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1 Departments of Physiology and
Medicine, Medical College of Virginia at Virginia Commonwealth
University, and Hunter Holmes McGuire Department of Veteran Affairs
Medical Center, Richmond, Virginia 23249;
2 Department of Cardiology and
Cardiovascular Sciences, Fundación Cardiovascular del Oriente
Columbiano, AA 1143 Bucaramanga, Santander, Columbia;
3 Department of Anesthesia, Mayo
Clinic and Foundation, Rochester, Minnesota 55905;
4 Department of Clinical
Physiology, We evaluated a method of baroreflex testing
involving sequential intravenous bolus injections of nitroprusside
followed by phenylephrine and phenylephrine followed by nitroprusside
in 18 healthy men and women, and we drew inferences regarding human sympathetic and vagal baroreflex mechanisms. We recorded
the electrocardiogram, photoplethysmographic finger arterial pressure,
and peroneal nerve muscle sympathetic activity. We then contrasted
least squares linear regression slopes derived from the depressor
(nitroprusside) and pressor (phenylephrine) phases with
1) slopes derived from spontaneous
fluctuations of systolic arterial pressures and R-R intervals, and
2) baroreflex gain derived from
cross-spectral analyses of systolic pressures and R-R
intervals. We calculated sympathetic baroreflex gain from
integrated muscle sympathetic nerve activity and diastolic pressures.
We found that vagal baroreflex slopes are less when arterial pressures
are falling than when they are rising and that this hysteresis exists
over pressure ranges both below and above baseline levels. Although
pharmacological and spontaneous vagal baroreflex responses correlate
closely, pharmacological baroreflex slopes tend to be lower than those derived from spontaneous fluctuations. Sympathetic baroreflex slopes
are similar when arterial pressure is falling and rising; however,
small pressure elevations above baseline silence sympathetic motoneurons. Vagal, but not sympathetic baroreflex gains vary inversely
with subjects' ages and their baseline arterial pressures. There is no
correlation between sympathetic and vagal baroreflex gains. We
recommend repeated sequential nitroprusside followed by phenylephrine
doses as a simple, efficientmeans to provoke and characterize human
vagal and sympathetic baroreflex responses.
baroreflex gain; hysteresis; muscle sympathetic nerve activity; aging
HUMAN ARTERIAL pressure-sympathetic and -vagal reflex
response relations are described well by reverse sigmoid and sigmoid functions (10, 36). Because some studies suggest that humans operate in
the threshold regions of both baroreceptor-sympathetic (12, 13, 36) and
baroreceptor-vagal (10) reflex response relations, it may be
particularly important to understand baroreflex function in terms of
arterial pressure changes just above and below prevailing levels.
In the first widely used experimental technique for provoking human
baroreflex responses, the "Oxford" vasoactive drug injection method (42), arterial pressure is either raised (42) or lowered (33),
and R-R interval responses are measured. In 1992, Ebert and Cowley (8)
described a variation on the Oxford method: sequential injections of
depressor and pressor drugs. This approach held an advantage over the
original method because baroreflex responses to falling and rising
pressures could be characterized efficiently during one sequence of
pressure changes. Although we (21, 30) and others (7) have used the
sequential vasoactive drug method, there appears to have been no
systematic evaluation of this method or of the physiology underlying
responses to this provocation. We evaluated sympathetic and vagal
responses to sequential intravenous bolus injections of nitroprusside
followed by phenylephrine and phenylephrine followed by
nitroprusside. From the results, we drew several
inferences regarding human baroreflex physiology.
