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1 Department of Integrative Physiology and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth 76107; and 2 Institute for Exercise and Environmental Medicine, Dallas, Texas 75231
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study was designed to investigate the importance of
vagal cardiac modulation in arterial blood pressure (ABP) stability before and after glycopyrrolate or atropine treatment. Changes in R-R
interval (RRI) and ABP were assessed in 10 healthy young (age, 22 ± 1.8 yr) volunteers during graded lower body negative pressure (LBNP)
before and after muscarinic cholinergic (MC) blockade. Transient
hypertension was induced by phenylephrine (1 µg/kg body wt), whereas
systemic hypotension was induced by bilateral thigh cuff deflation
after a 3-min suprasystolic occlusion. Power spectral densities of
systolic [systolic blood pressure (SBP)] and diastolic ABP
variability were examined. Both antimuscarinic agents elicited tachycardia similarly without significantly affecting baseline ABP. The
increase in SBP after phenylephrine injection (+14 ± 2 mmHg) was
significantly augmented with atropine (+26 ± 2 mmHg) or
glycopyrrolate (+27 ± 3 mmHg) and associated with a diminished reflex bradycardia. The decrease in SBP after cuff deflation
(
9.2 ± 1.2 mmHg) was significantly greater after atropine
(15 ± 1 mmHg) or glycopyrrolate (14 ± 1 mmHg), with
abolished reflex tachycardia. LBNP significantly decreased both SBP and
RRI. However, after antimuscarinic agents, the reduction in SBP was
greater (P < 0.05) and was associated with less
tachycardia. Antimuscarinic agents reduced (P < 0.05)
the low-frequency (LF; 0.04-0.12 Hz) power of ABP variability at
rest. The LF SBP oscillation was significantly augmented during LBNP,
which was accentuated (P < 0.05) after antimuscarinic
agents and was correlated (r = 0.79) with the decrease in SBP. We conclude that antimuscarinic agents compromised ABP
stability by diminishing baroreflex sensitivity, reflecting the
importance of vagal cardiac function in hemodynamic homeostasis. The
difference between atropine and glycopyrrolate was not significant.
baroreflex gain; glycopyrrolate; power spectral analysis; lower body negative pressure; phenylephrine; suprasystolic occlusion; Valsalva maneuver; vasomotion
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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WE RECENTLY
IDENTIFIED a greater decrease in arterial blood pressure (ABP)
associated with a diminished tachycardiac response at the onset of 40
Torr lower body negative pressure (LBNP) in elderly compared with young
adults (21). This attenuated increase in heart rate (HR)
at the onset of orthostatic challenge results primarily from an
age-related diminution in vagal cardiac function (21).
When the muscarinic cholinergic (MC) antagonists atropine or
glycopyrrolate were administered to young subjects to block cardiac
parasympathetic efferent influences, their tachycardiac response to the
onset of 40 Torr LBNP was abolished. The attenuated tachycardia was
associated with a significant hypotension, a response similar to that
seen in the elderly individual (21). When the 
1-adrenoceptor antagonist metoprolol was administrated
to the same young subjects to block the cardiac sympathetic nerve
efferent influence, neither the ABP nor the HR response was affected at the onset of 40 Torr LBNP (21). However, the impact of
vagal cardiac function on ABP variability during graded sustained
orthostatic challenge has yet to be established.
One of the major purposes of this study was to investigate the role of the parasympathetic efferent arm of the baroreflex in maintaining ABP stability. Previously, Saul et al. (19) observed that both systolic (SBP) and diastolic blood pressure (DBP) variance increased significantly during a body postural change from supine to standing with or without cardiac autonomic blockade. However, they did not describe the changes in SBP and DBP spectral density elicited by standing (19). Taylor et al. (24) demonstrated that the low-frequency (LF) power of ABP oscillation was significantly augmented during 40° head-up tilt. However, the augmentation in the LF power of ABP oscillation during tilt combined with atropine did not reach significance (23), probably due to the lack of significant hypotensive challenge. This investigation was designed to further consider the relationship between hypotension and LF ABP variability during graded and sustained hypotensive stimuli before and after vagal cardiac blockade.
