Journal of Applied Physiology Watch the video to see how APS reaches out to developing nations.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 100: 792-799, 2006. First published November 17, 2005; doi:10.1152/japplphysiol.00586.2005
8750-7587/06 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
100/3/792    most recent
00586.2005v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Masuki, S.
Right arrow Articles by Joyner, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Masuki, S.
Right arrow Articles by Joyner, M. J.

Reduced forearm {alpha}1-adrenergic vasoconstriction is associated with enhanced heart rate fluctuations in humans

Shizue Masuki,1 John H. Eisenach,1 Frank A. Dinenno,2 and Michael J. Joyner1

1Department of Anesthesiology, Mayo Clinic and Foundation, Rochester, Minnesota; and 2Department of Health and Exercise Science, Colorado State University, Fort Collins, Colorado

Submitted 19 May 2005 ; accepted in final form 8 November 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
In the present study, we assessed whether heart rate (HR) or arterial pressure fluctuations are enhanced in healthy young humans with reduced {alpha}-adrenergic vasoconstrictor responses and, if so, whether this occurs for both {alpha}1- and {alpha}2-adrenergic receptor-mediated vasoconstriction. Arterial pressure (brachial artery catheter) and HR (ECG) were monitored continuously, and {alpha}1- and {alpha}2-adrenergic responsiveness was determined by assessing the effects of brachial artery infusions of phenylephrine ({alpha}1-adrenergic agonist) and dexmedetomidine ({alpha}2-adrenergic agonist), respectively, on forearm blood flow (strain gauge plethysmography). {alpha}1-Adrenergic responsiveness varied markedly among the subjects (n = 20) and was inversely correlated with coefficient of variation for HR (R2 = 0.37, P < 0.01), whereas the responsiveness was not correlated with the coefficient of variation for either systolic or diastolic arterial pressure. {alpha}1-Adrenergic responsiveness was inversely and more strongly correlated with baroreflex sensitivity (R2 = 0.62, P < 0.0001), determined from beat-to-beat changes in HR and systolic arterial pressure, than the coefficient of variation for HR. On the other hand, {alpha}2-adrenergic responsiveness was not correlated with any of the parameters determined above. These results suggest that, in healthy young subjects, the enhanced HR response to changes in systolic pressure helps maintain the stability of arterial blood pressure when {alpha}1-adrenergic responsiveness is reduced.

blood flow; sympathetic nerve activity; baroreflex sensitivity

IN HUMANS, LITTLE IS KNOWN about how peripheral {alpha}-adrenergic vasoconstrictor responsiveness might influence the stability of arterial blood pressure. In mice, baroreflex control of heart rate (HR) is enhanced in animals genetically deficient of {alpha}-adrenergic vasoconstrictor responses so that arterial pressure is maintained at rest (23, 24). Additionally, {alpha}-adrenergic vasoconstrictor responsiveness in wild-type mice shows diurnal variation that is matched by inverse changes in the baroreflex control of HR (24). These results suggest that enhanced baroreflex control of HR might compensate for blunted peripheral {alpha}-adrenergic responsiveness in blood vessels.

In this study, we sought to determine whether {alpha}-adrenergic vasoconstrictor responsiveness had any apparent influence on the stability of arterial blood pressure or HR in healthy young humans. We hypothesized 1) that the beat-to-beat stability of arterial pressure would be independent of {alpha}-adrenergic vasoconstrictor responsiveness and 2) that, to maintain the stability of arterial blood pressure, beat-to-beat changes in HR would be inversely related to {alpha}-adrenergic vasoconstrictor responsiveness. To examine these hypotheses, we measured arterial pressure and HR continuously, and we determined both {alpha}1- and {alpha}2-adrenergic vasoconstrictor responsiveness in the forearm, because postsynaptic {alpha}2-adrenergic receptors as well as {alpha}1-adrenergic receptors contribute to basal sympathetic tone in humans (10).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects.   Twenty healthy young adults [11 women, 9 men; age, 24 ± 1 (SE) yr; weight, 67 ± 3 kg; height, 173 ± 2 cm] participated in this study (Table 1). All subjects were nonsmokers, nonobese, normotensive, free of cardiovascular disease, and not taking medications other than oral contraceptives. All women had a negative serum pregnancy test the day of the study. They were also studied in the early follicular phase of the menstrual cycle or in the low-hormone phase of oral contraceptives to minimize variability in autonomic control of cardiovascular function due to reproductive hormone status (12, 25). The studies were approved by the Institutional Review Board of the Mayo Clinic, and each subject gave written consent before participation. Data from 17 of 20 subjects in this paper represent an analysis of observations from experiments conducted on {alpha}1- and {alpha}2-adrenergic vasoconstrictor drugs that has been previously published (22).


