Published online before print May 1, 2008, doi: 10.1161/STROKEAHA.107.510008
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2008;39:1979.)
© 2008 American Heart Association, Inc.
Original Contributions |
Autonomic Neural Control of the Cerebral Vasculature
Acute Hypotension
From the Department of Integrative Physiology, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas.
Correspondence to Shigehiko Ogoh, PhD, Department of Integrative Physiology, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107. E-mail sogoh{at}hsc.unt.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background and Purpose— The effect of antihypertensive drugs on autonomic neural control of the cerebral circulation remains unclear. This study was designed to compare middle cerebral artery mean blood velocity responses to acute hypotension with and without
1-adrenoreceptor blockade (Prazosin) in young, healthy humans. Methods— Acute hypotension was induced nonpharmacologically in 6 healthy subjects (mean±SE; 28±2 years) by releasing bilateral thigh cuffs after 9 minutes of suprasystolic resting ischemia before and after an oral dose of Prazosin (1 mg/20 kg body weight).
Results— Prazosin had no effect on thigh cuff release-induced reductions in mean arterial pressure and middle cerebral artery mean blood velocity. However, Prazosin attenuated the amount of peripheral vasoconstriction through the arterial baroreflex as evidenced by a slower return of mean arterial pressure to baseline (P=0.03). Immediately after cuff release, cerebral vascular conductance index increased through cerebral autoregulation and returned to resting values as a result of an increased perfusion pressure mediated through arterial baroreflex mechanisms. The rate of regulation, an index of cerebral autoregulation, was attenuated with Prazosin (control versus Prazosin; rate of regulation=0.204±0.020 versus 0.006±0.053/s, P=0.037). In addition, as mean arterial pressure was returning to resting values, the rate of change in cerebral vascular conductance index was decreased with Prazosin (0.005±0.006/s) compared with control (0.025±0.005/s; P=0.010).
Conclusions— These data suggest that during recovery from acute hypotension, decreases in cerebral vascular conductance index were mediated by increases in arterial blood pressure and sympathetically mediated cerebral vasoconstriction.
Key Words: arterial blood pressure • middle cerebral artery blood velocity • sympathetic activity
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animal studies have shown that cerebral arteries are richly innervated with sympathetic nerve fibers.1,2 However, the role of autonomic neural control of the cerebral circulation remains controversial. The traditional thinking is that in the presence of normocapnia, changes in sympathetic tone appear to have limited effects on cerebral blood flow (CBF).3–5 Although sympathoexcitation has little effect on CBF during rest, several investigators have reported a direct effect of sympathoexcitation on CBF associated with pathophysiology.6–9
Hypertension is a major risk factor for the development of stroke and heart disease.10 In patients with hypertension, reductions in CBF and increases in cerebrovascular resistance have been reported.11,12 Although chronic hypertension appears to shift the lower limit of CBF autoregulation to higher pressures, cerebral autoregulation is notably impaired in patients with malignant hypertension.13 Antihypertensive drug-induced decreases in blood pressure reduce the risk of acquiring major cardiovascular or cerebrovascular diseases.11,14 In addition, previous studies have reported that antihypertensive drugs, ie, 1- and β1-adrenoreceptor blockers, angiotensin type I receptor blockers, and angiotensin-converting enzyme inhibitors, directly influence the vasculature in both the cerebral and skeletal muscle circulations7,15–17 and suggest that antihypertensive drugs may compromise CBF regulation. However, the effect of antihypertensive drugs on autonomic neural control of the cerebral circulation remains unclear.
Prazosin, the 1-adrenoreceptor blocker, does not influence CBF under resting conditions in individuals who are normotensive.17 However, in patients with hypertension, a small but significant increase in CBF along with a significant decrease in blood pressure was observed after Prazosin therapy.18 Previous animal studies17,19 demonstrated that cervical spinal cord stimulation augmented CBF with decreases in sympathetic nerve activity. Interestingly, Prazosin attenuates the cervical spinal cord stimulation-induced increases in CBF.17 These findings suggest that Prazosin-induced 1-adrenoreceptor blockade interferes with autonomic neural control of the cerebral circulation, especially during changes in sympathetic activity.
Therefore, the present study was designed to investigate the effect of the 1-adrenoreceptor blocker, Prazosin, on the regulation of middle cerebral artery blood velocity and cerebral vascular conductance index during a hypotensive-induced reduction in cerebral perfusion pressure. To accomplish this, we used a mechanical noninvasive technique to induce cerebral hypoperfusion to test the hypothesis that Prazosin would impair cerebral autoregulation and arterial baroreflex mediated sympathetic regulation of CBF.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
Four men and 2 women (age, 28±2 years; height, 177±4 cm; weight, 77±9 kg; mean±SEM) volunteered to participate in the present protocol. All subjects were healthy; nonsmokers; free of known cerebral vascular, cardiovascular, and respiratory disease; and were not using prescription or over-the-counter medications. Before the study, all subjects provided written informed consent, were familiarized with all the testing protocols, and were asked to abstain from drinking alcohol and caffeine and to not exercise for the 24-hour time period before any scheduled experiments. All experimental procedures were approved by the Institutional Review Board at the University of North Texas Health Science Center (Institutional Review Board 2006-33) and were in accordance with the guidelines of the Declaration of Helsinki.