Atropine is a common antimuscarinic agent that has been applied to study vagal cardiac function under the influence of heart disease (7, 13, 17) and during orthostatic challenge (19, 20, 22, 24). It has been established that baroreflex function is impaired after atropine treatment. Because atropine penetrates the blood-brain barrier, it blocks both central and peripheral MC receptors (1, 3) and alters central autonomic nervous system activity (10, 14). The antimuscarinic agent glycopyrrolate has little influence on the central nervous system (3). Equipotent doses of atropine and glycopyrrolate (2, 5) were thus applied to establish the vagal cardiac contribution to ABP stability during dynamic hypertensive and hypotensive stimuli. Although previous studies have compared atropine and glycopyrrolate differences in HR response (5) and HR variability (2), we believe that this is the first study to investigate the effects of these antimuscarinic agents on the dynamic control and regulation of ABP. We hypothesized that use of antimuscarinic agents would simulate vagal dysfunction and compromise ABP regulation but that the degree of change in ABP regulation with atropine blockade would differ from that during glycopyrrolate blockade of the MC receptors.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. Ten disease-free and drug-free volunteers (age, 22 ± 1.8 yr; n = 7 men and 3 women) were recruited as subjects. On a preliminary screening day, all subjects completed a medical history questionnaire and provided a resting 12-lead electrocardiogram (ECG) and arterial blood pressure (ABP). All female subjects who participated in the study had a negative pregnancy test before the initiation of the study. Eligible subjects received both oral and written explanation of the experimental protocol and signed a written consent form that was approved by the Institutional Review Board for the Protection of Human Subjects at the University of North Texas Health Science Center (Fort Worth, TX).
Measurements.
During each experiment, beat-to-beat HR, SBP, DBP, and mean ABP (MAP)
signals were digitized (Vetter Digital 3000) and collected using an
on-line personal computer (Gateway 2000, 486DX) interfaced by an
analog-to-digital board (Data Translation DT2801; Marlboro, MA) with a
software sampling rate at 150 Hz. The lead II ECG signal was used to
monitor HR on an electrocardiograph (Hewlett-Packard 78342A). On
experimental day 1, an ABP signal was established using
intraradial arterial catheterization. A physician, using local
anesthesia to minimize subject discomfort, performed the catheter
insertion. During experimental day 2, indirect radial tonometry (Colin 7000) was utilized. Previous data (11)
indicated a close correlation between tonographic and direct ABP
measurements. Our laboratory observations indicated that carefully
monitored indirect measurements of radial arterial pressure by
tonography were highly correlated with intraradial arterial catheter
measurements (Fig. 1). Although radial
pressure signals have a tendency to amplify systolic ABP values
compared with brachial or aortic pressure measurements, this effect is
insignificant when the comparisons are made before and after atropine
or glycopyrrolate in the same subjects. A venous catheter was inserted
into the subject's median antecubital vein for intravenous drug
injections and blood samples. Venous blood was collected during
baseline and 40 Torr LBNP before and after drug administration for
measurement of the plasma catecholamines. Each 5-ml sample was
centrifuged at 4°C for 15 min and frozen at 90°C, and the
supernatant was analyzed using HPLC within 2 wk. Stroke volume (SV) and
cardiac output (CO) values were collected by impedance plethysmography
(Minnesota Impedance Cardiograph). Minute SV was averaged from the data
collected over 50 s using commercially available software
(Bio-Impedance Technology; Chapel Hill, NC). Peripheral vascular
resistance (PVR) was then calculated from the equation PVR = MAP/CO. A 2.8% coefficient of variation was found for SV repeatedly
measured in one subject at rest on three different days. Because
thoracic impedance and tonographic ABP measurements shared the same
computer channel, SV and CO were only determined during the experiments
in which direct ABP was monitored.
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Protocol.