Subjects
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
Measurements
We recorded the surface electrocardiogram (lead II) and beat-by-beat photoplethysmographic arterial pressure (Finapres model 2300, Ohmeda). We recorded multiunit postganglionic peroneal nerve muscle sympathetic activity at the fibular head with tungsten electrodes with uninsulated tip diameters of ~1-5 µm. We inserted similar reference electrodes ~1 cm away. We connected the electrodes to a differential preamplifier with a gain of 1,000 and an amplifier with a gain of ~70. We identified muscle sympathetic nerves by their pulse rhythmicity and their increases with Valsalva straining. We amplified, rectified, and integrated the filtered microneurographic signal with a Nerve Traffic Analyzer (model 662C-3, University of Iowa Bioengineering). We digitized all signals at 250 Hz with commercial hardware and software (Windaq, Dataq Instruments).Experimental Protocol
We assessed baroreflex gain and baroreflex slopes from 5-min recordings during supine rest. Baroreflex responses were provoked by intravenous bolus injections of sodium nitroprusside [100 µg (n = 3 subjects) or 150 µg (n = 15 subjects)] followed ~60 s later by phenylephrine hydrochloride [150 µg (n = 18 subjects)]. The entire sequence was completed within ~3 min. We characterized systolic pressure responses to sequences of nitroprusside followed by phenylephrine and phenylephrine followed by nitroprusside as the maximum systolic pressure change minus the baseline systolic pressure. We also measured the minimum and maximum diastolic pressures of cycles associated with sympathetic bursts. Responses of one subject to the sequence of nitroprusside followed by phenylephrine are shown in Fig. 1. In 9 of the 18 subjects a second sequence was given with the order of drug injections reversed (phenylephrine was injected before nitroprusside).
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Data Analysis
We normalized sympathetic bursts as follows: the largest sympathetic burst occurring during the initial control period was assigned a value of 1,000 and all other bursts were normalized against this standard. Baseline muscle sympathetic nerve activity was quantified as the number of bursts per minute, the number of bursts per 100 heartbeats, and burst area in arbitrary units per heartbeat. Muscle sympathetic bursts were advanced by 1.3 s to compensate for peripheral nerve conduction delays (14).Sympathetic Baroreflexes
We calculated pharmacological sympathetic baroreflex gains after vasoactive drug injections according to the method of Ebert and Cowley (8) as adapted by our laboratory (21, 30). We integrated muscle sympathetic nerve activity over 2-mmHg changes of diastolic pressure, expressed as percentages of the average baseline sympathetic activity. We characterized sympathetic baroreflex gains as the slope of the linear regression between the integrals of muscle sympathetic bursts and the changes of diastolic pressure in all bins. Our analysis began at the time of the first vasoactive drug injection and ended at the time of recovery of arterial pressure after the second injection. For these regressions we did not include diastolic pressure bins that had no sympathetic bursts. As suggested by Fig. 1, pairs of sympathetic activity and diastolic pressure changes during rising and falling pressure fell on the same relation; therefore, we pooled all pairs during both falling and rising pressures to calculate a single baroreflex sympathetic gain.We also attempted to gauge sympathetic baroreflex gains from spontaneous changes of diastolic pressure and time-adjusted muscle sympathetic nerve activity during the 5-min control periods (45). For this, we performed least squares linear regression analysis of integrated muscle sympathetic nerve activity in all 2-mmHg diastolic pressure bins.
Vagal Baroreflexes
Vagal cardiac baroreflex gain was characterized with least squares linear regression analysis of each R-R interval plotted as a function of the systolic pressure of the preceding cardiac cycle [lag of one (11, 32)] beginning with the first concordant changes of systolic pressures and R-R intervals after the first drug injection and continuing until systolic pressure and R-R interval changes became discordant. We plotted responses to phenylephrine and nitroprusside separately and accepted only regressions with correlation coefficients (r)
0.70 (42).
We also characterized spontaneous vagal cardiac baroreflex gains in two ways with a menu-driven software package developed by our group (1). First, the software scanned recordings for concordant systolic pressure and R-R interval sequences (15, 22). We defined a spontaneous sequence as a ramp of three or more consecutive cardiac cycles with increasing or decreasing systolic pressures of at least 1 mmHg/heartbeat. After vasoactive drug injections, we correlated each systolic pressure with the R-R interval of the next heartbeat. We pooled and averaged data as "up sequences" and "down sequences."