Instrumentation
A standard 4-lead electrocardiogram was used for heart rate monitoring. A catheter (1.1-mm inner diameter, 20-gauge) was inserted into the radial artery using sterile techniques under local anesthesia with approximately 2 mL of lidocaine and aseptic conditions and was connected to a pressure transducer (Maxxim Medical, Athens, Texas) positioned at the level of the heart. This catheter was used for assessment of beat-to-beat arterial blood pressure (ABP) and for arterial blood samples, which were obtained at each condition and stored in ice water until analyzed for arterial pCO2 (PaCO2; Instrumentation Laboratory model #1735, Lexington, Mass). Additionally, a venous catheter (1.2-mm inner diameter, 18-gauge) was inserted into the median antecubital vein and was used for bolus drug injections during the phenylephrine (PE) challenge protocol. Middle cerebral artery blood velocity was obtained by transcranial Doppler ultrasonography (Multidop X, DWL, Sipplingen, Germany). A 2-MHz Doppler probe was placed over the temporal window and fixed with an adjustable headband and adhesive ultrasonic gel (Tensive; Parker Laboratories, Orange, NJ).
Protocol
On the experimental day, all subjects came to the laboratory in the morning approximately 2 hours after a light breakfast. After they were instrumented, the subjects were seated in a semirecumbent position (approximately 45°) in a modified car seat and rested quietly for approximately 10 minutes before any testing began. Abrupt decreases in ABP were induced nonpharmacologically by releasing bilateral thigh cuffs after 9 minutes of suprasystolic (220 mm Hg) resting ischemia.
Experimental Protocols
Control
The control protocol started with a 5-minute baseline period, which was followed by inflation of the thigh cuffs for 9 minutes. Immediately after the 9 minutes of cuff inflation, the cuffs were deflated and measurements were continued for an additional 3 minutes. Cuff deflation was initiated at normal end expiration as observed from the subject’s diaphragmatic movement. This ensured that all subjects were at the same point in the breathing cycle to minimize the effects of respiration on the comparison of responses between cuff release trials.
Intervention
The same protocol used in the control protocol was repeated in the afternoon. The only difference between the 2 protocols was that the intervention (afternoon) protocol was performed at least 2 hours after oral ingestion of the 1-adrenoreceptor antagonist Prazosin (Mylan Pharmaceuticals, Morgantown, WVa). The dose of Prazosin used was the usual clinical dose of 1 mg/20 kg of body weight. The 2-hour postingestion duration before beginning the intervention protocol was chosen because it has been previously demonstrated that peak Prazosin activity occurs approximately 2 hours postingestion.20
Phenylephrine Infusion Challenge
The validity of these results requires that the dose of Prazosin was capable of significantly inhibiting the pressor effects of 1-adrenoreceptor agonists during the afternoon protocol. Therefore, in the morning after catheterization (before any data collection), each subject received an intravenous bolus dose of 1.0 µg/kg body weight of the specific 1-adrenoreceptor agonist PE.21 This exact same bolus dose of PE was injected at 2 hours post-Prazosin ingestion and immediately before the afternoon intervention protocol. PE was diluted with physiological saline to yield a bolus dose equal to 1.0 µg/20 kg of body weight. The dose of PE was chosen because it has been demonstrated to evoke an increase in mean arterial pressure (MAP) of approximately 15 to 20 mm Hg.21 During the 2 PE infusion protocols, MAP was recorded and used to identify the degree of 1-adrenoreceptor receptor blockade.
Data Analysis
All data were sampled continuously at 1 kHz using an analog-to-digital converter interfaced with a computer. Beat-to-beat MAP and mean middle cerebral artery blood velocity (MCA Vmean) were obtained from each waveform. The cerebrovascular conductance index (CVCi) was calculated by dividing MCA Vmean by MAP and was used as an estimate of changes in cerebrovascular conductance. The derived CVCi during acute hypotension is not directly related to steady-state cerebrovascular conductance because changes in the vascular compliance and resistance affect CBF during dynamic regulation. Control values of MAP, MCA Vmean, and CVCi were defined by calculating their means during the 4 seconds immediately before the thigh cuff release. Changes in MAP, MCA Vmean, and CVCi during cuff release and recovery from cuff release were determined relative to their concomitant control values.
