TPR in humans has proven technically challenging until recent applications of Doppler ultrasound to determine beat-by-beat SV (13). This allows for comparisons between parallel observations of peripheral vascular and cerebrovascular responses, where the latter have been extensively characterized because of the availability of transcranial Doppler ultrasound (19, 23, 58). In the present study, we combined Doppler measurement of SV or forearm blood flow with continuous noninvasive blood pressure measurement to explore the dynamic nature of MAP and TPR interactions by transfer function analysis during supine (Sup) rest and HUT. Simultaneously, cerebrovascular responses were collected to permit comparisons of the vascular regulatory properties. Transfer function analysis was applied to SV to TPR, as a recent study (38) suggested that SV might act as a surrogate stimulus to the cardiopulmonary baroreflex. We included HUT in this study to modify the balance between parasympathetic and sympathetic control over the cardiovascular responses. In the HUT position, HR is elevated, but the gain of the vagally mediated HR component of the arterial baroreflex is reduced (24, 49, 56, 59). Additional compensations to prevent a decrease in MAP often include an increase in TPR (8) mediated by increased sympathetic nervous activity (35), as well as local and intrinsic characteristics of the vascular response (20). In this study, we included measurements of forearm blood flow with calculation of forearm vascular resistance to allow comparisons with TPR. We did this because Doppler measurements of Q̇ might be subject to movement while the forearm remains stable during measurements. It was hypothesized that the dynamic relationship between MAP and TPR in resting human subjects would be characteristic of the arterial baroreflex, in contrast to the autoregulatory pattern of the cerebrovascular system and, furthermore, that neither peripheral nor cerebral circulations would be affected by posture. The cerebrovascular responses have been presented in a different format as the normocapnia, “N-CO2,” group in a previous publication (12).
Nine healthy young adults (4 women, age range: 22–34 yr) volunteered to participate in this study. Because menstrual phase, in particular estrogen levels, might alter baroreceptor function, women were tested only between 3 and 10 days of their menstrual cycle to normalize for hormone levels. After a description of the experimental details and risks, each subject signed a consent form approved by the Office of Research Ethics at the University of Waterloo. All subjects refrained from the ingestion of alcohol and caffeine for 12 h and food for 2 h before the onset of testing.
On arrival to the laboratory, each subject voided his or her bladder and was measured for height and weight. Following instrumentation, baseline respiratory rate, tidal volume (Vt), and end-tidal carbon dioxide (PetCO2) levels were obtained over a 10-min period of spontaneous breathing with the subject in Sup rest.
For Sup and tilt conditions, a controlled breathing protocol was used to normalize for the effects of lung stretch receptors on sympathetic outflow (51) across all conditions. Subjects fixed their breathing frequency at 15 breaths/min by following a metronome and adjusted their Vt to a level that increased total ventilation by ∼50%. The appropriate level of Vt was achieved by displaying the excursions of a respiratory plethysmograph on a computer screen. A computer-controlled gas-mixing system supplied appropriate amounts of CO2 in 21% O2 to achieve PetCO2 that was equivalent to the level during the baseline period.
Each subject underwent 7 min of Sup and HUT while instrumented for the recording of R-wave-to-R-wave interval (standard ECG) and beat-by-beat arterial blood pressure (Finapres, Ohmeda 2300). The Finapres was positioned at heart level, and baseline blood pressures were corrected to systolic (SBP) and diastolic (DBP) values obtained by standard sphygmomanometry. MAP was determined as the average value over a complete cardiac cycle. Respiratory excursions were assessed by a plethysmograph (Respitrace). Beat-by-beat instantaneous lung volume (ILV) was obtained by taking the volume coinciding with the R-wave of each heartbeat. PetCO2 levels were assessed breath by breath by a gas mass spectrometer (Perkin-Elmer, MGA-1100).
