DISTENSIBILITY IN ARTERIES, ARTERIOLES AND VEINS IN HUMANS:
Adaptation to Intermittent or Prolonged Change in Regional Intravascular Pressure
Roger Kölegård
Thesis for doctoral degree (Ph.D.)
Department of Environmental Physiology
School of Technology and Health
KTH (Royal Institute of Technology)
Academic dissertation which, with permission from KTH (Royal Institute of Technology)
Stockholm, will be presented on Friday November 26, 2010, at 09.00, in lecture hall 3-221,
Alfred Nobels allé 10, Huddinge, Sweden.
TRITA-STH Report 2010:5
ISSN: 1653-3836
ISRN: ISRN KTH /STH/--2010:5--SE
ISBN: 978-91-7415-778-9
© Roger Kölegård, Stockholm 2010
ABSTRACT
The present series of in vivo experiments in healthy subjects, were performed to investigate
wall stiffness in peripheral vessels and how this modality adapts to iterative increments or
sustained reductions in local intravascular pressures. Vascular stiffness was measured as
changes in arterial and venous diameters, and in arterial flow, during graded increments in
distending pressures in the vasculature of an arm or a lower leg. In addition, effects of
intravascular pressure elevation on flow characteristics in veins, and on limb pain were
elucidated. Arteries and veins were stiffer (i.e. pressure distension was less) in the lower leg
than in the arm. The pressure-induced increase in arterial flow was substantially greater in
the arm than in the lower leg, indicating a greater stiffness in the arterioles of the lower leg.
Prolonged reduction of intravascular pressures in the lower body, induced by 5 wks of
sustained horizontal bedrest (BR), decreased stiffness in the leg vasculature. BR increased
pressure distension in the tibial artery threefold and in the tibial vein by 86 %. The pressureinduced increase in tibial artery flow was greater post bedrest, indicating reduced stiffness in
the arterioles of the lower leg. Intermittent increases of intravascular pressures in one arm
(pressure training; PT) during a 5-wk period decreased vascular stiffness. Pressure distension
and pressure-induced flow in the brachial artery were reduced by about 50 % by PT. PT
reduced pressure distension in arm veins by 30 to 50 %. High intravascular pressures
changed venous flow to arterial-like pulsatile patterns, reflecting propagation of pulse waves
from the arteries to the veins either via the capillary network or through arteriovenous
anastomoses. High vascular pressures induced pain, which was aggravated by BR and
attenuated by PT; the results suggest that the pain was predominantly caused by vascular
overdistension. In conclusion, vascular wall stiffness constitutes a plastic modality that
adapts to meet demands imposed by a change in the prevailing local intravascular pressure.
That increased intravascular pressure leads to increased arteriolar wall stiffness supports the
notion that local pressure load may serve as a “prime mover” in the development of vascular
changes in hypertension.
Keywords: arterial stiffness, venous distensibility, venous flow characteristics, bedrest,
“pressure training”
i
At a Royal Society meeting on the, 7th May 1662 Robert Hooke demonstrated an experiment
using Mr. Boyle´s Vaccuum: “ A man thrusting in his arme, upon exhaustion of the ayre,
had his flesh immediately swelled, so as the bloud was neere breaking the vaines, &
unsufferable: he drawing it out, we found it all speckled.”
De Beer; Diary of John Evelyn 3, p318. In: Lisa Jardine (2003) The Curious Life of Robert
Hooke, The Man who Measured London: p106.
ii
LIST OF ORIGINAL PUBLICATIONS:
This thesis is based on the following papers, which are referred to by their Roman numerals
(I-VI).
I.
Eiken O & Kölegård R (2004) Comparison of vascular distensibility in the
upper and lower extremity. Acta Physiol Scand 181: 281-287.
II.
Eiken O, Kölegård R & Mekjavic IB (2008) Pressure-distension relationship in
arteries and arterioles in response to 5 wk of horizontal bedrest. Am J Physiol
Heart Circ Physiol 295: H1296-H1302.
III.
Kölegård R, Mekjavic IB & Eiken O (2009) Increased distensibility in
dependent veins following prolonged bedrest. Eur J Appl Physiol 106: 547554.