During the cuff release protocol, the ABP decreased abruptly and remained at a low nadir for a limited time (6 to 8 seconds). At the end of the nadir of the ABP, the arterial baroreflex gradually restored ABP toward the control value. In the present study, we identify the measurements made during the time after deflation that were unaffected by the arterial baroreflex correction of the ABP as "Phase I." The time period starting from 1 second after the end of the nadir of ABP was identified as the onset of the arterial baroreflex control of ABP and its effect on CVCi and was designated as "Phase II" (see Figure 1).
|
During Phase I at time 1.0 to 3.5 seconds, the rate of the change in CVCi is directly related to cerebral autoregulation without arterial baroreflex regulation.22 The rate of regulation (RoR) is calculated as an index of cerebral autoregulation.22 
|
|
where 
CVCi/T is the slope of the linear regression between CVCi and time (T) and MAP was calculated by subtracting control MAP from averaged MAP during Phase I.22
One second after the onset of the arterial baroreflex correction of the nadir of the hypotensive ABP (ie, the beginning of Phase II) through the fourth second of Phase II, the rate of the change in CVCi is related to cerebral autoregulation and arterial baroreflex sympathetic activation. During Phase II, the slope of the linear regression between MAP and T (MAP/T), MCA Vmean and T (MCA Vmean/T), and CVCi and T (CVCi/T) were calculated to identify the effect of an increase in sympathetic activity on the cerebral vasculature. In addition, the ratio between MAP/T and MCA Vmean/T was calculated to identify the effect of perfusion pressure on MCA Vmean (ie, cerebral autoregulation) during Phase II.
Statistics
The difference between the hemodynamic measurements before and after 1-adrenoreceptor blockade with Prazosin were assessed by Student paired t tests using commercially available software (SigmaStat 3.10; Systat Software Inc, Point Richmond, Calif). Data are expressed as means±SE. The significance level was set at P<0.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The MAP responses to the PE challenge pre- and post-Prazosin ingestion are illustrated in the Table. During control rest, PE yielded an increase in MAP of 14.5±0.4 mm Hg. Two hours post-Prazosin ingestion (ie, immediately before the start of the afternoon’s intervention protocol), the same dose of PE yielded an increase in MAP of 3.5±0.2 mm Hg (76±2% blockade). This identifies a significant functional blockade of
1-adrenoreceptors during the afternoon intervention protocol. However, during the resting period all hemodynamic variables; heart rate, MAP, MCA Vmean, CVCi, and PaCO2, were unchanged by the oral ingestion of Prazosin.
|
Phase I (1 to 3.5 seconds after thigh cuff release)
The release of the thigh cuffs elicited an acute decrease in ABP (Figure 1). Changes in MAP were –30.1±2.6% and –33.8±3.1% without and with Prazosin, respectively. These decreases in ABP were sufficient to evoke a transient decrease in MCA Vmean and a marked cerebral autoregulatory response.22 Although the initial response to the decrease in ABP was a transient decrease in the MCA Vmean, the cerebral autoregulatory response gradually corrected the CVCi to prehypotensive values within 3.5 seconds of Phase I, thus preventing further decreases in MCA Vmean (Figure 1). Therefore, the return of MCA Vmean to the baseline velocity was much faster than that of ABP.
The RoR was calculated from the change in CVCi in Phase I (1 to 3.5 seconds) for each subject (Figure 2). The increase in CVCi was attenuated by Prazosin; thus, the RoR was significantly higher in the control condition compared with Prazosin (0.212±0.041 versus 0.089±0.050/s, P=0.021). Although there was no significant difference in the thigh cuff release-induced decrease in absolute MCA Vmean between the control and Prazosin conditions (Table), the percent change in MCA Vmean with Prazosin was significantly larger (–35.1±3.2%) compared with the control condition (–26.8±2.4%; P=0.020).
|
Phase II (1 to 4 seconds after the start of increasing arterial blood pressure)
There was no significant difference in the MAP response to the thigh cuff release in Phase I between control and Prazosin conditions (–27±3 versus –28±2 mm Hg, P=0.666 and –30.1±2.6 versus –33.8±3.1%, P=0.210; Table). However, the arterial baroreflex correction of the hypotensive ABP during Phase II was significantly decreased by Prazosin (0.025±0.005 to 0.009±0.05/s, P=0.030; see Figures 1 and 3).
|
Interestingly, the contribution of sympathetic activation on the return of ABP in Phase II was variable for each subject as evidenced by the variable effect of Prazosin on the rate of return of MAP compared with its respective control condition (Figure 3). In contrast, there was no significant difference in the rate of return of MCA Vmean between control and Prazosin conditions (0.007±0.007 versus 0.007±0.003/s, P=0.948; see Figures 1 and 4). However, in Phase II during the control condition, MCA Vmean was maintained constant, whereas Prazosin elicited a variable MCA Vmean response during Phase II (Figure 4). In addition, CVCi remained high and did not return to baseline values during the Prazosin condition. In contrast, the CVCi in the control condition returned to baseline values during Phase II (Figure 5). Therefore, the rate of return of MAP and MCA Vmean during the Prazosin condition was significantly different from the control (0.179±0.169 versus 1.756±0.518, P=0.023; Figure 6).