Cardiac SV and aortic dimensions were obtained to calculate Q̇ on a continuous basis (13). Aortic diameter was determined by echo Doppler (Toshiba, model SSH-140A) imaging by using a 3.75-MHz phased array probe. Aortic diameter measures were taken during systole from three single frozen-screen images and averaged. SV velocity was obtained from the suprasternal notch by using a hand-held 2-MHz continuous wave probe (Exerdop, Quinton Instrument). The quadrature output from the Doppler device was demodulated to provide continuous mean blood velocity (MBV) corrected to an angle of 20° between sound wave and aortic flow. MBV values over each cardiac cycle were determined by using the R-wave of the electrocardiogram to indicate the end of one blood pulse wave and the beginning of the next. SV was calculated from SV = MBV·πr2·s/beat, where r is the aortic radius, and Q̇ is from Q̇ = HR·SV. Beat-by-beat estimates of TPR were then determined from MAP/Q̇.
Forearm blood flow was also determined in a subset of subjects (N = 4) from the combined measures of brachial artery diameter (7.5-MHz probe operating in B mode) and MBV. Similar to SV velocity, beat-by-beat brachial artery MBV was determined from the spectra of a pulsed Doppler ultrasound (Multigon, model 500V) signal by using a flat 4-MHz probe with an angle of 45° between sound wave and brachial flow. Forearm blood flow was determined by the same method as Q̇, whereas forearm vascular resistance was calculated as MAP divided by forearm blood flow.
Cerebral blood flow was estimated by a 2-MHz transcranial Doppler ultrasound probe (Transpect TCD MedaSonics) fixed over a right temporal window to insonate the middle cerebral artery. An index of cerebrovascular resistance (CVRi) was determined from MAP corrected to the level of the middle cerebral artery divided by mean cerebral flow velocity. Velocity is taken to be proportional to flow under the assumption that the middle cerebral artery does not change its cross-sectional area (19, 58).
Data were recorded on digital format tape (Teac RD-111T Data Recorder) and then transferred for analysis by a computer-based system to yield a data set sampled at 100 Hz, except for the ECG signal, which was sampled at 1,000 Hz. Beat-by-beat data, including HR (beats/min), derived from the time between successive R-waves, SBP, MAP, SV, Q̇, TPR, ILV, CVRi, forearm blood flow, and forearm vascular resistance were determined for each cardiac cycle. The data were then interpolated and resampled by using the mean cardiac frequency to obtain an equal interval between samples, low-pass Butterworth filtered at 0.95 Hz, and detrended to remove any linear trends. Fast Fourier transform was completed with the Welch method (61) and Hanning window. The window size was set to one-fourth of the signal length with one-half overlap and low-frequency (LF: 0.03–0.15 Hz) and high-frequency (HF: 0.15–0.35 Hz) power spectral area for all variables. In addition, the mean transfer function gain and phase for the same frequency regions were determined for ILV→HR, SBP→HR, ILV→SBP, MAP→TPR, SV→TPR, and MAP→CVRi. It is common practice to accept gain and phase relationships only when coherence is ≥0.5 (25, 43, 49), and for our data set a statistically significant criterion level was determined as 0.45 (55). Some subjects were not used for statistical analysis as a lack of coherence (≥0.5) existed between two chosen variables within a given frequency range. For phase value interpretation, a negative phase suggested that changes in the input variable preceded changes in the output response, whereas a positive phase suggested the reverse.
All data were analyzed by one-way repeated-measures ANOVA for the effect of tilt. Statistical significance was set at P ≤ 0.05. All results are reported as means ± SE.
On going from a Sup to 45° HUT, HR significantly increased (Sup: 60.3 ± 3.2 beats/min vs. HUT: 76.1 ± 3.6 beats/min; P < 0.05). Blood pressure measurements revealed a small, nonsignificant increase in MAP with tilt (Sup: 96.6 ± 2.9 mmHg vs. HUT: 99.8 ± 3.7 mmHg). As well, steady-state TPR values showed a nonsignificant increase following tilt (Sup: 16.2 ± 2.0 mmHg·l−1·min vs. HUT: 19.2 ± 2.9 mmHg·l−1·min). CVRi was significantly greater in the Sup than HUT (Sup: 1.7 ± 0.1 mmHg·cm−1·s vs. HUT 1.4 ± 0.1 mmHg·cm−1·s) (12).