Before each experiment, subjects were familiarized with the procedures
and measurements to be used during the test. All experiments were
carried out with the subject supine in the LBNP chamber, with an
ambient temperature of 24-26°C. The subjects were encouraged to
stay relaxed throughout the testing. After 30 min of rest, baseline
values for 10 min of HR, ABP, SV, and CO were recorded. At the end of
baseline data collection, bilateral thigh cuffs were inflated to 
200
mmHg for 3 min to create regional ischemia. The tachycardiac
response to a systemic hypotension after deflation of the bilateral
thigh cuffs was monitored. Phenylephrine was then injected at 1.0 µg/kg body wt to create transient hypertension. In addition, the
Valsalva maneuver was performed in some subjects before and after
parasympathetic blockade to compare the difference in hypertensive
effect during the release phase (Fig. 2).
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40, 50, and 60 Torr. At the end of 40 Torr LBNP, blood
samples were taken for epinephrine and norepinephrine concentrations. After graded LBNP, the subject was released from the
LBNP box and allowed to rest for 45 min to allow recovery. After the
subject returned to the LBNP box, either atropine or glycopyrrolate was
injected intravenously (5.0 or 2.0 µg/kg, respectively) to achieve
full MC blockade. Injections were administered over several minutes
until the subject's HR achieved a plateau, such that two consecutive
doses did not yield any additional increase in HR, or until the maximum
allowable dosage (40 or 16 µg/kg, respectively). Upon completion of
drug injection, the above protocol was repeated in its entirety. After
the experiment was concluded, the subject was observed for 30 min to
ensure proper recovery. On the experimental day 2, the
subject received either atropine or glycopyrrolate, whichever drug was
not used on day 1, and the day 1 protocol was
repeated. The order of the experiments using atropine or
glycopyrrolate was randomly assigned.
Data management.
Each 10-min data set was plotted using SigmaPlot software and examined
for variance, beat-to-beat pulse interval [R-R interval (RRI)], HR,
SBP, and DBP from the selected 6-min segment with the least variation.
The data from the 6-min "steady-state" segment were then linearly
interpolated and resampled at 2 Hz. After resampling, the data were
detrended with a third-order polynomial fitting and divided into
128-point segments with 50% overlap for fast Fourier transform
analysis using the templates created with the data analysis and display
software (DADiSP/ AdvDSP, DSP Development; Cambridge, MA). Group
power spectral density curves for RRI, SBP, and DBP variability are
shown in Fig. 3. Harmonic power in the high frequency (HF; 0.20-0.28 Hz) and LF (0.04-0.12 Hz) was
extracted. In addition, HF and LF of RRI variability was normalized
from the ratio of HF to LF + HF [HF/(LF + HF)] and the
ratio of LF to LF + HF [LF/(LF + HF)]. The magnitude at LF
and HF spectra was compared between the baseline and during LBNP before
and after parasympathetic blockade.
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(f) = arctan[HI(f)]/[HR(f)] between the SBP and RRI signals. The coherence
[C(f)] was calculated as
C(f) = CS(SBP)(RRI)(f) 2/[ASRRI(f) × ASSBP(f)], where
ASRRI(f) is the autospectrum RRI variability, to determine the linear relation between the signals as
described previously (19, 27).
The slopes of the HR response to ABP changes after phenylephrine
injection (hypertensive stimulus) and bilateral thigh cuff deflation
after 3-min suprasystolic occlusion (hypotensive stimulus) were
calculated as the index of baroreflex sensitivity (gain). The rate of
change in ABP after hypertensive and hypotensive intervention was
determined by the magnitude of the change divided by the time (t; in s).
Data are reported as group means ± SE. Because only one subject
completed the protocol of 60 Torr LBNP after MC blockade using
atropine or glycopyrrolate, the single subject data were excluded
(Table 1). One-way (e.g., drug factor) or
two-way (e.g., drug and LBNP factors) ANOVA was used to test for
significance. If the ANOVA P value was 
0.05 in drug factor
(i.e., control, atropine, and glycopyrrolate) or LBNP factor (i.e.,
baseline, 40, 50, and 60 Torr), a post hoc test for multiple
comparison of the means (Duncan's method) was applied. Simple linear
regression analysis was used to test for significance in the
correlation between the variables. Analysis of covariance was used to
test for differences in the rate of changes for different slopes.