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
By comparing changes in cerebral vascular conductance during the early phase (Phase I) and late phase (Phase II) of the recovery response to a transient hypotension with and without
1-adrenergic blockade using Prazosin, we have identified an important functional role of sympathetic vasoconstriction in the regulation of CBF. These findings are in contrast to a number of investigations, which indicate little or no effect of sympathetic activation on the regulation of CBF.3–5 The different conclusions of the present study compared with the previous studies are probably related to the different experimental designs and analyses. The present study evaluated dynamic cerebrovascular responses to transient perturbations of ABP, whereas the previous investigations evaluated the cerebrovascular responses to changes in ABP during steady-state hemodynamic conditions.
Phase I: Cerebral Autoregulation
In the present study, we examined the CBF response to an acute hypotensive stimulus during Phase I, ie, the time before any possibility of an arterial baroreflex-mediated restoration of ABP.22 Prazosin significantly decreased the RoR of the cerebral vascular conductance by cerebral autoregulation to resting values (see Figure 2). In addition, Prazosin blockade accentuated the decrease in MCA Vmean during the acute hypotensive stimuli. These results suggest that cerebral autoregulation was impaired by 1-adrenoreceptor blockade and suggests that sympathetic vasoconstriction affects cerebral autoregulation. This finding is in accord with previous studies.23,24 Morita et al23 reported in rats that CBF was decreased with stepwise reductions in ABP after sympathetic denervation, indicating impaired cerebral autoregulation. Moreover, Zhang et al24 analyzed transfer function gain, phase, and coherence between MAP and CBF in humans before and after ganglion blockade with trimethaphan. The findings indicated an increased gain and diminished phase after ganglion blockade, suggesting that dynamic cerebral autoregulation was impaired by the removal of autonomic neural activity.
Cerebral autoregulation of CBF has been demonstrated to be primarily mediated by myogenic and metabolic mechanisms.22,25,26 However, Aaslid et al22 have reported that cerebral autoregulation was also affected by the basal vascular tone. They demonstrated that there was a highly significant relationship between PaCO2 and cerebral autoregulation and confirmed a previous report in which PaCO2 was found to strongly influence the vascular tone of cerebral vascular smooth muscle and resultant changes in CBF. Recently, it has been demonstrated that the autonomic nervous system does have a controlling influence on cerebral vasculature tone.27,28 D’Alecy et al27 demonstrated that direct electric stimulation of the stellate ganglion in dogs reduced CBF even during profound hypercapnic-mediated vasodilation. In addition, Jordan et al28 demonstrated that sympathetic nerve activation attenuated the CO2-induced increase in CBF. Moreover, sympathetic activation decreased PaCO2 by causing hyperventilation; thus, it can indirectly increase cerebrovascular tone.28
In the present study, the oral ingestion of the 1-adrenergic-blocking drug, Prazosin, during rest did not directly increase MCA Vmean (Table). However, it has been reported that medications that induce vasodilation tend to cause mild changes in vascular tone20; therefore, it was possible that after Prazosin ingestion, cerebral autoregulatory mechanisms compensated for the decreases in vascular tone and maintained CBF constant. In contrast, previous studies3,8,27,29–32 using direct stimulation of sympathetic nerves in rats, cats, and primates demonstrated that cerebral vasoconstriction occurred in response to sympathetic nerve activation.3,8,27,29–32 Furthermore, parasympathetic nerve stimulation resulted in cerebral vasodilation in rats.32 These findings suggest that the autonomic nervous system regulates the cerebral circulation through altering the vascular tone of the cerebral smooth muscle. In addition, although baseline CBF was not altered after removal of autonomic neural activity in humans, cerebral autoregulation was impaired.24
Lassen33 established cerebral autoregulatory range of MAP in humans to be on average from 60 to 150 mm Hg. In the present study, Prazosin tended to decrease MAP (Table). If Prazosin were to have decreased MAP to a pressure below the lower blood pressure limit (60 mm Hg) of cerebral autoregulation, we would have expected to have observed impaired cerebral autoregulation. However, the individual MAPs with and without Prazosin in all subjects (78 to 102 mm Hg) remained within their cerebral autoregulatory range. In addition, during the control period, Prazosin did not significantly decrease MCA Vmean, suggesting that static cerebral autoregulation was well maintained. Moreover, the differences in Prazosin-induced changes in MAP did not influence the RoR response, indicating that the Prazosin blockade of the 1-adrenergic receptor and its corresponding change in MAP was not a limitation to our interpretation of the data. However, during the cuff release hypotension challenges, the minimum MAP was close to the lower blood pressure limit of cerebral autoregulation in both conditions. In addition, the minimum MAP in the Prazosin condition was lower than control (57±4 mm Hg with Prazosin compared with 64±4 mm Hg during the control; P=0.125). It has been shown that maximal or near-maximal dilatation at the arteriolar bed that occurs at cerebral autoregulation threshold alters the autoregulatory response.34–36 Therefore, it is possible that the greater vasodilation that occurred during the Prazosin condition may have been a factor in the observed impaired RoR response.