Tilt effects on variability.
An example of the central and peripheral vascular beat-by-beat data collected in both Sup and 45° HUT for a single subject is depicted in Fig. 1. The vertical dotted lines were placed in Fig. 1 to correspond with the minimal value of the MAP, which can be seen to correspond to the minimal value of SV and Q̇ and to the peak values of HR, ILV, and TPR. That is, a change in SV was not sufficiently compensated by a directionally opposite change in HR so that Q̇ fluctuated with SV, causing a decrease in MAP on inspiration and an increase on expiration. Thus, at least at the respiratory frequency, the observation that TPR changed in the opposite direction to MAP has the consequence that fluctuations in MAP were smaller than they would have been if TPR had either not changed or had changed in the same direction as MAP. The group mean autospectral power distribution in the LF and HF regions for these variables is summarized in Fig. 2. The LF HR power spectrum showed a significant increase (P < 0.05; Fig. 2), whereas a trend toward a decrease in the HF power was found on going to HUT (P = 0.077; Fig. 2). Compared with Sup, the LF (P = 0.053) and HF (P = 0.064) power tended to increase during tilt for SBP. Similar directional changes were observed in the spectral power for MAP in the LF (P = 0.11) and HF (P = 0.087) regions with tilt, but, again, these did not reach the criterion level for statistical significance. The HF power for ILV increased in 45° HUT (P < 0.01; Fig. 2). For TPR, there was a trend on going from Sup to HUT for an increase in LF spectral power (P = 0.066), whereas power increased in the HF region (P < 0.05; Fig. 2). Similarly for Q̇, there was a trend for increased spectral power with the change in body position from Sup to HUT, with the difference in the HF region approaching the criterion value (P = 0.051).
Tilt effects on transfer function.
The group mean responses for the transfer function gain, phase, and coherence are displayed for the relationships between MAP→TPR and MAP→CVRi in Fig. 3. These and other transfer function gain results are summarized in Table 1. The transfer functions that define the change in HR, both ILV→HR and SBP→HR, were significantly reduced during HUT compared with the Sup position. The SBP→HR transfer function that describes the HR component of the baroreflex relationship in the frequency domain was reduced in both the LF and HF regions. The ILV→SBP relationship was not affected by tilt nor was the relationship of MAP→TPR. It should be noted that, for the MAP→TPR transfer gain, means in Table 1 are calculated from all data sets with coherence >0.5; however, statistics were done only on the subjects who had data under both the Sup and tilt conditions based on the minimal coherence criterion. The MAP→CVRi transfer function gain was significantly reduced in the HF region on going from Sup to HUT but was not different in the LF region. The gain for the SV→TPR transfer function was significantly increased in both LF and HF regions in HUT compared with Sup.
Compared with Sup posture, HUT caused little change in phase in either the LF or HF regions for any pair of variables (Table 2). Only for the SBP→HR relationship in the LF range was there a small but significant increase in phase. Positive-phase values for ILV→HR and SBP→HR suggested that an increase in HR preceded an increase in both ILV and SBP input variables. However, from a baroreflex perspective, this means that an increase in SBP is followed by an opposite direction change in HR. The negative phase relationship for MAP→TPR as well as for MAP→CVRi suggested that increases in MAP preceded increases in TPR and CVRi with no change on going from Sup to HUT. The mean values presented in Fig. 3 show that, for each of TPR in Sup and CVRi in Sup and HUT, there is a progressive reduction in phase with increasing frequency (at least to 0.2 Hz in Fig. 3). This pattern is consistent with a pure time delay of ∼2 s. The ∼0° phase at the relatively low frequencies for TPR in the HUT condition (Fig. 3) was based on all subjects. However, when mean values of Table 2 were calculated based on only those subjects who had coherence >0.5, the negative phase in the LF region was not significantly different in Sup compared with HUT. The phase for SV-TPR was consistently −150° to −160°, suggesting that changes in SV were followed by changes in TPR (Fig. 4).