Statistical analysis system software was used for all analyses, and
significance was set at P < 0.05 for all statistical
tests.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Baseline HR or pulse interval (RRI), SBP, DBP, MAP, pulse pressure (PP), RRI variability, and ABP variability were not different in the two experiments before MC blockade using atropine or glycopyrrolate. Thus the baseline data were combined into one baseline. Both atropine and glycopyrrolate increased the baseline HR without a significant effect on ABP (Table 1). Previously, studies (19, 23) have shown a significant increase in ABP after atropine, whereas others (17, 22) found no significant ABP augmentation. The cause for the inconsistency is unknown. The tachycardiac effect was not different between the two antimuscarinic agents. LBNP elicited significant tachycardia associated with significant decreases in SBP and PP. However, MAP and DBP were not significantly altered by LBNP. The magnitude and the rate of decrease in PP or SBP during LBNP were greater after MC blockade with atropine or glycopyrrolate. However, this change in PP or SBP was not statistically different between atropine and glycopyrrolate (Table 1).
Atropine and glycopyrrolate administration produced similar reductions
(P < 0.05) in the baroreflex slope (calculated from the changes in HR to SBP) during systemic hypotension induced by the
bilateral thigh cuff deflation after 3-min suprasystolic occlusion and
systemic hypertension induced by a phenylephrine injection of 1 µg/kg
body wt (Table 2). However, there was no drug-related difference in the baroreflex slopes between the two antimuscarinic agents. After atropine or glycopyrrolate blockade, the
increase in ABP to the same dose of phenylephrine and the decrease in
ABP to the same cuff deflation protocol were significantly augmented
(Table 2).
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Figure 2 illustrates individual changes in RRI and MAP after release of
the Valsalva maneuver (a nonpharmacological intervention) before and
after atropine administration. The group SBP and DBP (n = 5) were not different before the Valsalva maneuver with (134 ± 8 and 73 ± 9 mmHg) or without MC blockade (136 ± 5 and
72 ± 6 mmHg). After the release of the Valsalva maneuver,
increases in SBP and DBP were substantially (P < 0.05)
augmented with MC blockade (+51 ± 12 and +40 ± 7 mmHg)
compared with control (+26 ± 9 and +13 ± 4 mmHg). The
duration and intensity of the Valsalva strain, indicated by the
increases in thoracic impedance, were similar before (15.1 ± 1.8 s and +1.75 ± 0.22 
) and after (14.4 ± 1.4 s and +1.49 ± 0.15 ) MC blockade (Fig. 2). This augmented ABP
overshoot was associated with a significant diminution of the
bradycardiac response (before vs. after parasympathetic blockade: 
RRI/t, +40.6 ± 7.0 vs. +6.8 ± 1.3 ms/s; or
HR/t, 3.8 ± 0.8 vs. 1.9 ± 0.4 beats · min
1 · s1; Fig. 2).
Parasympathetic blockade using atropine or glycopyrrolate significantly
diminished RRI variability (Fig. 3). The density of the LF spectrum of
the baseline RRI variability was significantly less after
glycopyrrolate than after atropine blockade (Table 3). After normalization with the control
(before the antimuscarinic agents), this difference between atropine
(410 ± 121 ms2/Hz) and glycopyrrolate (346 ± 123 ms2/Hz) blockade was not statistically significant.
The control values before atropine (416 ± 120 ms2/Hz)
and glycopyrrolate (349 ± 123 ms2/Hz) blockade were
not statistically different. During LBNP, RRI variability tended to
increase in the LF spectrum and to decrease in the HF spectrum with or
without normalization (Table 3). The LF spectrum of RRI variability
during LBNP tended to be greater with atropine than glycopyrrolate
(P = 0.08). However, the changes in RRI variability
during LBNP were not significantly different between atropine and
glycopyrrolate. The RRI variability LF-to-HF ratio was not affected by
MC blockade; however, it was increased with LBNP (Table 3).