Second, we estimated vagal-cardiac baroreflex gain with a method based on the modulus of cross-spectral analysis of systolic pressures and R-R intervals (1, 6, 37, 43). We estimated baroreflex gain with the square root of ratios of systolic pressure and R-R interval powers in the low-frequency (0.05-0.15 Hz) band, over ranges with coherence >0.50 (6, 46).
Statistical Analysis
Some data sets were distributed normally and others were not. For paired comparisons, we used the paired t-test for normally distributed data and we used Wilcoxon's signed rank test for nonnormally distributed data. For multiple measures in the same subjects, we used the repeated-measures analysis of variance with the Student-Newman-Keuls test for pairwise comparisons for normally distributed data, and we used the Friedman test for nonnormally distributed data. We assessed interrelations among these parameters and their relations to the subjects' baseline characteristics with linear regression analysis. Differences were considered significant when P
0.05.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hemodynamic Responses
Average systolic pressure responses of all subjects to vasoactive drugs are depicted in Fig. 2 and listed in Table 1. Initial injections of nitroprusside [100 µg (n = 3 subjects) or 150 µg (n = 15 subjects)] reduced average systolic pressures by 31 ± 18 (SD) mmHg. The range of pressure reductions was wide (12-76 mmHg), and the extent of the reductions in the 15 subjects given 150-µg doses was inversely related to the subjects' ages [r =
0.812,
P < 0.001 (Fig.
3)]. Nitroprusside given after
phenylephrine reduced average systolic pressures to
26 ± 12 mmHg below baseline levels, a reduction similar
(P = 0.55) to that which occurred when
nitroprusside was given first.
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Phenylephrine given before nitroprusside increased average systolic pressures by 22 ± 7 mmHg. Phenylephrine given after nitroprusside returned average systolic pressures to 18 ± 11 mmHg above baseline levels, a level similar to that attained when phenylephrine was given first (P = 0.40). The extent of pressure elevations after phenylephrine was unrelated to the age of the subject (P = 0.17).
Sympathetic Mechanisms
Subjects' ages correlated directly and significantly with their baseline muscle sympathetic nerve activity [expressed as bursts/min (r = 0.68, P = 0.002), bursts/100 heartbeats (r = 0.62, P = 0.006), and burst area/heartbeat (r = 0.50, P = 0.04)]. There was no significant correlation (P = 0.55) between subjects' diastolic pressures and their baseline muscle sympathetic nerve activity.We required pharmacological sympathetic baroreflex gains to have
r > 0.50 (5). Fifteen slopes derived
from the sequence of nitroprusside followed by phenylephrine (average
r = 0.75 ± 0.15) and seven
slopes derived from the phenylephrine followed by nitroprusside
sequence (average r = 0.68 ± 0.17) met this criterion. Subdivision of responses from complete
(nitroprusside followed by phenylephrine or phenylephrine followed by
nitroprusside) sequences into increasing and decreasing segments
usually yielded only short segments with few data points and
insignificant correlation coefficients. In subjects (including the one
whose data are shown in Fig. 1) for whom the separate segment analysis
was feasible, sympathetic baroreflex gains during increasing segments
were not significantly less (P = 0.06)
than gains during decreasing segments.
Significant slopes derived from both drug sequences were found in only
five subjects. In these subjects, the average gain from the sequence of
nitroprusside followed by phenylephrine was not significantly higher
than the average gain from the sequence of phenylephrine followed by
nitroprusside (12.5 ± 6.4 vs. 7.4 ± 4.9%/mmHg,
P = 0.15). Baseline diastolic
pressures before the two sequences were similar (66.2 ± 14.3 vs.
68.1 ± 14.9 mmHg; P = 0.17).