Forearm blood flow.
We obtained forearm blood flow and forearm vascular resistance from four of our nine subjects in both postures. The autospectral power for both the LF and HF regions tended to increase in HUT (Table 3) in a manner similar to the pattern observed for Q̇ (Fig. 2). The similarity between forearm blood flow and Q̇, as well as forearm vascular resistance and TPR during each of Sup and HUT positions, is apparent for our sample subject in Fig. 5.
The major new observation of the present study was that the MAP→TPR relationship in healthy humans, especially in the Sup position, was consistent with a mechanism whereby a change in MAP was followed, after a short time delay of ∼2 s, by a directionally similar change in TPR across a wide range of input-to-output frequencies. In these same subjects, the cerebrovascular system, where the process of autoregulation has been well documented (19, 23, 46, 58), followed an almost identical pattern of phase relationship for MAP to CVRi. There was no change in gain for the MAP→TPR relationship on going from Sup to HUT. These observations contrast with the equivalent relationships between SBP→HR that characterize the HR component of the arterial baroreflex, where a change in SBP is often followed by a compensatory, directionally opposite change in HR, and the gain of the relationship decreases in HUT. We interpret these data to mean that the vascular component of the arterial baroreflex cannot be characterized in the Sup or 45° HUT positions by the simple relationship between MAP→TPR. Rather, the MAP→TPR response was similar to the blood pressure-to-resistance relationships observed in vascular beds that exhibit autoregulation, such as the cerebral circulation (19, 23, 46, 58), the kidney (28), and skeletal muscles (20, 28). These relatively steady-state relationships that might reflect autoregulation countering the arterial baroreflex (4) appear to be separate from arterial baroreceptor detection of changes in MAP, such as in the transition from Sup to head-up posture that evokes changes in sympathetic nerve activity (1, 35) or with neck pressure or suction (15, 41) to increase TPR and maintain MAP. New data are also presented for transfer function analysis of the SV→TPR relationship. The TPR and SV were strongly correlated across the LF to HF region, the gain was increased in the HUT compared with the Sup position, and the phase was constant at −150° to −160° across the entire range of frequencies investigated.
Previous studies employed continuous measurements of HR in conjunction with a noninvasive estimate of arterial pressure from the finger cuff device to explore the HR component of the arterial baroreflex. The new variables obtained in the present study were the beat-by-beat estimation of Q̇ from Doppler ultrasound, along with calculation of TPR from MAP/Q̇. Estimates of Q̇ from Doppler ultrasound have been validated against thermodilution and electromagnetic flow probes (6, 26). In this study, it was essential to maintain high-quality Doppler signals from the ascending aorta for relatively long periods of time. Our methods were consistent with those described by Eriksen and Walloe (13).
Our observation of marked HF power in measured Q̇ and calculated TPR differed from that of Evans et al. (14), who found no variation >0.2 Hz. We suspected that the HF variability of Q̇ and TPR in this study could have resulted from two possibilities, one being true physiological variation in Q̇, whereas the other was motion of the probe relative to the ascending aorta caused by respiration. To investigate this, we employed an independent indicator of blood flow and vascular resistance. Forearm blood flow was measured by Doppler ultrasound at a site where there was no motion, and forearm vascular resistance was calculated from MAP divided by forearm blood flow. The similarity of the time series plots that compared forearm blood flow with Q̇ and forearm vascular resistance with TPR (Fig. 5), as well as the pattern of LF and HF power distribution (Table 3, Fig. 2), provides compelling evidence that HF variability in Q̇ and TPR was not simply caused by motion of the probe. Innes and colleagues (26) also noted that left ventricular SV was reduced with inspiration due to the change in pleural pressure induced by respiration and not probe movement. The reason for the differences between our results and those of Evans et al. (14) is probably related to their use of impedance cardiography, which estimates changes in SV from instantaneous thoracic impedance that probably cannot be isolated to left heart output (31).