View this table:
[in this window]
[in a new window]
  		Table 1. Baseline characteristics

 
Arterial catheterization.   Under aseptic conditions, a 5-cm 20-gauge catheter was inserted into the brachial artery of the nondominant arm under local anesthesia (2% lidocaine). The arterial catheter was connected to a pressure transducer for determination of arterial pressure and continuously flushed at 3 ml/h with heparinized saline (2 U/ml) (8). A 3-cm 18-gauge catheter was also inserted into an antecubital vein and directed toward the hand. Forearm venous blood samples were obtained before any drugs infusions for determination of plasma norepinephrine concentrations using previously described methods (22).

Body mass index and forearm volume.   Body mass index was calculated as body weight (kilograms) divided by height (meters) squared. Forearm volume was determined by water displacement for normalization of drug administration.

Forearm blood flow and vascular conductance.   Forearm blood flow (FBF) was measured using venous occlusion plethysmography with mercury-in-Silastic strain gauges (13). Briefly, a pediatric blood pressure cuff was placed around the wrist and inflated to 220 mmHg to arrest the circulation of the hand, and a venous occlusion cuff was placed on the upper arm and rapidly inflated to 50 mmHg every 7.5 s, yielding one blood flow every 15 s. FBF was expressed as milliliters per 100 ml tissue per minute. Forearm vascular conductance (FVC) was calculated as [FBF/mean arterial pressure (MAP)] x 100, and it was expressed as arbitrary units.

Experimental protocol.   All measurements were performed after a 12-h overnight fast with the subject supine. After catheterization, the subjects rested for 30 min. Arterial pressure and HR were then measured for 2 min to determine coefficients of variation (CV) for systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and HR. Drugs were then administered via the brachial artery catheter. Propranolol was administered (10 µg·100 ml forearm volume–1·min–1) for 5 min to block beta-adrenergic receptors, and a low "maintenance" dose (5 µg/min) was then infused throughout the protocol. This dose blocks forearm vasodilation to isoproterenol (14) and was performed to control for any direct or indirect beta-mediated vasodilatory effects of phenylephrine (PE) (35). PE was administered at 0.031 µg·100 ml forearm volume–1·min–1 for 2 min to selectively stimulate {alpha}1-adrenergic receptors and provide an index of peripheral {alpha}1-adrenergic responsiveness. Additionally, to determine {alpha}2-adrenergic responsiveness, dexmedetomidine (Dex) was administered at 6.25 ng·100 ml forearm volume–1·min–1 for 2 min (22). {alpha}-Agonist infusion trials were separated by 30 min of quiet rest, and during the middle of the rest sodium nitroprusside was administered at 1.0 µg·100 ml forearm volume–1·min–1 for 2 min to facilitate drug washout and reestablish baseline FBF.

FBF, HR, and arterial pressure analyses.   Our general strategy was to relate {alpha}1- or {alpha}2-adrenergic responsiveness (as assessed by changes in FBF from baseline in response to PE or Dex) with fluctuations in arterial pressure and HR using several indexes. In this context, data were digitized and stored on a computer at 200 Hz and analyzed offline with signal-processing software (Windaq, Dataq Instruments, Akron, OH). HR was determined from the ECG signal (3-lead ECG). SAP, DAP, and MAP were derived from the arterial pressure waveform. To assess the stability of the hemodynamic variables, CV (percent variability) for HR, SAP, and DAP was calculated as (SD/mean) x 100, and it was used as our main index of variability for each parameter. We used this approach because it may be a better way to compare stability of the hemodynamics when there are differences in individual mean values. However, we also used SD (absolute variability) as an another index of variability (20).

FBF was determined from the derivative of the forearm plethysmogram. For PE and Dex, the data reported represent an average of FBF during the last minute of each drug infusion (9). MAP and HR were also averaged to confirm that the forearm drug infusions did not cause any changes in systemic hemodynamics. Because MAP did not change during local infusions of the {alpha}-agonists, forearm vasoconstrictor responses were expressed as changes in FBF. Additionally, to account for any small individual changes in arterial pressure, forearm vasoconstrictor responses were also expressed as changes in FVC. Finally, there is controversy about what index of blood flow or conductance is the best way to compare vasoconstrictor responses between subjects or when there are differences in baseline values. Therefore, we calculated percent changes in FBF and FVC and used this as our main index of {alpha}-adrenergic responsiveness because it may be a better way to compare vasoconstrictor responses under these circumstances (4, 27). However, we also report the mean data and ranges for FBF and FVC at baseline and in response to PE or Dex.