IV.
Eiken O & Kölegård R. Repeated exposures to moderately increased
intravascular pressure increases stiffness in human arteries and arterioles (in
manuscript).
V.
Kölegård R & Eiken O. Distensibility in human veins as affected by five weeks
of repeated elevations of local transmural pressure (in manuscript).
VI.
Kölegård R & Eiken O (2009) Antegrade pulsatile arterial-like flow in human
limb veins at increased intravascular pressure. Clin Physiol Funct Imaging 29:
209-215.
Publications protected by copyrights are reproduced with permission from the publishers.
iii
TABLE OF CONTENTS
ABSTRACT………………………………………………………..………………………
i
LIST OF ORIGINAL PUBLICATIONS……………………………………………………….
iii
TABLE OF CONTENTS……………………………………………………...…………….
iv
LIST OF ABBREVIATIONS…………………………………………………………….…..
vi
INTRODUCTION …………………………………………………………………………
1
AIMS……………………………………………………………………………..………
Specific aims…………………………………………………………………………
4
4
METHODS AND PROCEDURES……………………………………..………………………
Subjects and ethical considerations…………………………………………..……
Experimental techniques and measurements…………………………….…….…
Elevation of local intravascular pressure using a
pressure-chamber model………………………………………….………………
Vascular distensibility……………………………….……….………………...…
Vessel diameters and arterial flow………………………….………………….…
Intima-media thickness………………………………………………….……...…
Forearm and lower-leg tissue impedance………………………….…………..…
Pressure-induced pain……………………………………………………..……..
Arterial pressures and heart rate………………………………………………...
Vasodilatation…………………………….………………….………..……..…..
Experimental protocols……………………………………………..……………..
Study I. Vascular distensibility in arm vs. leg……………………………….…....
Study II-III. Vascular distension as affected by prolonged
reductions of local intravascular pressure………………………………….…...
Bedrest protocol………………………………………………………….…..
Vascular distensibility test…………………………………………………....
Study IV-V. Distensibility in precapillary vessels (IV) and veins (V)
as affected by intermittent elevations of local intravascular pressure
(pressure training; PT)…………………………………………………………..
Study VI. Venous flow pattern during elevated venous pressure………………...
Analyses…………………………………………………………………...………..
Threshold and gain determinations……………………………………….…….
Statistics……….……………………………………………………………..….
RESULTS AND COMMENTS…………………………………………………………..….
Arterial and arteriolar distensibility……………………………………….…….
Venous distensibility………………………………………………………...…….
Forearm and lower-leg tissue impedance………………………..…………...….
Intima-media thickness……………………………………………………..…….
5
5
5
iv
5
6
7
8
8
8
8
9
9
9
10
10
10
10
11
11
11
11
12
12
15
17
18
Vasodilatation……………………………………………………………….…….
Pressure-induced pain…………………………………………………………….
Venous-flow pattern at high distending pressures……………………….…...…
Arterial pressures and heart rate…………………………………………….….
Coefficient of variation (CV)…………………………………………………...…
18
18
19
19
19
DISCUSSION………………………………………………………………………....….
Arterial and arteriolar distensibility………………………………………..…...
Venous distensibility……………………………………………………….….….
Habituation effects on vascular distensibilities; implications for
circulatory control…………………………………………….……………..…...
Pressure-induced pain…………………………………………………..….…….
Venous flow characteristics…………………………………………………..….
Methodological considerations…………………………………………….…….
Pressure transmission and distending pressures……………………………….
Noninvasive measurements of vascular distensibility…………….………….….
Diameter and intima-media measurements…………………….…………...….
SUMMARY AND CONCLUSIONS…………………………………………………...…….
20
20
23
ACKNOWLEDGEMENTS……………………………………………..………………….
33
REFERENCES………………………………………………………………….……….