Phase II: Cerebral Autoregulation and Arterial Baroreflex Control of the Cerebral Vasculature
To identify arterial baroreflex-mediated increases in sympathetic activity in response to the cuff release-induced hypotension, we analyzed the CBF response to changes in ABP in Phase II from the first to the fourth second of responses recorded from the start of increases in ABP after the nadir in ABP (see Figure 1). We observed no significant difference in the decrease of MAP in response to the thigh cuff release between control and Prazosin conditions (P=0.666; Table); however, in Phase II, Prazosin significantly (P=0.030) decreased the rate of return of MAP (Figures 1 and 3
). These findings clearly demonstrate that increased sympathetic activity through arterial baroreflex disengagement37 was an important mechanism for the return of ABP to baseline values after acute hypotension. It should be noted that the contribution of sympathetic activation to the degree of the ABP correction in Phase II was variable among the individual subjects. This variability in the baroreflex correction appeared to be related to the differences in the correction rate of the MAP in the Prazosin condition compared with the control condition (see Figure 3).
In contrast to the changes in ABP during Phase II, there was no significant difference in the rate of return of MCA Vmean with and without Prazosin (Figure 4). The change in MCA Vmean observed during the control condition is consistent with a previous report.22 Because the intrinsic cerebral autoregulatory mechanisms correct changes in CBF faster than those of the arterial baroreflex mediated regulation of ABP,22 the MCA Vmean returned to baseline values before the arterial baroreflex-mediated corrections of ABP were completed.
Importantly, during the control condition, MCA Vmean was well maintained around its baseline value (1.0) in Phase II despite increased ABP (Figure 4). This phenomenon is clearly related to the autonomic nervous system, because Prazosin varied the MCA Vmean response. During the Prazosin condition in Phase II, the MCA Vmean of some subjects continued to increase above baseline values, whereas the MCA Vmean of other subjects was lower than their baseline value (Figure 4). These MCA Vmean responses are related to the change in CVCi in Phase II. The recovery CVCi remained high and did not return to baseline during the Prazosin condition in Phase II; in contrast, the high CVCi returned to baseline during Phase II of the control condition (Figure 5). These findings suggest that, in contrast to the control condition, Prazosin maintained cerebral vasodilation in the Phase II period of recovery. In addition, the ratio of the return rate of MAP and MCA Vmean was significantly higher during the Prazosin condition than in the control condition (P=0.023; Figure 6). These findings indicate that in the Prazosin condition, the effect of perfusion pressure on MCA Vmean was much higher than the control.
The data from the present investigation strongly suggest that in humans sympathetic neural control of the cerebral vasculature provides dynamic functional control of CBF during acute hypotension. In animal models, the response of the cerebral vasculature to changes in sympathetic nerve activity during hypertension has been demonstrated to protect the blood-brain barrier from disruption.8 Furthermore, direct stimulation of the stellate ganglion and the superior cervical ganglion produced marked vasoconstriction in the normotensive primate.29 In addition, the data of the present study identify that arterial baroreflex regulation of systemic ABP during hypotension works in consort with cerebral autoregulation to return CBF to baseline values.
Clinical Implications
Chronic untreated hypertension increases one’s risk for stroke.10 In general, when diuretic or angiotensin inhibition therapy fails or becomes accommodated,38 additional antihypertensive drug-induced therapy using 1-adrenergic receptor inhibition is used to decrease the risk of acquiring major cardiovascular diseases and stroke.11,14 In the present study, a single dose of the antihypertensive drug, Prazosin, impaired the normal regulation of CBF during acute hypotension. This finding suggests that during 1-adrenorecepor blockade, there could potentially be hyperperfusion of the brain after a transient hypotensive stimuli, which may result in a breakdown of the blood-brain barrier. However, the present study only investigated healthy subjects. Patients with hypertension usually have high sympathetic nerve activity and increases in cerebrovascular resistance.11,12 In addition, patients with hypertension chronically using antihypertyensive therapy may respond differently than the healthy subjects used in these experiments.