Importantly, the minimum and maximum pressures associated with
sympathetic bursts were similar after the sequences of nitroprusside followed by phenylephrine and phenylephrine followed by nitroprusside (51.8 ± 14.4 vs. 55.8 ± 17.1, P = 0.30 and
70.8 ± 12.3 vs. 75.1 ± 16.2 mmHg,
P = 0.56). There was no significant
correlation (P = 0.72) between
subjects' ages and sympathetic baroreflex gains.
Significant spontaneous sympathetic baroreflex gains were found in baseline recordings of only five subjects. Sympathetic baroreflex gains did not correlate significantly with pharmacological sympathetic gains (r = 0.44, P = 0.46). Comparisons of recordings from subjects who had significant spontaneous baroreflex gains with those subjects who did not indicated that subjects with significant spontaneous sympathetic baroreflex gains had lower levels of baseline sympathetic nerve activity (11.2 ± 5.7 vs. 23.3 ± 11.3 bursts/min, P = 0.04).
Vagal Mechanisms
We documented acceptable (coherence > 0.50) cross-spectral baroreflex gains in only 8 of the 18 subjects (44%). Conversely, we identified spontaneous up- and down-sequence baroreflex relations in all subjects. Down-sequence baroreflex gains correlated well (r = 0.78, P = 0.001) with nitroprusside gains; however, the average spontaneous down-sequence gain was substantially higher than the pharmacological gain (14.5 ± 10.3 vs. 7.8 ± 4.8 ms/mmHg and average difference 4.3 ± 3.7 ms/mmHg; P < 0.01). Similarly, up-sequence baroreflex gains correlated well (r = 0.75) with phenylephrine gains [13.2 ± 10.5 vs. 12.5 ± 7.8 ms/mmHg and average difference 1.5 ± 5.2 ms/mmHg; P = not significant (NS)]. Correlations between cross-spectral baroreflex gains and nitroprusside and phenylephrine gains were strikingly good (r = 0.89 and 0.95, both P = 0.003); however, the average cross-spectral baroreflex gain (18.9 ± 12.0 ms/mmHg) was substantially higher than the average nitroprusside and phenylephrine slopes (average differences: 8.5 ± 6.1 and 3.6 ± 3.6 ms/mmHg; P < 0.01 and NS, respectively).Table 1 gives average pharmacological vagal baroreflex gains for all study subjects. Slopes with acceptable correlation coefficients (r values arbitrarily set at 0.70) were present after 23 out of 27 nitroprusside injections and after 20 out of 27 phenylephrine injections. In the nine subjects given sequences of both nitroprusside followed by phenylephrine and phenylephrine followed by nitroprusside, acceptable nitroprusside slopes were obtained in all nine and acceptable phenylephrine slopes were obtained in eight subjects. In contrast, in the nine subjects given only one sequence, acceptable nitroprusside slopes were obtained in seven subjects and acceptable phenylephrine slopes were obtained in six subjects. There was no significant correlation between sympathetic and vagal baroreflex gains after either sequences of nitroprusside followed by phenylephrine or phenylephrine followed by nitroprusside (r = 0.16 and 0.003; P = 0.58 and 0.99, respectively).
Baroreflex slopes calculated from pressure reductions were similar when
nitroprusside was given before and after phenylephrine (8.1 ± 4.8 vs. 8.5 ± 6.0 ms/mmHg, P = 0.87).
Similarly, baroreflex slopes calculated from pressure elevations were
similar when phenylephrine was given before or after nitroprusside
(12.8 ± 8.1 vs. 12.9 ± 5.6 ms/mmHg;
P = 0.96). When baroreflex responses
during both sequences were pooled, nitroprusside slopes were
significantly lower than phenylephrine slopes (8.3 ± 5.1 vs. 12.8 ± 7.2 ms/mmHg; P = 0.02). Baroreflex slopes
measured during falling and rising pressures correlated closely with
each other (r = 0.85, P < 0.001). Both nitroprusside and
phenylephrine slopes were related significantly and inversely to
subjects' ages (r = 0.77 and
0.73, P = 0.003) and baseline
arterial pressures (r = 0.56
and 0.60, P = 0.006).