Beat-to-beat baroreflex analyses.   To gain insight into the possible role of arterial baroreflexes in any patterns of HR and arterial pressure variability obtained from our primary analysis, SAP and HR during 2 min of resting data (~110 individual cardiac cycles) were used to estimate baroreflex sensitivity in each subject. Because changes in SAP and subsequent changes in the duration of the next heartbeat were observed, the relation between change in SAP ({Delta}SAP) and in HR ({Delta}HR) was analyzed. The {Delta}SAP and {Delta}HR were determined from following formula:

Formula

Formula
where SAPn is the SAP occurring during R-R intervaln, and HRn is the HR calculated from the R-R intervaln. A correlation between beat-to-beat changes in SAPn and R-Rn interval has been previously observed in humans, and it has been assumed that this correlation is the result of a baroreflex mechanism (7, 16) and this interpretation has been confirmed in conscious dogs (11). It has also been reported that SAPn can influence R-R intervaln through baroreflex mechanisms and that the highest correlation coefficient is obtained between SAPn and R-R intervaln when HR is <75 beats/min in humans (30). Similar to these previous studies, we also observed the highest correlation coefficient between {Delta}SAPn and {Delta}HRn (determined from all the cardiac cycles during rest) in all of the subjects, and this relationship was statistically significant and negative. Therefore, we used this time frame for the analyses. On the other hand, there was no correlation between {Delta}SAPn and {Delta}HRn –1 in most of the subjects. As a result of these observations, a regression equation was determined from the pooled data during rest in each subject, where {Delta}HR/{Delta}SAP was negative. The slope of the regression line was used as an index of the baroreflex sensitivity.

Statistics.   Values are expressed as means ± SE. The effects of PE and Dex on FBF, FVC, MAP, and HR were analyzed using paired t-tests (baseline vs. drug infusion). Gender group comparisons for vasoconstrictor responses and the slope of {Delta}HR/{Delta}SAP were performed using two-sample t-tests (men vs. women). All P values < 0.05 were considered statistically significant and are not adjusted for multiple comparisons because all hypotheses were identified a priori (29). Regression analyses of {alpha}-adrenergic responsiveness vs. hemodynamic variables were performed by Brace's methods (3).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
{alpha}-Adrenergic responsiveness.   {alpha}1-Adrenergic vasoconstrictor responses were determined from the FBF and FVC responses to the brachial artery infusion of PE. The reductions in FBF to 0.031 µg·100 ml forearm volume–1·min–1 of PE varied from –0.3 to –1.3 ml·100 ml–1·min–1 in the subjects. Average FBF was 2.0 ± 0.2 ml·100 ml–1·min–1 at baseline, and it decreased by 0.6 ± 0.1 ml·100 ml–1·min–1 with PE infusion (P < 0.0001). Similarly, the reductions in FVC to 0.031 µg·100 ml forearm volume–1·min–1 of PE varied from –0.3 to –1.4 units in the subjects. Average FVC was 2.3 ± 0.2 units at baseline, and decreased by 0.7 ± 0.1 units with PE infusion (P < 0.0001). MAP and HR were 89 ± 2 mmHg and 54 ± 2 beats/min at baseline, and 89 ± 2 mmHg and 54 ± 2 beats/min with PE infusion, respectively. MAP and HR were not affected by local infusion of PE (P > 0.3).

{alpha}2-Adrenergic vasoconstrictor responses were determined from the FBF and FVC responses to the brachial artery infusion of Dex. The reductions in FBF to 6.25 ng·100 ml forearm volume–1·min–1 of Dex varied from –0.1 to –1.0 ml·100 ml–1·min–1 in the subjects. Average FBF was 1.8 ± 0.2 ml·100 ml–1·min–1 at baseline, and it decreased by 0.4 ± 0.1 ml·100 ml–1·min–1 with Dex infusion (P < 0.0001). Similarly, the reductions in FVC to 6.25 ng·100 ml forearm volume–1·min–1 of Dex varied from –0.1 to –1.1 units in the subjects. Average FVC was 2.1 ± 0.2 units at baseline, and it decreased by 0.5 ± 0.1 units with Dex infusion (P < 0.0001). MAP and HR were 89 ± 1 mmHg and 53 ± 2 beats/min at baseline, and 89 ± 1 mmHg and 53 ± 2 beats/min with Dex infusion, respectively. MAP and HR were not affected by local infusion of Dex (P > 0.4).

Additionally, the decrease in FBF and FVC from baseline was similar between PE and Dex (P > 0.1). There was no evidence to suggest that PE- or Dex-mediated vasoconstriction was influenced by gender.

{alpha}-Adrenergic responsiveness vs. arterial pressure and HR variability.   CV for SAP and DAP varied from 1.5 to 4.0% and from 2.1 to 5.8% in the subjects, respectively. CV for HR varied from 2.2 to 10.6% in the subjects. The percent changes in FBF and FVC to 0.031 µg·100 ml forearm volume–1·min–1 of PE were not significantly correlated with either CV for SAP (P > 0.7) or CV for DAP (P > 0.1) (Fig. 1A). On the other hand, the percent changes in FBF and FVC were inversely and significantly correlated with the CV for HR (R2 = 0.37, P < 0.01 for FBF; R2 = 0.43, P < 0.01 for FVC) (Fig. 1B). As shown in the figure, individuals with the greatest vasoconstrictor responses to PE had limited CV for HR, whereas the individuals with more modest vasoconstrictor responses to PE had greater CV for HR. Similarly, the percent changes in FBF and FVC to 0.031 µg·100 ml forearm volume–1·min–1 of PE were not correlated with either SAP SD (P > 0.7) or DAP SD (P > 0.08), whereas they were inversely correlated with the HR SD (R2 = 0.28, P < 0.02 for FBF; R2 = 0.36, P < 0.01 for FVC).