Limitations
Potential limitations of the present study should be considered. Transcranial Doppler is widely used to detect acute changes in cerebral perfusion. However, transcranial Doppler measures CBF velocity in the MCA rather than CBF. Blood velocity reflects blood flow only if the diameter of the insonated blood vessel remains constant. However, the middle cerebral artery diameter changes little with acute hemodynamic perturbations39 such as those elicited during the thigh cuff release protocol.22 In addition, during conditions in which increases in sympathetic activity are manifest, the middle cerebral artery diameter remains relatively constant.40 Therefore, we assumed that because the steady-state measures of the middle cerebral artery blood velocity reflected the steady-state measures of the CBF, the transcranial Doppler measures of the transient changes in MCA Vmean reflected the transient changes in CBF.22,39–41
Recently, Ainslie et al42 demonstrated that cerebral autoregulation exhibited a diurnal rhythm in which cerebral autoregulation was lowest in the morning and highest in the afternoon. In the present study, the protocol required a period of 2 hours postingestion of Prazosin to establish maximum efficacy. These 2 hours were incorporated between morning and afternoon in an experimental session and required that we incorporate an order effect in to the experimental design. Because the decrease in cerebral autoregulation through 1-adrenoreceptor blockade was observed in the afternoon protocol, the presence of a normal diurnal rhythm in cerebral autoregulation would further support the conclusions of the present study. In contrast to the previous investigations in which more than one thigh deflation test was used to analyze RoR for each condition,22 the present study incorporated only one thigh cuff deflation-induced hypotensive challenge during control and Prazosin conditions. Although the repeatability of the data was unclear, we suggest that the conclusions drawn from the data would be unchanged, even if we had identified a variability in the response across repeated challenges because of the large difference in the RoR between the 2 conditions, ie, the RoR of Phase I without drug was 2.5 times more than that with Prazosin.
|
Acknowledgments |
|---|
We appreciate the time and effort spent by our volunteer subjects.
Source of Funding
This work was supported in part by National Institutes of Health grant RO1 HL 045547.
Disclosures
None.
Received November 13, 2007; revision received November 27, 2007; accepted December 5, 2007.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Edvinsson L. Neurogenic mechanisms in the cerebrovascular bed. Autonomic nerves, amine receptors and their effects on cerebral blood flow. Acta Physiol Scand Suppl. 1975; 427: 1–35.[Medline] [Order article via Infotrieve]
2. Nelson E, Rennels M. Innervation of intracranial arteries. Brain. 1970; 93: 475–490.
3. Harper AM, Deshmukh VD, Rowan JO, Jennett WB. The influence of sympathetic nervous activity on cerebral blood flow. Arch Neurol. 1972; 27: 1–6.
4. Heistad DD, Marcus ML. Evidence that neural mechanisms do not have important effects on cerebral blood flow. Circ Res. 1978; 42: 295–302.
5. LeMarbre G, Stauber S, Khayat RN, Puleo DS, Skatrud JB, Morgan BJ. Baroreflex-induced sympathetic activation does not alter cerebrovascular CO2 responsiveness in humans. J Physiol. 2003; 551: 609–616.
6. Jordan J, Shannon JR, Black BK, Paranjape SY, Barwise J, Robertson D. Raised cerebrovascular resistance in idiopathic orthostatic intolerance: evidence for sympathetic vasoconstriction. Hypertension. 1998; 32: 699–704.
7. Ide K, Boushel R, Sorensen HM, Fernandes A, Cai Y, Pott F, Secher NH. Middle cerebral artery blood velocity during exercise with beta-1 adrenergic and unilateral stellate ganglion blockade in humans. Acta Physiol Scand. 2000; 170: 33–38.[CrossRef][Medline] [Order article via Infotrieve]
8. Heistad DD, Marcus ML, Gross PM. Effects of sympathetic nerves on cerebral vessels in dog, cat, and monkey. Am J Physiol. 1978; 235: H544–552.[Medline] [Order article via Infotrieve]
9. Pearce WJ, D'Alecy LG. Hemorrhage-induced cerebral vasoconstriction in dogs. Stroke. 1980; 11: 190–197.
10. Kannel WB, Dawber TR, Sorlie P, Wolf PA. Components of blood pressure and risk of atherothrombotic brain infarction: the Framingham study. Stroke. 1976; 7: 327–331.
11. Nobili F, Rodriguez G, Marenco S, De Carli F, Gambaro M, Castello C, Pontremoli R, Rosadini G. Regional cerebral blood flow in chronic hypertension. A correlative study. Stroke. 1993; 24: 1148–1153.
12. Shaw TG, Mortel KF, Meyer JS, Rogers RL, Hardenberg J, Cutaia MM. Cerebral blood flow changes in benign aging and cerebrovascular disease. Neurology. 1984; 34: 855–862.
13. Immink RV, van den Born BJ, van Montfrans GA, Koopmans RP, Karemaker JM, van Lieshout JJ. Impaired cerebral autoregulation in patients with malignant hypertension. Circulation. 2004; 110: 2241–2245.