Parasympathetic blockade decreased (P < 0.05) the
baseline LF ABP variability without affecting the HF ABP variability
(Table 4). Baseline LF ABP variability
was significantly less after glycopyrrolate than after atropine
blockade, and the effect was associated with the baseline LF RRI
variability (Fig. 4). Application of LBNP
augmented both LF SBP variability (P = 0.002) and LF
DBP variability (P = 0.001; Fig. 3 and Table 4). The
augmented LF ABP variability during LBNP was greater after parasympathetic blockade, and the interaction of LBNP factor and drug
factor (parasympathetic blockade) on both SBP variability (P = 0.038) and DBP variability (P = 0.020) was significant (Table 4). The augmented LF ABP variability was
significantly associated with the LBNP-induced systemic hypotension
(Fig. 5). Figure 5 illustrates the group
increases in LF SBP variability associated with decreases in SBP before
and after parasympathetic blockade during graded LBNP
(r = 0.79, P = 0.037), which was
consistent with the correlation when calculated using individual data
(r = 0.46, P = 0.001).
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Atropine tended to have a greater effect on LBNP-induced augmentation
in LF ABP variability compared with the glycopyrrolate effect. However,
the difference between the two drugs did not reach a significance level
in SBP variability (P = 0.09) or DBP variability
(P = 0.16). Parasympathetic blockade with atropine or
glycopyrrolate significantly decreased the magnitude of the transfer
function of SBP variability to RRI variability (Table 4 and Fig.
6). There was no difference in the
abolished transfer function between the two drugs. The coherence of the
transfer function at the HF spectrum disappeared after atropine or
glycopyrrolate treatment. LBNP significantly decreased the HF magnitude
of the transfer function in the control condition (without
parasympathetic blockade) but had no apparent effect on the LF transfer
function. The coherence of the transfer function during LBNP tended to
increase at the LF spectrum and decrease at the HF spectrum (Table 4).
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Baseline plasma epinephrine and norepinephrine concentrations
(0.43 ± 0.18 and 1.42 ± 0.21 pmol/ml) were not affected by
atropine (0.22 ± 0.07 and 1.18 ± 0.33 pmol/ml) or
glycopyrrolate (0.38 ± 0.12 and 1.21 ± 0.11 pmol/ml)
blockade. LBNP (40 Torr) did not change epinephrine (0.39 ± 0.08, 0.18 ± 0.05, and 0.30 ± 0.01 pmol/ml in control,
atropine, and glycopyrrolate, respectively) but significantly increased
norepinephrine in the control (2.05 ± 0.27 pmol/ml) and MC
blockade conditions (atropine and glycopyrrolate: 2.44 ± 0.78 and
1.63 ± 0.28 pmol/ml). The relative increase in norepinephrine
during LBNP appeared to be greater (P = 0.18) after atropine (+108 ± 25%) than glycopyrrolate (+49 ± 26%)
compared with the responses before MC blockade (+61 ± 31% vs.
+61 ± 15%, P = 0.99).