Figure 1
View larger version (17K):
[in this window]
[in a new window]
  		Fig. 1. Individual percent changes (%{Delta}) in forearm blood flow (FBF; left) and forearm vascular conductance (FVC; right) responses to 0.031 µg·100 ml forearm volume–1·min–1 of phenylephrine (PE) vs. coefficient of variation (CV) for systolic arterial pressure (SAP; A), diastolic arterial pressure (DAP; A), and heart rate (HR; B) in 20 healthy young subjects (males = 9, females = 11). FBF and FVC responses to PE were significantly correlated with the CV for HR (P < 0.01) but not correlated with the CV for SAP (P > 0.7) or DAP (P > 0.1). The CVs for HR are greater in subjects with reduced vasoconstrictor responses to PE. NS, not significant.

 
The percent changes in FBF and FVC to 6.25 ng·100 ml forearm volume–1·min–1 of Dex were not significantly correlated with CV for SAP, CV for DAP (Fig. 2A), SAP SD, or DAP SD (P > 0.2). Also, they were not significantly correlated with the CV for HR (Fig. 2B) or HR SD (P > 0.7). Additionally, the percent changes in FBF to PE were not significantly correlated with forearm volume (P > 0.1) or baseline FBF (P > 0.3), and the percent changes in FBF to Dex were not significantly correlated with forearm volume (P > 0.6) or baseline FBF (P > 0.5).


Figure 2
View larger version (17K):
[in this window]
[in a new window]
  		Fig. 2. Individual percent changes in FBF (left) and FVC (right) responses to 6.25 ng·100 ml forearm volume–1·min–1 of dexmedetomidine (Dex) vs. CV for SAP (A), DAP (A), and HR (B) in 20 healthy young subjects (males = 9, females = 11). FBF and FVC responses to Dex were not correlated with the CV for SAP (P > 0.3), DAP (P > 0.5), or HR (P > 0.7).

 
{alpha}-Adrenergic responsiveness vs. spontaneous baroreflex sensitivity.   To gain insight into the possible role of arterial baroreflexes in the pattern of HR variability, baroreflex sensitivity was determined from regression analysis of the pooled data, where {Delta}HR/{Delta}SAP was negative in each subject (Fig. 3). For this analysis, 76 ± 2% of the cardiac cycles met the criterion for inclusion (Table 2). As shown in the table, the negative slope of {Delta}HR/{Delta}SAP varied among the subjects. When the {Delta}HR/{Delta}SAP is compared men vs. women, it was –1.1 ± 0.1 vs. –1.1 ± 0.1 beats·min–1·mmHg–1, with no significant difference between the groups (P > 0.9). Therefore, data from both genders were considered as a group.


Figure 3
View larger version (13K):
[in this window]
[in a new window]
  		Fig. 3. Typical example of the relationship between change is SAP ({Delta}SAP) and change in HR ({Delta}HR) in a subject. The slope of the regression line was used as an index of the spontaneous baroreflex sensitivity. A total of 104 cardiac cycles was plotted in this subject.

 

View this table:
[in this window]
[in a new window]
  		Table 2. Spontaneous baroreflex sensitivity ({Delta}HR/{Delta}SAP)

 
The percent changes in FBF and FVC to 0.031 µg·100 ml forearm volume–1·min–1 of PE were inversely and more strongly correlated with the negative slope of {Delta}HR/{Delta}SAP (R2 = 0.62, P < 0.0001 for FBF; R2 = 0.62, P < 0.0001 for FVC) (Fig. 4) than CV for HR. As shown in the figure, individuals with the greatest vasoconstrictor responses to PE had limited {Delta}HR/{Delta}SAP slopes, whereas the individuals with more modest vasoconstrictor responses to PE had greater {Delta}HR/{Delta}SAP slopes. On the other hand, the percent changes in FBF and FVC to 6.25 ng·100 ml forearm volume–1·min–1 of Dex were not significantly correlated with the slope of {Delta}HR/{Delta}SAP (P > 0.6).


Figure 4
View larger version (12K):
[in this window]
[in a new window]
  		Fig. 4. Relationship between individual percent changes in FBF (left) and FVC (right) responses to 0.031 µg·100 ml forearm volume–1·min–1 of PE vs. spontaneous baroreflex sensitivity ({Delta}HR/{Delta}SAP) in 20 healthy young subjects (males = 9, females = 11). FBF and FVC responses to PE were significantly correlated with the {Delta}HR/{Delta}SAP (P < 0.0001).