14. Larrue V, Dupui P, Pavy-Le Traon A, Allavoine T, Geraud G, Bes A. Effects of captopril on the cerebral blood flow in the hypertensive aged subjects [in French]. Arch Mal Coeur Vaiss. 1994; 87: 997–1000.[Medline] [Order article via Infotrieve]
15. Fu CH, Yang CC, Kuo TB. Effects of different classes of antihypertensive drugs on cerebral hemodynamics in elderly hypertensive patients. Am J Hypertens. 2005; 18: 1621–1625.[CrossRef][Medline] [Order article via Infotrieve]
16. Oku N, Kitagawa K, Imaizumi M, Takasawa M, Piao R, Kimura Y, Kajimoto K, Matsumoto M, Hori M, Hatazawa J. Hemodynamic influences of losartan on the brain in hypertensive patients. Hypertens Res. 2005; 28: 43–49.[CrossRef][Medline] [Order article via Infotrieve]
17. Patel S, Huang DL, Sagher O. Sympathetic mechanisms in cerebral blood flow alterations induced by spinal cord stimulation. J Neurosurg. 2003; 99: 754–761.[Medline] [Order article via Infotrieve]
18. Rutland MD, Lee TY, Nimmon CC, Granowska M, Britton KE. Measurement of the effects of a single dose of prazosin on the cerebral blood flow in hypertensive patients. Postgrad Med J. 1980; 56: 818–822.
19. Visocchi M, Cioni B, Vergari S, Marano G, Pentimalli L, Meglio M. Spinal cord stimulation and cerebral blood flow: an experimental study. Stereotact Funct Neurosurg. 1994; 62: 186–190.[CrossRef][Medline] [Order article via Infotrieve]
20. Jaillon P. Clinical pharmacokinetics of prazosin. Clin Pharmacokinet. 1980; 5: 365–376.[CrossRef][Medline] [Order article via Infotrieve]
21. Rudas L, Crossman AA, Morillo CA, Halliwill JR, Tahvanainen KU, Kuusela TA, Eckberg DL. Human sympathetic and vagal baroreflex responses to sequential nitroprusside and phenylephrine. Am J Physiol. 1999; 276: H1691–1698.[Medline] [Order article via Infotrieve]
22. Aaslid R, Lindegaard KF, Sorteberg W, Nornes H. Cerebral autoregulation dynamics in humans. Stroke. 1989; 20: 45–52.
23. Morita Y, Hardebo JE, Bouskela E. Influence of cerebrovascular sympathetic, parasympathetic, and sensory nerves on autoregulation and spontaneous vasomotion. Acta Physiol Scand. 1995; 154: 121–130.[Medline] [Order article via Infotrieve]
24. Zhang R, Zuckerman JH, Iwasaki K, Wilson TE, Crandall CG, Levine BD. Autonomic neural control of dynamic cerebral autoregulation in humans. Circulation. 2002; 106: 1814–1820.
25. Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation. Cerebrovasc Brain Metab Rev. 1990; 2: 161–192.[Medline] [Order article via Infotrieve]
26. Berne RM, Winn HR, Rubio R. The local regulation of cerebral blood flow. Prog Cardiovasc Dis. 1981; 24: 243–260.[CrossRef][Medline] [Order article via Infotrieve]
27. D'Alecy LG, Rose CJ, Sellers SA. Sympathetic modulation of hypercapnic cerebral vasodilation in dogs. Circ Res. 1979; 45: 771–785.
28. Jordan J, Shannon JR, Diedrich A, Black B, Costa F, Robertson D, Biaggioni I. Interaction of carbon dioxide and sympathetic nervous system activity in the regulation of cerebral perfusion in humans. Hypertension. 2000; 36: 383–388.
29. Meyer JS, Yoshida K, Sakamoto K. Autonomic control of cerebral blood flow measured by electromagnetic flowmeters. Neurology. 1967; 17: 638–648.
30. James IM, Millar RA, Purves MJ. Observations on the extrinsic neural control of cerebral blood flow in the baboon. Circ Res. 1969; 25: 77–93.
31. Aubineau PF, Sercombe R, Seylaz J. Continuous recordings of local cerebral blood flow during cervical sympathetic nerve blockade or stimulation. J Physiol. 1975; 246: 104P–106P.[Medline] [Order article via Infotrieve]
32. Morita-Tsuzuki Y, Hardebo JE, Bouskela E. Interaction between cerebrovascular sympathetic, parasympathetic and sensory nerves in blood flow regulation. J Vasc Res. 1993; 30: 263–271.[Medline] [Order article via Infotrieve]
33. Lassen NA. Cerebral blood flow and oxygen consumption in man. Physiol Rev. 1959; 39: 183–238.
34. Harper AM. Autoregulation of cerebral blood flow: influence of the arterial blood pressure on the blood flow through the cerebral cortex. J Neurol Neurosurg Psychiatry. 1966; 29: 398–403.
35. Fitch W, MacKenzie ET, Harper AM. Effects of decreasing arterial blood pressure on cerebral blood flow in the baboon. Influence of the sympathetic nervous system. Circ Res. 1975; 37: 550–557.