There was no significant difference in CO after either atropine
(n = 5) or glycopyrrolate (n = 3)
administration. Because there was no observed drug difference and the
sample size was small, CO and PVR data were merged and classified into
"before" and "after MC blockade" groups. Drug administration
did not significantly change CO (7.0 ± 0.3 vs. 6.1 ± 0.2 l/min), although SV decreased significantly from a baseline of 113 ± 8.5 to 58.3 ± 2.8 ml/beat after drug administration. PVR
tended to increase after MC blockade (12.8 ± 0.7 to 14.9 ± 0.7 peripheral resistance units, P = 0.06). Figure 7 shows the decrease in CO in all
groups during minute 2 (before vs. after blockade:
17.5 ± 2.2% vs. 29.6 ± 6.4%), minute 5 (20.3 ± 2.8% vs. 34.8 ± 4.5%), and minute
8 (22.4 ± 3.0% vs. 28.8 ± 3.9%) of 40 Torr
LBNP and minute 2 (24.8 ± 3.3% vs. 29.2 ± 6.2%), minute 5 (27.5 ± 2.5% vs. 34.4 ± 4.0%), and minute 8 (28.4 ± 2.4% vs. 35.4 ± 5.1%) of 50 Torr LBNP, associated with a decrease in MAP (Fig. 7,
left). The changes in CO and MAP were consistently greater
after MC blockade (P = 0.001 from ANOVA for drug factor
on %CO, P = 0.003 from ANOVA for drug factor on
%MAP), although post hoc analysis with stratification of time or
LBNP did not reach significance. However, the rate of decrease in MAP
per unit decrease in CO was similar to the control condition
(slope = 0.43 for both groups, P = 0.66 from analysis of covariance). In addition, a greater relative decrease in CO
was explained by a reduced tachycardiac compensation after MC blockade
(Fig. 7, right), because the decrease in CO in terms of per
unit decrease in SV was greater (P = 0.016 from
analysis of covariance) after antimuscarinic agents.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The present study provided three new findings that extend previous observations on the importance of vagal cardiac function in maintaining ABP. First, our data manifested that MC blockade using atropine or glycopyrrolate was associated with an augmented amplitude of ABP fluctuations during dynamic hypertensive and hypotensive stimuli. These augmented ABP fluctuations were related to diminished baroreflex sensitivity. Second, our data indicated that sustained LBNP increased the LF spectral density of ABP variability and that the increased LF ABP oscillation was associated with systemic hypotension, which was augmented after MC blockade. Third, the difference in the arterial baroreflex function and ABP variability elicited by atropine and glycopyrrolate was not statistically significant. These data demonstrated that the integrity of vagal cardiac function was essential for the maintenance of ABP stability during various hemodynamic challenges.
Mechanism of the augmented amplitude of ABP variability.
A previous study (8) reported that the pressor response to
phenylephrine injection in tranquilized dogs was substantially augmented after atropine treatment combined with the -adrenoceptor antagonist propranolol. These authors postulated that the augmented pressor response to phenylephrine after propranolol and atropine was
related to the blockade of a peripheral vasodilation mechanism modulated by the -adrenoceptor and the cholinergic fiber
(8). Our data indicated that an augmented pressor response
to phenylephrine was present after MC blockade alone with either
atropine or glycopyrrolate (Table 2), suggesting that the
-adrenoceptor mechanism of peripheral vasodilation described by
Evans et al. (8) had little effect on ABP changes elicited
by phenylephrine. Sanders et al. (18) reported a
significant increase in forearm blood flow during contralateral arm
exercise, which was attenuated after atropine. However, the overall
response to exercise was an increase in MAP, indicating a limited
functional significance for the cholinergic vasodilatory mechanism.
Conversely, administration of atropine in conscious rats has
demonstrated no effect on the resting ABP or blood flow in various
tissues and organs (4). Although species and protocol differences must be considered when interpreting these results, we
believe that these previous studies and our current data suggest a
minimal physiological contribution from the -adrenoceptor or cholinergic fiber elicited vasodilation at rest. Furthermore, neither
the previous study (8) nor the current data support the
theory of a sensitized 
-adrenoceptor mechanism in the augmented pressor response to phenylephrine. If the -adrenoceptor sensitivity were enhanced by MC blockade, a hypotension or depressor response after
bilateral thigh cuff inflation/deflation would be diminished after
atropine or glycopyrrolate. However, MC blockade significantly exacerbated the systemic hypotension after the cuff deflation (Table
2).
LF ABP oscillations after antimuscarinic drugs. The LF spectral density of ABP variability tended to decrease after MC blockade. These data were consistent with a previous study (23) describing a significant decrease in the LF power of ABP variability after atropine with or without atenolol. This diminished LF ABP oscillation was more significant after glycopyrrolate than atropine administration (Table 4). The mechanism underlying this difference in the LF ABP oscillation before and after the MC blockade or between the two antimuscarinic agents was associated with a low LF RRI variability (Fig. 4).