 
Venous norepinephrine concentration at baseline varied from 48 to 325 pg/ml in the subjects, and average norepinephrine concentration was 171 ± 20 pg/ml. The percent changes in FBF and FVC to 0.031 µg·100 ml forearm volume–1·min–1 of PE were not significantly correlated with the venous norepinephrine concentration (P > 0.4). The percent changes in FBF and FVC to 6.25 ng·100 ml forearm volume–1·min–1 of Dex were not significantly correlated with the venous norepinephrine concentration (P > 0.1).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The major findings in the present study are as follows. 1) {alpha}1-Adrenergic vasoconstrictor responses to PE in healthy young subjects were variable. 2) This variability was inversely correlated with both CV for HR and the slope of {Delta}HR/{Delta}SAP, but it was not correlated with CV for either SAP or DAP. 3) {alpha}2-Adrenergic vasoconstrictor responses to Dex in the subjects were not correlated with CV for HR, the slope of {Delta}HR/{Delta}SAP, the CV for SAP, or the CV for DAP. In general, these observations confirm our original hypotheses.

{alpha}-Adrenergic responsiveness vs. arterial pressure and HR.   In the present study, individual variation of {alpha}1-adrenergic responsiveness was inversely correlated with CV for HR (Fig. 1). By contrast, arterial pressure variability was similar in subjects with differing {alpha}1-adrenergic responsiveness. This suggests that HR may fluctuate more to control arterial pressure when {alpha}1-adrenergic vasoconstrictor responses are reduced.

In animals, variation in HR and baroreflex control of HR are related to {alpha}-adrenergic vasoconstrictor responses. {alpha}-Adrenergic vasoconstrictor responsiveness in mice shows diurnal variation that is matched by inverse changes in both HR variability and baroreflex control of HR so that arterial pressure is maintained (24). Enhanced HR variability and baroreflex control of HR are also seen in several types of knockout mice with deficient {alpha}-adrenergic vasoconstrictor responses (23, 24).

Because the primary data collected in this study seemed similar to the observations in animals noted above, and because greater HR fluctuations can be caused by greater HR responses to a given change in SAP via baroreflexes to stabilize arterial pressure (21), we sought to clarify the possible role of arterial baroreflexes in the linkage between CV for HR and {alpha}1-adrenergic responsiveness in humans. We therefore estimated spontaneous baroreflex sensitivity from beat-to-beat {Delta}HR and {Delta}SAP. Although there are clearly limitations with "observational" approaches to baroreflex assessment, this seemed reasonable because the correlation between spontaneous beat-to-beat changes in SAP and pulse interval is abolished after carotid sinus denervation in conscious dogs (11). Along these lines, the CV for HR was correlated with the slope of {Delta}HR/{Delta}SAP (Fig. 5), and individual variation of {alpha}1-adrenergic responsiveness was inversely and more strongly correlated with the slope of {Delta}HR/{Delta}SAP (Fig. 4) than CV for HR. This suggests that baroreflex control of HR may be enhanced to regulate arterial pressure when {alpha}1-adrenergic vasoconstrictor responsiveness is reduced.


Figure 5
View larger version (11K):
[in this window]
[in a new window]
  		Fig. 5. Relationship between spontaneous baroreflex sensitivity ({Delta}HR/{Delta}SAP) vs. CV for HR in 20 healthy young subjects (males = 9, females = 11). The individual variation of {Delta}HR/{Delta}SAP was significantly correlated with the CV for HR (P < 0.001).

 
In contrast to {alpha}1-adrenergic responsiveness, {alpha}2-adrenergic responsiveness was not correlated with CV for HR (Fig. 2) or the slope of {Delta}HR/{Delta}SAP. This is likely due to the fact that vasoconstrictor responses to {alpha}2-adrenergic receptor stimulation represent the net effect of contraction of smooth muscle cells, presynaptic inhibition of norepinephrine release by Dex, and potential {alpha}2-adrenergic receptor-mediated endothelial vasodilation (1). Indeed, we observed reduced deep forearm venous norepinephrine concentrations during Dex infusion (22). Together, these factors might make it difficult to see a clear relationship between pharmacologically determined {alpha}2-adrenergic responsiveness and fluctuations in HR. Additionally, the order of drug infusions may have also affected the {alpha}2-adrenergic responsiveness. The lack of the relation between {alpha}2-responsiveness and HR might also suggest that {alpha}1-adrenergic vasoconstriction plays a more dominant role in short-term control of arterial pressure than {alpha}2-adrenergic vasoconstriction.