36. Fitch W, Ferguson GG, Sengupta D, Garibi J, Harper AM. Autoregulation of cerebral blood flow during controlled hypotension in baboons. J Neurol Neurosurg Psychiatry. 1976; 39: 1014–1022.
37. Fadel PJ, Stromstad M, Hansen J, Sander M, Horn K, Ogoh S, Smith ML, Secher NH, Raven PB. Arterial baroreflex control of sympathetic nerve activity during acute hypotension: effect of fitness. Am J Physiol Heart Circ Physiol. 2001; 280: H2524–2532.
38. Arnett DK, Claas SA, Glasser SP. Pharmacogenetics of antihypertensive treatment. Vascul Pharmacol. 2006; 44: 107–118.[CrossRef][Medline] [Order article via Infotrieve]
39. Giller CA, Bowman G, Dyer H, Mootz L, Krippner W. Cerebral arterial diameters during changes in blood pressure and carbon dioxide during craniotomy. Neurosurgery. 1993; 32: 737–741;discussion 741–742.
40. Serrador JM, Picot PA, Rutt BK, Shoemaker JK, Bondar RL. MRI measures of middle cerebral artery diameter in conscious humans during simulated orthostasis. Stroke. 2000; 31: 1672–1678.
41. Secher NH, Seifert T, Van Lieshout JJ. Cerebral blood flow and metabolism during exercise, implications for fatigue. J Appl Physiol. 2008; 104: 306–314.
42. Ainslie PN, Murrell C, Peebles K, Swart M, Skinner MA, Williams MJ, Taylor RD. Early morning impairment in cerebral autoregulation and cerebrovascular CO2 reactivity in healthy humans: relation to endothelial function. Exp Physiol. 2007; 92: 769–777.
This article has been cited by other articles:
 |
|
 |
|
  S. Ogoh and P. N. Ainslie Cerebral blood flow during exercise: mechanisms of regulation J Appl Physiol, November 1, 2009; 107(5): 1370 - 1380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. V. Immink, J. Truijen, N. H. Secher, and J. J. Van Lieshout Transient influence of end-tidal carbon dioxide tension on the postural restraint in cerebral perfusion J Appl Physiol, September 1, 2009; 107(3): 816 - 823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Ocon, M. S. Medow, I. Taneja, D. Clarke, and J. M. Stewart Decreased upright cerebral blood flow and cerebral autoregulation in normocapnic postural tachycardia syndrome Am J Physiol Heart Circ Physiol, August 1, 2009; 297(2): H664 - H673. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Brothers, J. E. Wingo, K. A. Hubing, and C. G. Crandall The effects of reduced end-tidal carbon dioxide tension on cerebral blood flow during heat stress J. Physiol., August 1, 2009; 587(15): 3921 - 3927. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Mitchell, G. Lambert, N. H. Secher, P. B. Raven, J. van Lieshout, and M. D. Esler Jugular venous overflow of noradrenaline from the brain: a neurochemical indicator of cerebrovascular sympathetic nerve activity in humans J. Physiol., June 1, 2009; 587(11): 2589 - 2597. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. N. Ainslie and J. Duffin Integration of cerebrovascular CO2 reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretation Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2009; 296(5): R1473 - R1495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Low, J. E. Wingo, D. M. Keller, S. L. Davis, J. Cui, R. Zhang, and C. G. Crandall Dynamic cerebral autoregulation during passive heat stress in humans Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2009; 296(5): R1598 - R1605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Cassaglia, R. I. Griffiths, and A. M. Walker Cerebral sympathetic nerve activity has a major regulatory role in the cerebral circulation in REM sleep J Appl Physiol, April 1, 2009; 106(4): 1050 - 1056. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. N. Ainslie Have a safe night: intimate protection against cerebral hyperperfusion during REM sleep J Appl Physiol, April 1, 2009; 106(4): 1031 - 1033. [Full Text] [PDF]
|
|
|
|
 |
|
 E.S. Prakash Effect of Prazosin on Dynamic Cerebral Autoregulation During Acute Hypotension in Healthy Human Subjects Stroke, November 1, 2008; 39(11): e167 - e167. [Full Text] [PDF]
|
|
|
|
|
|
S. Ogoh Response to Letter by Prakash Stroke, November 1, 2008; 39(11): e168 - e169. [Full Text] [PDF]
|
|
|
|
|
|
B. D. Levine, R. Zhang, M. Visocchi, P. N. Ainslie, S. Ogoh, L. Edvinsson, M. Yildiz, O. B. Paulson, G. M. Knudsen, P. A. Cassaglia, et al. Comments on Point:Counterpoint: Sympathetic activity does/does not influence cerebral blood flow J Appl Physiol, October 1, 2008; 105(4): 1369 - 1373. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||