It has been proposed that atropine administration may elicit opposing central and peripheral effects on vagal cardiac control (6, 10). Recent human studies (14, 26) have shown that low-dose intravenous atropine injection prolongs RRI, indicating an increase in central parasympathetic activation. Atropine also decreased the LF RRI variability in these studies, associated with a reduced LF muscle sympathetic nerve activity (MSNA) variability (14, 26). These previous data suggest that blocking central MC receptors with atropine releases the central inhibitory influence on peripheral sympathetic nerve activity. However, this central influence on HR was overcome by the effect of high-dose atropine on the sinoatrial node of the heart. In the present study, full MC blockade using atropine or glycopyrrolate elicited a similar tachycardia with no significant effect on ABP. Although the baseline LF density of ABP variability in the present investigation tended to be greater after atropine than glycopyrrolate, neither norepinephrine nor epinephrine concentration in the blood plasma was different before and after MC blockade or between the two different antimuscarinic drugs. These data suggest that the baseline sympathetic nerve activity was similar and that the difference in the baseline LF ABP oscillation (greater after atropine than glycopyrrolate) was not due to an atropine-related central effect on peripheral sympathetic nerve activity. This postulation is supported by a recent report (25) demonstrating that baseline LF ABP fluctuations without unusual maneuvers were not related to the directly measured MSNA. Furthermore, a study (12) of tetraplegic subjects who lost sympathetic neural control of vasomotor tone indicated that the LF spectral densities of RRI and LF ABP variability were correlated. Therefore, we postulated that the reduced baseline LF ABP oscillation after glycopyrrolate could be explained by a more significant decrease in LF RRI variability (Table 3 and 4). The difference in baseline LF RRI and ABP variability between atropine and glycopyrrolate was probably due to preantimuscarinic drug differences (Fig. 4). We suggested that in a closed circuit without unusual hemodynamic disturbances, the LF ABP oscillation was significantly related to the LF spectral density of RRI variability at rest (Fig. 4).LF ABP oscillation during LBNP.
Previously, Taylor et al. (24) demonstrated that the LF
power of SBP and DBP variability were significantly increased following postural change from supine to 40° head-up tilt. When the HR
response was fixed by paced rhythm, the increased LF DBP power during
head-up tilt was significantly greater than that during sinus rhythm
(24). It has been demonstrated that the ABP variability
around 0.1 Hz is significantly and positively correlated with the LF
power density of MSNA over the variety of ABP range induced by
nitroprusside and phenylephrine infusion (16).
Furthermore, it has been observed that prazosin, an
-adrenoceptor antagonist, reduces hemorrhage-augmented LF ABP
variability (9, 15). Oz et al. (15) compared
the LF ABP variability between Wistar-Kyoto normotensive (WKY) rats and
spontaneously hypertensive rats (SHR) before and after hemorrhage with
and without prazosin or the angiotensin enzyme inhibitor captopril.
They demonstrated that hemorrhage increased the ABP variability in both
groups of rats (15). Although the baseline ABP variability
was significantly less in SHR than WKY rats, the increase in ABP
variability after hemorrhage was greater in SHR than WKY rats. This
hemorrhage-induced augmentation in the ABP variability was diminished
to a similar degree in SHR and WKY groups after prazosin or captopril
administration, suggesting that activation of both the sympathetic
nervous system and the renin-angiotensin system was required for the
response to hemorrhage (15). However, LF ABP oscillation
is not significantly altered by blocking angiotensin-converting enzyme
using enalaprilat in humans during a posture change from supine to
40° head-up tilt (23) or captopril in rats during
hypotensive hemorrhage (9).
Implication of the difference in LF ABP oscillation. Application of LBNP has been commonly applied to simulate hemorrhage or orthostatic challenge. In this study, the augmented LF ABP oscillation during LBNP was attributed to changes in arterial vasomotion, modulated by the activation of the sympathetic nervous system. This enhanced vasomotion appeared to be related to systemic hypotension during LBNP, which in turn appeared to be an indication of ABP instability (Fig. 5). Our data indicated that this ABP instability, evidenced by the augmented LF ABP oscillation during LBNP, was exacerbated after vagal cardiac blockade.