In this study, the overall similarity of forearm vascular resistance and TPR suggests that the beat-by-beat sequence for TPR provides a valid means to assess the vascular response to a change in MAP. These beat-by-beat values of TPR, determined from the ratio of mean arterial pressure to mean Q̇ for an individual beat, do not reflect the beat-by-beat relationship for arterial compliance as studied with the windkessel effect (36). At present, it is unknown whether compliance effects can act across several beats and whether this could have influenced the lower frequency results of the present study.
Cross-spectral analysis provides insight into the linear interrelationships between two variables, but it does not evaluate causality (45, 49). Therefore, any interpretation of relationships must be made with caution. The relatively low coherence between MAP and TPR in the LF range suggests that either there is a nonlinear relationship between these variables that is not incorporated in the linear model of cross-spectral analysis or that other variables cause changes in either or both of the MAP and TPR such that there is not a tight link between them. That this might be the case is evidenced by the higher values of coherence for the cerebrovascular response where there is evidence that autoregulation plays a large part (assuming relatively constant arterial Pco2) in the control of blood flow. Thus independent or more complex factors, including uncoordinated vascular responses in different organ systems, should be sought to explain the variability of TPR and MAP. Similarly, the high coherence for the SV→TPR relationship might reflect a strong linear relationship, but the possibility that SV influences blood pressure that could invoke an autoregulatory-type response cannot be excluded.
HR baroreflex during passive tilt.
Consistent with past studies (49, 56, 59), we used SBP→HR to represent a measure of HR baroreflex function. Focus on the SBP as opposed to DBP or MAP stems from the observation that, with an increase in SBP, HR decreases, despite little change in both the DBP and MAP. Decreasing HR or lengthening the R-wave-to-R-wave interval with an increase in SBP attenuates any increase in DBP by allowing more time for blood pressure to reach a minimum value. Therefore, correlation between SBP and HR is much stronger than that of MAP or DBP, especially in the HF range (10).
In this investigation and previous research, blood pressure variability in both the LF and HF range increased with HUT (37, 56). This increase in variability was caused in part by the reduction in HR variability observed during passive tilt due to the reduced HR baroreflex control (49, 56, 59), in combination with only slightly reduced SV variability (Fig. 1) and increased Q̇ variability (Figs. 1 and 2). Consistent with reduced parasympathetic nervous activity, the gain for the SBP→HR relationship was reduced in both the LF and HF bands at 45° HUT (49). The fact that the phase relationship for SBP→HR did not correspond exactly to the anticipated value of 180° for a pure baroreflex feedback control system suggests that both arterial baroreflex feedback and feed-forward properties contributed to the interaction between SBP and HR (49).
The reduced gain of the ILV→HR relationship in 45° HUT was expected (49) due to reduced parasympathetic nervous activity. Unlike Saul and colleagues (49, 59), we found little coherence between ILV→HR and ILV→SBP in the LF range, probably because of our fixed breathing protocol (0.25 Hz) compared with their random breathing protocol.
Peripheral vascular response during passive tilt.
The relationship between blood pressure and TPR has been studied during application of neck chamber pressure over the carotid sinus (15, 33) and by HUT (8). Unlike studies of the HR component of the arterial baroreflex where drug-induced manipulations in blood pressure have proven useful (54), the TPR response cannot be studied because the drug directly affects TPR. While transfer function analysis has been applied to study the interrelationship between muscle sympathetic nerve activity and MAP (1, 40, 57), it has not been used previously to investigate the links between MAP and TPR.