In the present study, there were no gender differences in either {alpha}-adrenergic responsiveness or {Delta}HR/{Delta}SAP. However, Kneale et al. (18) reported that norepinephrine causes less forearm vasoconstriction in premenopausal women than it does in men due to greater beta2-adrenergic vasodilation in women. In the present study, we used propranolol to eliminate the potential confounding effects of beta2-adrenergic receptor-mediated vasodilation on our FBF responses. Additionally, it has been reported that cardiovagal baroreflex sensitivity and effective baroreflex buffering are lower in eumenorrheic women compared with men (2, 5). Because we studied both eumenorrheic women and women taking oral contraceptives, this difference might be explained by inclusion of both groups (26). Nevertheless, we observed the relationship between {alpha}1-adrenergic vasoconstrictor responses and the slope of {Delta}HR/{Delta}SAP in both men and women, suggesting an important interaction between {alpha}1-adrenergic responsiveness and baroreflex control of HR in both genders.

Experimental considerations.   There are four main experimental considerations that deserve additional discussion. First, whereas observational techniques to assess baroreflex function are controversial and clearly limited (19, 31), the correlation between spontaneous beat-to-beat changes in SAP and pulse interval is clearly dependent on intact carotid baroreceptors in conscious dogs (11). The data from dogs suggest that our interpretation that fluctuations in HR, SAP, and {alpha}1-adrenergic responsiveness can be explained via baroreflex mechanisms is reasonable.

Second, it is also important to recognize that the level of sympathetic outflow to vascular beds could also compensate for reduced {alpha}1-adrenergic vasoconstrictor responses. For example, baseline sympathetic outflow can vary severalfold in normotensive healthy subjects (15, 17). However, there was no relation between {alpha}1-adrenergic responsiveness and baseline venous plasma norepinephrine concentration, suggesting that the level of sympathetic outflow is not correlated with {alpha}1-adrenergic responsiveness. Moreover, speculating on how "sympathetic nerve activity/arterial pressure gain" could contribute to the beat-to-beat stability of arterial pressure is more difficult due to the time delays associated with sympathetic nerve conduction, transmitter release, and end-organ responses. In humans, the conduction time of baroreceptor-muscle sympathetic nerve activity takes ~1.3 s (34), much longer than ~0.5 s of the conduction time of baroreceptor-vagal activity (30). Thus HR is likely to play a more dominant role in buffering very rapid changes in arterial pressure.

Third, although the FBF response to PE was used as our index of {alpha}1-adrenergic responsiveness, this response may not reflect a whole body vascular responsiveness. However, most blood flow in the resting forearm goes to muscle and skin, and muscle is a key target for blood pressure regulation via changes in sympathetic traffic. Because laboratory temperature was maintained at 20–22°C during the study, it is likely that changes in FBF mainly reflected changes in muscle blood flow (33). Additionally, changes in muscle sympathetic outflow and limb blood flow are similar in the arm and leg, and whole body sympathetic outflow and muscle sympathetic nerve activity are correlated (32, 37, 38, 39). On the other hand, {alpha}1-adrenergic responses in the calf may be greater than in the forearm, but little is known about intersubject variability in these responses (28). Together the above observations suggest that our FBF responses to PE are likely to provide some insight into whole body adrenergic responsiveness.

The fourth issue is that the subjects were studied while supine. In the upright posture, the ability of fluctuations in HR to influence systemic BP may be less effective (6, 36) due to reduced preload and central blood volume. Therefore, further studies are needed to assess how our findings in the forearm relate to whole body responses in both upright and supine humans.

In summary, the results from the present study support our original hypotheses that the beat-to-beat stability of arterial pressure would be independent of {alpha}-adrenergic vasoconstrictor responsiveness and that to maintain the stability of arterial blood pressure, beat-to-beat changes in HR would be inversely related to {alpha}-adrenergic vasoconstrictor responsiveness. Although we estimated baroreflex sensitivity using an observational approach, the inverse relationship between {Delta}HR/{Delta}SAP and forearm {alpha}1-adrenergic responsiveness suggested that enhanced baroreflex control of HR may serve as a compensatory adaptation to reduced {alpha}1-adrenergic responsiveness in young humans. How these relationships operate, along with individual and regional differences in sympathetic outflow, may offer additional insight into the integrated control of arterial pressure in humans.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This research was supported by National Institutes of Health (NIH) Grants NS-32352 and HL-46493 (M. J. Joyner), by National Center for Research Resources Grant K23-17520 (J. H. Eisenach), by NIH General Clinical Research Center Grant RR-00585 (to the Mayo Clinic, Rochester, MN), and by Uehara Memorial Foundation (S. Masuki).