34
PUBLICATIONS: I-VI
v
25
26
28
28
28
29
30
31
LIST OF ABBREVIATIONS
ANOVA
AT-II
AVAs
B-mode
BR
CN
CSA
CV
DP
ET-1
FMD
G
Gz
HR
IM
IMCSA
IMT
L/IMT
NMD
SD
PT
Analysis of variance
Angiotensin II
Arteriovenous anastomoses
Brightness mode
Bedrest
Control
Cross-sectional area
Coefficient of variation
Distending pressure
Endothelin-1
Flow-mediated dilatation
Gravitoinertial force; a dimensionless unit, expresses the magnitude of a
gravitational force field as a multiple of the gravitational force field or the
weight on the surface of the earth (g = 9.81 N/kg or m/s2)
G in the head-to-foot direction
Heart rate
Intima-media complex
Intima-media cross-sectional area
Intima-media thickness
Lumen to IM thickness ratio
Nitroglycerin-mediated dilatation
Standard deviation
Pressure training
vi
INTRODUCTION
This thesis deals with in vivo distensibility (and its inverse, stiffness) of the vasculature in
human limbs. The physiological responses to acute exposure of increased vascular pressure,
as well as the vessel wall adaptation in response to iterative exposures to increased and
prolonged exposures to reduced intravascular pressures, were studied. The pressuredistension relationships were investigated across a wide range of vascular pressures.
Mechanical properties and tone of the vascular wall are affected by, and affect,
cardiovascular control. Distensibilities of the veins determine vascular capacitance and thus
influence the distribution of the circulating blood volume and hence preload on the heart and
cardiac output. The luminal cross-sectional areas of the arterioles determine flow resistance
and therefore arterial pressure regulation. In the upright body position, the capacity of
dependent blood vessels to withstand pressure load is challenged by gravity-induced
pressure increments. Thus, about 10 % of the total blood volume is relocated from the thorax
to the dependent regions in response to a transition from supine to upright body positions
(Gauer & Thron 1965). The gravity-induced high hydrostatic pressure in dependent circuits
that is endured throughout life in an erect posture, seems to be at least partly compensated
for by adaptive changes in the vascular design (von Kügelgen 1955; Svejcar et al. 1962).
It has also long been proposed that certain pathological conditions, resulting in chronic
changes of transmural vascular pressures, may alter both the function and structure of bloodvessel walls. Thus, Ewald (1877) introduced the notion that sustained arterial pressure
elevation may increase the stiffness of precapillary vessels, an idea that was subsequently
supported by Turnbull (1915), who observed that the precapillary vessels from hypertensive
patients were hypertrophied. More recent investigations have revealed that the most
prominent hypertrophic changes are usually observed in arteries and larger resistance
vessels, whereas it appears that the degree of media hypertrophy gradually decreases along
the vessels towards the capillary level (Furayama 1962; Rizzoni & Rosei 2006). In
hypertensive humans, hypertrophic remodeling involves thickening of the media causing an
increased wall/lumen ratio, which per se constitutes a functional aspect of structural changes
of resistance vessels (Folkow et al. 1958; Folkow & Sivertsson 1968; Folkow 1990).
The mechanical characteristics of relaxed vessels are not only affected by the thickness of
the smooth muscle layer, but have to a great extent also been attributed to the properties of
the fibrous connective tissues in the wall, in particular to those of elastin and collagen.
Elastin is a fibrous, elastomeric protein capable of extending more than 100 % (Cox 1977).
In contrast, collagen fibers constitute a jacket with much stiffer material (Dobrin 1983).
Microfibrils, composed of glycoproteins may also affect the mechanical properties in arteries
at both high and low intravascular pressures (Faury 2001). It is well established from
experiments in animals that prolonged changes of the transmural pressure may indeed
change the content and arrangement of elastin, collagen and myofibrils in the vessel walls
(Intengan & Shiffrin 2000; Monos et al. 2003). In addition, the notion that sustained changes
of intravascular pressures induce not only structural but also functional changes in the
1
vessel-wall properties, is predominantly based on results from experiments in animals
(Kernohan et al. 1929; Folkow et al. 1958; Monos et al. 2003; Intengan & Schiffrin 2001).