We found that the gain and phase relationships for MAP→TPR were not different between Sup and passive 45° HUT. Although no significant change in MAP was found with HUT, the beat-by-beat variability increased in both the LF and HF regions (Fig. 2). The greater variation in MAP was matched by an increase in TPR spectral power in both frequency bands such that MAP→TPR gain and phase were not modified on going to HUT. In contrast to the HR component of the arterial baroreflex where the SBP→HR phase relationship was consistent with a large component of feedback regulation, the MAP→TPR relationship was not consistent with a feedback control system. If the SV can be taken as a surrogate for the stimulus to the cardiopulmonary baroreflex (38), then the phase relationship for SV→TPR is consistent with a predominantly reflex regulation. The increase in gain for the SV→TPR is a consequence of the larger change in TPR required to maintain MAP when SV changes from a lower value in the HUT position. This finding is consistent with the recent observation of enhanced gain of the sympathetic nerve activity response to a change in DBP in the head-up posture (42).
It is well documented that the arterial and cardiopulmonary baroreflexes regulate changes in sympathetic nervous activity (35) that are probably superimposed on other important vascular resistance regulating factors, such as the local release of dilatory and constrictor compounds, plus the myogenic response. The constant gain and phase for MAP→TPR in Sup and HUT positions suggest that the interaction between sympathetic activity and local factors was not influenced by a change in baseline vascular tone in the head-up posture (9). In fact, Shoemaker et al. (52) reported a dissociation between muscle sympathetic nerve activity and leg vascular resistance under specific circumstances. It was argued that the sympathetic nervous system affects blood pressure primarily through vascular changes in nonskeletal vascular beds, and blood pressure influences limb vascular resistance through the myogenic effect. These observations are consistent with recent experiments that showed that the ∼0.1-Hz oscillations in arterial pressure in humans, referred to as Mayer waves, are often found to be poorly correlated with muscle sympathetic nerve activity (7, 39, 57). In contrast, animal research has found strong relationships between these variables (27) and human experiments, with blockade of α-adrenergic receptors revealing that 0.1-Hz oscillations disappeared (60).
Phase and gain interpretation of the vascular response.
The primarily negative phase for the MAP→TPR relationship, over both the LF and HF range, indicates that changes in TPR followed those of the MAP. The linear increase in negative phase, at least from 0 to ∼0.25 Hz (Fig. 3), is consistent with a system that has a pure time delay (49) of ∼2 s between an increase in MAP and a directionally similar change in TPR. It is this progressive linear change in phase that allows interpretation of the data as a nonbaroreflex mechanism. That is, if one examined only the breathing frequency as in Fig. 1, it might be possible to state that an increase in MAP is matched immediately with zero delay, or alternatively 4 s later by a directionally opposite change in TPR that could indicate a baroreflex response. However, this is not consistent with known physiology, as there is no mechanism for a zero-lag system and a lag of 4 s is too long (34, 35). Furthermore, the interpretation of the progressive linear increase in negative phase with TPR following MAP would mean that matching a change in MAP by a directionally opposite change in TPR could be accomplished only by a variable delay that is again inconsistent with known physiology of the arterial baroreflex (34).