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank Karen Krucker, Shelly Roberts, Pamela Engrav, Branton Walker, Diane Wick, and Christopher Johnson for excellent technical assistance and the subjects who participated in this study. We also thank Dr. Sunni Barnes, who provided input of the statistical approaches used.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. J. Joyner, Dept. of Anesthesiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (e-mail: joyner.michael{at}mayo.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.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. Angus JA, Cocks TM, and Satoh K. The alpha adrenoceptors on endothelial cells. Fed Proc 45: 2355–2359, 1986.[Web of Science][Medline]
  2. Beske SD, Alvarez GE, Ballard TP, and Davy KP. Gender difference in cardiovagal baroreflex gain in humans. J Appl Physiol 91: 2088–2092, 2001.[Abstract/Free Full Text]
  3. Brace RA. Fitting straight lines to experimental data. Am J Physiol Regul Integr Comp Physiol 233: R94–R99, 1977.[Abstract/Free Full Text]
  4. Buckwalter JB and Clifford PS. The paradox of sympathetic vasoconstriction in exercising skeletal muscle. Exerc Sport Sci Rev 29: 159–163, 2001.[CrossRef][Medline]
  5. Christou DD, Jones PP, Jordan J, Diedrich A, Robertson D, and Seals DR. Women have lower tonic autonomic support of arterial blood pressure and less effective baroreflex buffering than men. Circulation 111: 494–498, 2005.[Abstract/Free Full Text]
  6. Cooper VL and Hainsworth R. Effects of head-up tilting on baroreceptor control in subjects with different tolerances to orthostatic stress. Clin Sci (Lond) 103: 221–226, 2002.[Medline]
  7. De Boer RW, Karemaker JM, and Strackee J. Relationships between short-term blood-pressure fluctuations and heart-rate variability in resting subjects. II. a simple model. Med Biol Eng Comput 23: 359–364, 1985.[CrossRef][Web of Science][Medline]
  8. Dietz NM, Rivera JM, Eggener SE, Fix RT, Warner DO, and Joyner MJ. Nitric oxide contributes to the rise in forearm blood flow during mental stress in humans. J Physiol 480: 361–368, 1994.[Abstract/Free Full Text]
  9. Dinenno FA, Dietz NM, and Joyner MJ. Aging and forearm postjunctional alpha-adrenergic vasoconstriction in healthy men. Circulation 106: 1349–1354, 2002.[Abstract/Free Full Text]
  10. Dinenno FA, Eisenach JH, Dietz NM, and Joyner MJ. Post-junctional alpha-adrenoceptors and basal limb vascular tone in healthy men. J Physiol 540: 1103–1110, 2002.[Abstract/Free Full Text]
  11. Frankel RA, Metting PJ, and Britton SL. Evaluation of spontaneous baroreflex sensitivity in conscious dogs. J Physiol 462: 31–45, 1993.[Abstract/Free Full Text]
  12. Freedman RR and Girgis R. Effects of menstrual cycle and race on peripheral vascular alpha-adrenergic responsiveness. Hypertension 35: 795–799, 2000.[Abstract/Free Full Text]
  13. Greenfield AD, Whitney RJ, and Mowbray JF. Methods for the investigation of peripheral blood flow. Br Med Bull 19: 101–109, 1963.[Free Full Text]
  14. Johnsson G. The effects of intra-arterially administered propranolol and H 56-28 on blood flow in the forearm–a comparative study of two beta-adrenergic receptor antagonists. Acta Pharmacol Toxicol (Copenh) 25: 63–74, 1967.[Medline]
  15. Jones PP, Shapiro LF, Keisling GA, Jordan J, Shannon JR, Quaife RA, and Seals DR. Altered autonomic support of arterial blood pressure with age in healthy men. Circulation 104: 2424–2429, 2001.[Abstract/Free Full Text]
  16. Karemaker JM and Borst C. Measurement of baroreflex sensitivity in hypertension research. In: Arterial Baroreceptors and Hypertension, edited by Slight P. Oxford, UK: Oxford University Press, 1980, p. 455–461.
  17. Kienbaum P, Karlssonn T, Sverrisdottir YB, Elam M, and Wallin BG. Two sites for modulation of human sympathetic activity by arterial baroreceptors? J Physiol 531: 861–869, 2001.[Abstract/Free Full Text]
  18. Kneale BJ, Chowienczyk PJ, Brett SE, Coltart DJ, and Ritter JM. Gender differences in sensitivity to adrenergic agonists of forearm resistance vasculature. J Am Coll Cardiol 36: 1233–1238, 2000.[Abstract/Free Full Text]
  19. Lipman RD, Salisbury JK, and Taylor JA. Spontaneous indices are inconsistent with arterial baroreflex gain. Hypertension 42: 481–487, 2003.[Abstract/Free Full Text]
  20. Mancia G, Bertinieri G, Cavallazzi A, Di Rienzo M, Parati G, Pomidossi G, Ramirez AJ, and Zanchetti A. Mechanisms of blood pressure variability in man. Clin Exp Hypertens A 7: 167–178, 1985.[Web of Science][Medline]