Presumably, due to the practical problem of accurately measuring vascular flow and/or
diameter responses to graded changes in distending pressure in vivo, information is scanty as
regards the pressure-distension relationships of arteries, arterioles and veins in humans, and
in particular with respect to how such relationships are influenced by prolonged or
intermittent changes in local transmural pressure. The in vivo distensibility of a vessel can be
described as the relative change in diameter or flow as a function of a change in distending
pressure (relative ∆diameter/∆pressure); (Figure 1; 2). To establish the pressure-distension
relationships in human pre and post-capillary vessels, changes in diameter and/or flow
should be investigated across a wide range of distending pressures. By use of a technique
described in the methods section of the present thesis, we have previously determined the
pressure-distension relationships of arteries, arterioles and veins in the arm of healthy
humans (Eiken & Kölegård 2001). With increasing pressure, veins initially show large
diameter changes (Figure 1). However, diameter increments at this low-pressure portion of
the pressure-∆diameter curve should be interpreted with caution since they may not merely
represent true wall distension but also filling of the vein (cf. Öberg 1967); i.e. in this phase,
the cross-sectional shape of the vein may change from ellipsoidal to circular, after which the
vessel distends in a seemingly linear manner with increasing pressures (Figure 1).
Figure 1. Relative change in brachial vein diameter as a function of distending pressure. The
pressure-distension curve may be divided in a filling phase and a true distending phase (see also
text, n=8; adapted from (Eiken & Kölegård 2001).
One way of describing the pressure-distension relationship of precapillary vessels (Figure 2)
is to determine the pressure threshold and the gain of the pressure distension (cf. Folkow &
Sivertsson 1968; Sivertsson 1970; Folkow 1982); according to Folkow and co-workers, a
2
change in pressure threshold predominantly reflects a change in smooth-muscle reactivity,
whereas a change of the slope (gain) reflects a change in the mechanical characteristics of
the vessel wall.
Relative change in diameter (%)
35
30
25
20
15
10
slope = gain
threshold
5
0
-5
autoreguled phase, by myogenic tone
-10
0
50
100
150
200
Distending Pressure (mmHg)
250
300
Figure 2. Relative change in arterial diameter as a function of distending pressure. The pressuredistension curve may be described by identifying the pressure threshold and slope (gain) of the
pressure distension. (see also text, n=8; adapted from Eiken & Kölegård 2001).
The primary aim of the present thesis was, as mentioned, to investigate vascular pressuredistension relationships. It can be argued that the stimuli used to determine such
relationships were “unphysiological” in the sense that the applied pressures were somewhat
higher than those encountered during daily life activities. However, in pilots exposed to high
gravitoinertial forces in the head-to-foot direction, local intravascular pressures commonly
exceed those applied during the present pressure provocations (Lambert & Wood 1946;
Howard 1965; Green 1997). High pressures in the vasculature of the arms/legs may not only
result in vascular distension but may also cause an aching, dull pain. G-induced arm pain or
foot/leg pain is known since the development of anti-G garments in the 1940s-1960s (Wood
1990), and has been suggested to be caused by overdistension of local vascular segments
(Greenfield & Patterson 1954; Ernsting 1966; Linder 1992; Green 1997; Watkins et al. 1998;
Eiken & Kölegård 2001). A secondary aim of the thesis was to investigate if, and in what
manner, limb pain induced by high intravascular pressures is affected by intermittent and/or
sustained changes in local intravascular pressure.
3
AIMS
The main objectives of this thesis were to investigate the pressure-distension relationship in
peripheral vessels, especially at high distending pressures and to study the adaptations in
distensibility in the vessel wall evoked by prolonged reductions and iterative increases in
vascular pressure.
Specific aims were:
•
To compare vessels in an arm with those in a leg regarding the pressure-distension
relationships in arteries, resistance vessels and veins.
•
To investigate the effect of sustained reduction in intravascular pressure on the
pressure-distension relationships in arteries, resistance vessels and veins.
•
To investigate the effect of repeated intravascular pressure elevations on the
pressure-distension relationships in the arteries, resistance vessels and veins.
•
To investigate the effect both of repeated increments and of sustained reduction in
intravascular pressure on pain in the arm/lower leg induced by markedly increased
intravascular pressure.
•
To investigate the effect of intravascular pressure elevations on the flow
characteristics in limb veins.