Figure 4 shows average changes in
pharmacological baroreflex responses for all subjects.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We critically evaluated the method of baroreflex testing with sequential intravenous bolus injections of nitroprusside followed by phenylephrine and phenylephrine followed by nitroprusside in healthy subjects and drew inferences regarding human vagal and sympathetic baroreflex physiology. Our results suggest that when human baroreflexes are tested with vasoactive drugs, both nitroprusside and phenylephrine should be given, and the dose of nitroprusside should be smaller for older than for younger subjects. Vagal baroreflex slopes are greater when pressures are rising than when they are falling. This difference represents true hysteresis rather than movement of subjects from the linear to the threshold regions of their arterial pressure R-R interval response relations (36), because differential responsiveness is present when pressures are lowered from supranormal, as well as from usual levels. Sympathetic baroreflex gain is comparable during falling and rising arterial pressures; however, because small pressure elevations silence muscle sympathetic motoneurons, sympathetic responses are elicited primarily when arterial pressures fall below usual levels.
Sequential Vasoactive Drug Injections as a Test of Human Baroreflex Function
Our analysis yielded several practical insights into human baroreflex testing with sequential vasoactive drugs. First, the range of arterial pressure reductions after nitroprusside injections is wide, and the extent of pressure reductions is related directly to subjects' ages. Although the anesthesiology literature indicates clearly that nitroprusside doses should be adjusted for the age of the patient (49), we found no evidence that this practice is followed when nitroprusside is given for baroreflex testing. However, Sellgren and colleagues (39) gave an initial small nitroprusside dose to their subjects with no reference to age and then increased the dose until the desired pressure reduction was achieved. On the basis of our findings (Fig. 3), we suggest that nitroprusside doses given to older subjects should be smaller than doses given to younger subjects.Second, in some subjects, phenylephrine given after nitroprusside failed to raise systolic pressure to 20 mmHg above baseline levels (Fig. 2). Accordingly, we recommend, as did Parlow (31) and James (24) and their co-workers, that arterial pressure elevations provoked by the first injection of phenylephrine should be evaluated and the phenylephrine dose increased if the pressor response is inadequate.
Third, we found that very similar sympathetic baroreflex responses are obtained during both of the vasoactive drug sequences we used. Therefore we make no recommendation regarding which drug, nitroprusside or phenylephrine, should be given first.
Fourth, because sympathetic responses fall on the same trajectory with both sequences, we recommend that the two drugs be given close together as a sequence rather than separately with an intervening period to allow pressures to return to preinjection levels (28). This recommendation is made simply on the basis of efficiency to reduce the amount of time required for experimental observations to be made.
Fifth, we were more likely to obtain satisfactory
(r 0.70) nitroprusside and
phenylephrine vagal baroreflex relations when we gave two sequences
rather than one. Therefore, we recommend that at least two drug
sequences be given and the results pooled.
Finally, we found that as in an earlier study (13), the small pressure elevations provoked by phenylephrine silence muscle sympathetic nerve firing. Therefore, we recommend that if only one vasoactive drug were to be given, it should be nitroprusside rather than phenylephrine. However, because vagally mediated R-R interval responses are less when pressures are reduced than when they are increased, we recommend that phenylephrine also be given if the goals include characterization of full vagal baroreflex responses. Separate responses to falling and rising pressures yield more information about vagal baroreflex gain than lumped results. A corollary of this is that when spontaneous baroreflex responses to concordantly increasing and decreasing arterial pressure and R-R interval sequences are measured, results from down and up sequences should be reported separately (24) rather than averaged (22, 31, 47). This may also be an argument in favor of baroreflex estimates based on systolic pressure R-R interval sequences, rather than cross spectra, because cross-spectral analyses are based on concordant arterial pressure and R-R interval changes independent of their direction.