The phase relationships of the MAP→TPR were similar over certain frequencies (Fig. 3) to those observed for the MAP→CVRi in these same subjects. As observed here and in other research, the phase for MAP→CVRi approached 0° at higher frequencies, such that cerebral circulation acts as an effective high-pass filter (19). It has been shown repeatedly for cerebral (12, 23) and renal (62) circulations that the gain of the MAP to blood flow relationships is damped at low frequencies but is increased at high frequencies. Thus, as found here, the gain of the MAP→CVRi relationship was high in the LF range but was reduced at higher frequencies, allowing changes in pressure to be transmitted directly as changes in cerebral blood flow. These observations of gain for the whole body MAP→TPR response differed from those of the cerebral circulation as whole body gain increased at higher frequencies. Evidence is mounting that cerebrovascular autoregulation involves a major contribution from the stretch-induced production and/or release of 20-HETE (17). The 20-HETE is produced by breakdown of arachidonic acid by the cytochrome P-450 4A enzyme pathway (48). 20-HETE is released in response to increases in cerebral artery blood pressure, and it is a potent vasoconstrictor, although the mechanism of action, perhaps acting through cascades involving protein kinase C, remains unresolved (48). Little is known about the time course of these mechanisms and to what extent they can explain the dynamic cerebrovascular autoregulation explored in this study as opposed to sustained changes in pressure. It is possible that these mechanisms might explain the high-pass filter characteristics of the cerebrovascular autoregulatory process. However, Kaley (29) noted that a role of 20-HETE in the autoregulatory process of skeletal muscle of humans has yet to be confirmed. Our observations that gain for the MAP→TPR response increased at higher frequencies suggest that the mechanisms of whole body autoregulation might be different from that in the cerebrovascular system, and it is possible that intrinsic vascular properties, such as arterial compliance, might contribute to this response. Our results were consistent with observations of greater amplitude myogenic response with fast rates of rise in arterial pressure in skeletal muscle vascular beds of sympathectomized animals (21).
The overall regulation of TPR and MAP is dependent on interaction of many factors in addition to baroreflex feedback of sympathetic vasoconstrictor activity. These factors include the current level of sympathetic nervous system vasoconstrictor tone, local concentrations of dilatory or constrictor factors such as metabolites and hormone release from endocrine or paracrine organs, and the myogenic response. In HUT compared with the Sup posture, sympathetic vasoconstrictor activity is elevated (9, 53), and circulating vasoactive hormone concentrations change (18). The myogenic response is expected to be enhanced during high sympathetic stimulation (47), although there are between-vascular bed differences in the nature of the myogenic response (5, 21, 28, 30). Despite these changes, we found no difference in the gain of the MAP→TPR relationship due to posture.
In conclusion, consistent with previous observations of the HR component of the arterial baroreflex (43, 49, 50), we found that the dominant response was a negative feedback with changes in HR countering changes in SBP and that the gain of the SBP→HR relationship decreased in HUT compared with the Sup posture. New insights from the present investigation come from the description of the phase and gain relationships for MAP→TPR and SV→TPR. We observed that, in the frequency range of 0–0.2 Hz, changes in MAP were followed after ∼2-s time delay by a directionally similar change in TPR in a manner similar to that observed in the cerebrovascular system. Thus transfer function analysis did not reveal a feedback regulation of the vascular component of the arterial baroreflex. Rather, the interaction between MAP and TPR was consistent with some characteristics of an autoregulated system, although other mechanisms cannot be ruled out. It should be noted that we did not induce large changes in arterial pressure, such as achieved by neck pressure or suction (15, 33, 41), that would be expected to activate both HR and vascular components of the arterial baroreflex. The observation of high coherence between SV and TPR and the constant phase of −150° to −160° are suggestive of neural responses that might reflect cardiopulmonary baroreflex activation. However, transfer function analysis is noncausal, and the potential for SV to influence TPR through some intervening variable, such as arterial pressure, requires further investigation. It has been suggested (4) that the intrinsic myogenic property of vascular smooth muscle counteracts an activated arterial baroreflex, and the present data provide support for this in the resting human. Analysis of beat-by-beat cardiovascular data might provide an approach to study the interplay between intrinsic vascular properties with the arterial and cardiopulmonary baroreflexes in closed-loop cardiovascular control in health and disease.
This research was supported by the Canadian Space Agency (9F007–9-3303/001/ST), and a Collaborative Health Research Project grant from National Sciences and Engineering Research Council (30578). D. D. O'Leary was supported by a Heart and Stroke Foundation of Canada Research Traineeship.
The authors are thankful for the expert technical assistance of David Northey, Tim Wilson, and Derek Kimmerly during data collection and analysis.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Copyright © 2004 the American Physiological Society