4
METHODS AND PROCEDURES
The methods used are described in detail in each publication. An overview and some
comments of the techniques and methods are given below.
Subjects and ethical considerations
A total of 62 healthy male volunteers participated in the present investigations. Their basic
characteristics are given in Table 1. None of the subjects had a history of cardiovascular
disease or were taking medication at the time of the study. They were instructed to refrain
from caffeine and nicotine on days of experiments.
All experiments were conducted in accordance with the Declaration of Helsinki (1964;
amended 2008; http://www.wma.net/en/30publications/10 policies/b3/index.html). The
subjects were given written and oral information about the aims, experimental procedures
and possible risks before giving their consent to participate. The regional Ethics review
Board, in Stockholm approved the experimental protocols of studies I, IV, V and VI. Study
II and III were approved by the Committee for Medical Ethics of the Ministry of Health,
Republic of Slovenia.
Table 1. Physical characteristics of the subjects.
Study
I
II/III
IV
V
VI main study
suppl. study
n
11
10
11
8
7
15
Age (years)
28 (21-44)
23 (18-32)
30 (23-44)
29 (23-42)
27 (25-33)
24 (18-36)
Height (cm)
182 ± 6
179 ± 9
181 ± 8
181 ± 6
176 ± 6
179 ± 8
Weight (kg)
74 ± 9
70 ± 8
78 ± 9
76 ± 11
74 ± 3
72 ± 14
Values are mean ± SD or (range)
Experimental techniques and measurements
Elevation of local intravascular pressure using a pressure-chamber model
In all experiments, a hyperbaric pressure chamber was used to increase distending pressure
(DP) locally in the vasculature of one arm or a lower leg (Figure 3). The subject was
positioned inside the chamber with one arm or one lower leg (test limb) protruding to the
outside via a hole in the chamber door. The test limb was kept at heart level by resting it on a
stand positioned outside the chamber. The test limb was sealed to the door slightly distally of
the axilla or slightly proximally of the knee, respectively, by use of a cone-shaped loosely
fitting rubber sleeve. The chamber was pressurized with compressed air. As chamber
pressure was elevated, pressure increased in all tissues enclosed in the chamber and the
pressure was also transmitted to the blood vessels of the test limb (outside the chamber).
Arterial pressure in the test limb increased immediately upon pressurization of the chamber,
5
whereas pressure in the test-limb veins increased gradually until it overcame the pressure in
proximal veins enclosed in the chamber, and antegrade flow was resumed. Consequently,
transmural pressure in the vasculature of the test limb increased in direct proportion to the
applied chamber pressure (see also under methodological considerations).
When pressure inside the chamber increases, the test limb tends to be pushed out. To prevent
skeletal muscle activity and movements during pressurization of the chamber, the test
subject was provided with a harness around the thorax during arm-vessel experiments.
Likewise, during leg-vessel experiments the subject was equipped with a harness around the
thighs and waist.
Vascular distensibility
Pressure-distension relationships in arteries, arterioles and veins were investigated during
increasing pressure (Table 2). Each experiment started with a 10-min baseline period with
normal atmospheric pressure in the chamber, followed by step-wise increasing chamber
pressure. During the last 1-1.5 min at each pressure plateau, recordings of vascular
diameters, arterial flow velocity, tissue impedance, heart rate, arterial pressures and ratings
of perceived pain were performed. Thereafter, pressure in the chamber was released and a
recovery period at atmospheric pressure started.
Figure 3. Schematic illustrations of the experimental arrangements used to increase transmural
pressure in the vasculature of an arm (left) and a lower leg (right). The subject is positioned inside
the pressure chamber with the test limb protruding to the outside. When chamber pressure is
elevated, transmural pressure in the vasculature of the test limb increases in direct proportion to the
applied pressure (in these examples by 100 mmHg from normal atmospheric pressure, 760 mmHg, to
860 mmHg).
6
Table 2. Chamber pressure levels and duration at each pressure plateau during the distensibility tests.