We, as others before us (1, 24, 31, 34, 47), documented close correlations between pharmacological and spontaneous baroreflex responses. Such significant correlations suggest that both types of measurements reflect arterial baroreflex mechanisms. This was proven more directly by Bertinieri and co-workers (2), who reported that sequences of concordant arterial pressure and R-R interval changes in cats are nearly abolished by arterial baroreceptor denervation.
We also confirmed previous observations (1, 24, 31, 47) that baroreflex gain derived from pharmacological and spontaneous baroreflex measurements are not identical. Our study, and an earlier study (24), indicate that pharmacological baroreflex gains are lower (usually by a small amount) than spontaneous baroreflex gains. It is not clear which method should be considered the "gold standard." The pharmacological method (42) was described before the sequence method (2, 15) and therefore has historical precedence. However, drugs have complex modes of actions and probably exert influences on baroreflex function that are independent of the changes of arterial pressure they provoke (47, 48). It may not be necessary to decide if one method is "wrong" and the other "right." Human arterial baroreflex gain is influenced by many factors and is changing continuously (16, 40). Therefore, there may be no reason to expect that baroreflex gain measured at different times during an experimental session should be identical. Indeed, Airaksinen and co-workers (1) showed that correlations between phenylephrine and spontaneous (cross-spectral) baroreflex gains were closer when the two measurements were made one after the other than when the two measurements were separated by an interval. Finally, because there is strong statistical correlation among the various methods, it may not matter which method is used, if the aim is merely to derive an index that quantifies baroreflex gain in an individual subject.
Human Sympathetic and Vagal Baroreflex Physiology
Baroreflex hysteresis. Shortly after the Oxford method for studying human arterial baroreflexes was described (42), Pickering and his colleagues (33) reported that R-R interval shortening during arterial pressure reductions is less than R-R interval lengthening during arterial pressure elevations. Subsequently, Eckberg (10) made similar observations from responses to reductions and increases of baroreceptor activity triggered by neck pressure and suction. In his study, the resting positions of the healthy young volunteers lay on the linear portion of their sigmoid carotid distending pressure R-R interval relations [described by Koch (25)] but close to the threshold. Therefore, it seemed likely that disparities between responses to falling and rising levels of baroreceptor stimulation resulted simply because responses to pressure reductions occurred over the less steep threshold portion of the baroreflex stimulus response relation.
This possibility is supported by the very recent observations of Bonyhay and colleagues (3), who measured common carotid artery diameter echographically and showed that increases of carotid artery diameter are steeper after phenylephrine administration than decreases after nitroprusside. Further support for this hypothesis comes from the study of Burke and co-workers (4), who documented hysteresis in single and multiple fiber carotid sinus nerve firing in response to mechanically induced arterial pressure changes. We did not measure carotid artery dimensions in the present study, and therefore, we do not know if asymmetries of carotid responses to falling and rising pressures were present in our subjects. However, it seems unlikely that the hysteresis we observed reflects differences in the portion of the sigmoid baroreceptor cardiac reflex relation over which pressure changes occurred. We found that the disparity between R-R interval responses to falling and rising pressures is present when pressures are lowered from supranormal levels (i.e., when nitroprusside is given after phenylephrine), as well as from usual levels (when nitroprusside is given first). A second reason to exclude a shift on the operating range of the arterial pressure baroreflex relation is that sympathetic responses of our subjects [and those reported by Ebert and Cowley (8)] to falling and rising pressures lay on the same trajectory (Figs. 1 and 4). This finding also mitigates against the resetting of baroreflexes, which can occur in healthy subjects within seconds of changes of barorecepror input (40). Differences between sympathetic and vagal responses to falling and rising pressures may exist because vagal and sympathetic motoneurons are modulated by different aspects of baroreceptor firing. Sundlöf and Wallin (44) proposed that muscle sympathetic nerve firing is modulated by diastolic but not systolic pressure. According to this construct, any firing of baroreceptor neurons silences muscle sympathetic motoneurons. After the peak of systolic pressure, when baroreceptors fall silent (26), sympathetic motoneuron activity resumes in inverse proportion to the level of diastolic pressure achieved. In this connection, Bonyhay and colleagues (3) reported that although the systolic pressure common carotid artery diameter relationship is more shallow when arterial pressure is reduced than when it is increased, the diastolic pressure carotid diameter relationship is nearly equal during pressure reductions and elevations. Therefore, all of our results can be explained on the basis of mechanical hysteresis of baroreceptive arteries.Baroreflex Responsiveness and Baseline Autonomic Outflow