It has been established that LBNP-induced central hypovolemia is able to elicit systemic hypotension. However, we observed that central hypovolemia did not necessarily produce a proportional systemic hypotension with reflex vasoconstriction until the decrease in CO reached 20% (Fig. 7). In the present study, the LBNP-induced rate of decrease in CO with MAP was identical before and after MC blockade, suggesting that the efficacy of reflex vasoconstriction was not compromised by antimuscarinic drugs during sustained LBNP. However, the decrease in MAP was consistently greater (ANOVA, P < 0.05) after MC blockade, which was explained by a greater decrease in CO during LBNP. These data implied that the susceptibility to systemic hypotension during sustained LBNP (simulated hemorrhage or orthostatic challenge) was exacerbated with MC blockade. This finding appears to confirm our previous conclusion that the integrity of vagal cardiac function was important in the maintenance of ABP at the onset of LBNP challenge (21). This ABP instability during LBNP was not due to a lack of vasomotor responsiveness but was a result of the diminished HR reflex sensitivity after MC blockade. The diminished HR response induced a relatively greater decrease in CO, which explained a greater systemic hypotension (Fig. 7). Subsequently, the vasomotor compensation mediated by neurohumoral factors was accentuated for the relatively greater unloading of the arterial and cardiopulmonary baroreceptors, which was related to ABP instability. Furthermore, this finding complements our previous report (21) by indicating that the vagal cardiac function is important in the maintenance of ABP stability during sustained orthostatic challenge.Comparison of atropine and glycopyrrolate blockade. The present study suggested that after high-dose intravenous injection of atropine and glycopyrrolate, changes in HR and ABP during pressor and depressor response were not statistically different in young healthy humans. A relatively greater increase in plasma norepinephrine levels during LBNP occurred after atropine than after glycopyrrolate blockade. However, this difference did not reach statistical significance. The baseline LF ABP and RRI variabilities were lower after glycopyrrolate than atropine blockade. This antimuscarinic agent-related difference in the baseline LF ABP and RRI variability was related to the subject's individual control values, because the changes in baseline LF ABP and RRI variability (normalized with the values before the blockade) were not statistically different. The present study confirmed that the atropine inhibitory effect on the vagal cardiac function was dominant and that the efficacy of parasympathetic blockade using 40 µg/kg atropine and 16 µg/kg glycopyrrolate was equivalent.
In summary, our data demonstrate that vagal cardiac function plays an important role in cardiovascular homeostasis. Vagal cardiac dysfunction, whether simulated with parasympathetic blockade or associated with aging, diminishes the HR reflex buffering effect and augments the amplitude of ABP fluctuations during hypertensive and hypotensive stimuli. Therefore, chronic vagal dysfunction may impose damage to the end organs and can cause clinical syndromes. During LBNP-simulated hemorrhage or orthostatic challenge, the LF ABP oscillation is augmented progressively with a systemic hypotension. These data confirm that the augmented LF ABP oscillation is an indication of ABP instability, which appears to be accentuated after vagal cardiac blockade. The difference in full parasympathetic blockade using the antimuscarinic agents atropine and glycopyrrolate was nominal.| |
ACKNOWLEDGEMENTS |
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We are indebted to Dr. Barbara Baron, Dr. James Caffrey, and Darice Yoshishige for assistance in blood sample analyses. We also sincerely thank all of our subjects for cheerful cooperation during the experiment.
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FOOTNOTES |
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The study was supported by National Institutes of Health Grants AG-14219 and HL-45547 and by University of North Texas Health Science Center Faculty research grants.
This research was submitted in partial fulfillment of the requirements for the degree of Master of Science for D. W. Wray as submitted to the University of North Texas Health Science Center.
Address for reprint requests and other correspondence: X. Shi, Dept. of Integrative Physiology, Univ. of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107 (E-mail: xshi{at}hsc.unt.edu).
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.
Received 21 February 2001; accepted in final form 26 July 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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