  21. Mancia G, Parati G, Pomidossi G, Casadei R, Di Rienzo M, and Zanchetti A. Arterial baroreflexes and blood pressure and heart rate variabilities in humans. Hypertension 8: 147–153, 1986.[Abstract/Free Full Text]
  22. Masuki S, Dinenno FA, Joyner MJ, and Eisenach JH. Selective {alpha}2-adrenergic properties of dexmedetomidine over clonidine in the human forearm. J Appl Physiol 99: 587–592, 2005.[Abstract/Free Full Text]
  23. Masuki S, Takeoka M, Taniguchi S, and Nose H. Enhanced baroreflex sensitivity in free-moving calponin knockout mice. Am J Physiol Heart Circ Physiol 284: H939–H946, 2003.[Abstract/Free Full Text]
  24. Masuki S, Todo T, Nakano Y, Okamura H, and Nose H. Reduced alpha-adrenoceptor responsiveness and enhanced baroreflex sensitivity in Cry-deficient mice lacking a biological clock. J Physiol 566: 213–224, 2005.[Abstract/Free Full Text]
  25. Minson CT, Halliwill JR, Young TM, and Joyner MJ. Influence of the menstrual cycle on sympathetic activity, baroreflex sensitivity, and vascular transduction in young women. Circulation 101: 862–868, 2000.[Abstract/Free Full Text]
  26. Minson CT, Halliwill JR, Young TM, and Joyner MJ. Sympathetic activity and baroreflex sensitivity in young women taking oral contraceptives. Circulation 102: 1473–1476, 2000.[Abstract/Free Full Text]
  27. O'Leary DS. Regional vascular resistance vs. conductance: which index for baroreflex responses? Am J Physiol Heart Circ Physiol 260: H632–H637, 1991.[Abstract/Free Full Text]
  28. Pawelczyk JA and Levine BD. Heterogeneous responses of human limbs to infused adrenergic agonists: a gravitational effect? J Appl Physiol 92: 2105–2113, 2002.[Abstract/Free Full Text]
  29. Perneger TV. What's wrong with Bonferroni adjustments. BMJ 316: 1236–1238, 1998.[Free Full Text]
  30. Pickering TG and Davies J. Estimation of the conduction time of the baroreceptor-cardiac reflex in man. Cardiovasc Res 7: 213–219, 1973.[Web of Science][Medline]
  31. Pitzalis MV, Mastropasqua F, Passantino A, Massari F, Ligurgo L, Forleo C, Balducci C, Lombardi F, and Rizzon P. Comparison between noninvasive indices of baroreceptor sensitivity and the phenylephrine method in post-myocardial infarction patients. Circulation 97: 1362–1367, 1998.[Abstract/Free Full Text]
  32. Rea RF and Wallin BG. Sympathetic nerve activity in arm and leg muscles during lower body negative pressure in humans. J Appl Physiol 66: 2778–2781, 1989.[Abstract/Free Full Text]
  33. Rowell LB. Thermal stress. In: Human Circulation: Regulation During Physical Stress. New York: Oxford University Press, 1986, p. 174–212.
  34. Sundlof G and Wallin BG. Human muscle nerve sympathetic activity at rest. Relationship to blood pressure and age. J Physiol 274: 621–637, 1978.[Abstract/Free Full Text]
  35. Torp KD, Tschakovsky ME, Halliwill JR, Minson CT, and Joyner MJ. beta-Receptor agonist activity of phenylephrine in the human forearm. J Appl Physiol 90: 1855–1859, 2001.[Abstract/Free Full Text]
  36. Tyden G. Aspects of cardiovascular reflex control in man. An experimental study. Acta Physiol Scand Suppl 448: 1–62, 1977.
  37. Vissing SF, Scherrer U, and Victor RG. Relation between sympathetic outflow and vascular resistance in the calf during perturbations in central venous pressure. Evidence for cardiopulmonary afferent regulation of calf vascular resistance in humans. Circ Res 65: 1710–1717, 1989.[Abstract/Free Full Text]
  38. Wallin BG, Esler M, Dorward P, Eisenhofer G, Ferrier C, Westerman R, and Jennings G. Simultaneous measurements of cardiac noradrenaline spillover and sympathetic outflow to skeletal muscle in humans. J Physiol 453: 45–58, 1992.[Abstract/Free Full Text]
  39. Wallin BG. Muscle sympathetic activity and plasma concentrations of noradrenaline. Acta Physiol Scand Suppl 527: 21–24, 1984.



This article has been cited by other articles:


Home page
 J. Appl. Physiol.Home page
S. Masuki, J. H. Eisenach, W. G. Schrage, N. M. Dietz, C. P. Johnson, B. W. Wilkins, R. A. Dierkhising, P. Sandroni, P. A. Low, and M. J. Joyner
Arterial baroreflex control of heart rate during exercise in postural tachycardia syndrome
J Appl Physiol, October 1, 2007; 103(4): 1136 - 1142.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow All Versions of this Article:
100/3/792    most recent
00586.2005v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Masuki, S.
Right arrow Articles by Joyner, M. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Masuki, S.
Right arrow Articles by Joyner, M. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2006 by the American Physiological Society.