Several reports document significant relations among levels of baseline autonomic nerve activity and sympathetic and vagal baroreflex gains. Goldstein (17) and Carlson et al. (5) reported significant inverse relations between the vagal baroreflex gain and resting levels of plasma norepinephrine or muscle sympathetic nerve activity. Grassi and colleagues (18, 19) found significant inverse relations between baseline muscle sympathetic nerve activity and the baroreceptor-sympathetic response relations. We found no significant relation between baseline sympathetic nerve activity and vagal or sympathetic baroreflex gain. We suggest that the significant correlations reported by others result from inclusion of patients with hypertension (17), sleep apnea (5), heart failure (18), or obesity (19), who have pathologically increased baseline levels of sympathetic activity and decreased levels of vagal activity. This conclusion is supported by the study of heart failure patients by Porter and co-workers (35), which documented a steep inverse relation between plasma norepinephrine or muscle sympathetic nerve activity and peak minus valley R-R interval fluctuations, taken as an index of resting vagal-cardiac nerve activity.The inverse relation between resting sympathetic nerve activity and sympathetic baroreflex gain in patients may represent, in part, a ceiling effect; levels of sympathetic nerve traffic that are high at baseline may have limited capacity to increase further. Smith and co-workers (41) showed that the intensity of muscle sympathetic nerve responses to sudden arterial pressure reductions provoked by induced premature ventricular beats is related inversely to baseline sympathetic activity. When sympathetic nerve activity is high (in the study by Smith, during nitroprusside infusion), sympathetic responses to pressure reductions are low. Schobel and colleagues (38) reported that healthy subjects with high resting levels of muscle sympathetic nerve activity have reduced sympathetic augmentation during lower body suction. A ceiling effect may also explain the limited sympathetic responses of aged subjects who have elevated baseline levels of sympathetic nerve activity to upright tilt (27).
Aging
In agreement with previous studies (20, 23, 45, 50), we found that baseline muscle sympathetic nerve activity correlates directly and vagal baroreflex gain correlates inversely with subjects' ages. In contrast, we and others (9, 28) have found no correlation between sympathetic baroreflex gain and age.Relation Between Sympathetic and Vagal Baroreflexes
Miyajima and co-workers (29) reported an inverse correlation between sympathetic baroreflex slope and nitroprusside-induced vagal baroreflex slope (but not phenylephrine-induced vagal baroreflex slope). We found no correlation between sympathetic and vagal baroreflex gains and suggest that the correlation reported by Miyajima resulted from inclusion of hypertensive patients in his study.In conclusion, we systematically evaluated sympathetic and vagal responses of healthy subjects to sequential injections of nitroprusside and phenylephrine. Our study provides new guidelines for use of vasoactive drug sequences to study baroreflex responses and yields some new insights into mechanisms governing human autonomic cardiovascular neural outflow.
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ACKNOWLEDGEMENTS |
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This study was supported in part by grants from the Department of Veterans Affairs, the National Institutes of Health (HL-22296), and National Aeronautics and Space Administration (Contracts NAS9-19541 and NAG2-408).
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FOOTNOTES |
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L. Rudas is a visiting scientist from Albert Szent-Gyorgyi Medical University, Szeged, Hungary and supported by a grant from the Soros Foundation.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: D. L. Eckberg, Hunter Holmes McGuire Dept. of Veterans Affairs Medical Center, 1201 Broad Rock Blvd., Richmond, VA 23249 (E-mail: deckberg{at}aol.com).
Received 1 October 1998; accepted in final form 26 January 1999.
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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