Study
I
II/III arm
leg
IV
V
VI
Applied chamber pressures (mmHg)
0, 30, 60, 90, 120, 150, 180, 210
0, 15, 60, 90, 120, 150,
0, 15, 60, 90, 150, 180, 210, 240
0, 30, 60, 90, 120, 150, 180
0, 30, 60, 90, 120, 150, 180
0, 50, 100, 150
Time on plateau (min)
2.5
2
2
2.5
2.5
4
Vessel diameters and arterial flow
Diameter changes in arteries and veins in response to DP elevations were measured during
end-diastole using ultrasonographic equipment (Aspen, Acuson, Mountain View, CA, USA)
with a linear array transducer, 7-11 MHz. The vessel segments investigated in the studies are
listed in Table 3. Intra- and extravascular “landmarks” were chosen to ensure that insonation
of the same segment of the vessel was performed during repeated measurements. Twodimensional measurements of the vessel lumen were made from B-mode images in long-axis
view. The cursors were placed at the leading edge echos in both the near and far wall. All
images were stored digitally in DICOM format on magneto-optical discs.
Table 3. This table lists anatomical locations of vessel segments investigated.
Study
I
II/III
IV
V
VI main study
suppl. study
Insonated vessel
a. brachialis
a. radialis
a. tibialis posterior
v. cephalica
v. saphena magna
a. brachialis
a. tibialis posterior
v. brachialis
v. tibialis posterior
a. brachialis
v. brachialis
v. cephalica
a. brachialis
a. radialis
v. brachialis
v. radialis
v. cephalica prox
v. cephalica dist
a. tibialis posterior
v. tibialis posterior
Anatomical location
5 cm proximal to the cubital fossa
5 cm proximal to the wrist
5 cm proximal to the ankle
5 cm proximal to elbow joint
5-10 cm proximal to medial malleolus
2-10 cm proximal to the cubital fossa
5 cm proximal to the ankle
2-10 cm proximal to the cubital fossa
5 cm proximal to the ankle
5 cm proximal to the cubital fossa
4-8 cm proximal to the cubital fossa
4-8 cm proximal to the cubital fossa
5 cm proximal to the cubital fossa
15 cm proximal to the wrist
5 cm proximal to the cubital fossa
15 cm proximal to the wrist
5 cm proximal to the cubital fossa
15 cm proximal to the wrist
5 cm proximal to the ankle
5 cm proximal to the ankle
Flow in the brachial and/or posterior tibial artery was estimated by simultaneous
measurements of vessel diameter and mean flow-velocity using ultrasonographic/Doppler
techniques. Flow was calculated by multiplying vessel cross-sectional area by the time
integral of the mean flow velocity. Flow velocity was collected with the sample volume of
7
the Doppler transducer covering more than 75 % of the arterial lumen and the transducer
aligned with the vessel wall; the angle correction was always kept at 50°.
Figure 4. Photograph from a pressure-distension experiment on the lower-leg vasculature. The
subject is positioned supine inside the pressure chamber with a lower leg protruding to the outside.
The tibial posterior vessels are examined using an ultrasound/Doppler technique. Lower-leg volume
is estimated using an impedance technique. The sonographer is using a head-set to be in contact with
the chamber operator as well as with the physician and the subject inside the chamber.
Intima-media thickness
The thickness of the arterial intima-media (IM) complex was measured from B-mode,
longitudinal images in studies II and IV. The mean thickness was calculated from five
measurements of the distance from the leading edge of the lumen-intima echo to the intimaadventitia echo in the far wall of the artery. The IM cross-sectional area (CSA) was
calculated by multiplying vessel CSA by the IM thickness. Lumen-to-IM thickness was
calculated by dividing lumen diameter with IM thickness.
Forearm and lower-leg volume (tissue impedance)
Relative changes in forearm and lower-leg volumes were estimated from tissue impedance
measurements using a tetrapolar constant-current impedance system (Minnesota Impedance
Cardiograph Model 304A; Instrumentation for medicine Inc. Greenwhich, CT, USA). Four
pairs of pre-gelled surface electrodes were applied to the skin between the knee and ankle or
elbow and wrist, respectively.
Pressure-induced pain
During each test of pressure-distension relationship, the subject rated pain in the test limb
using a 10-graded ratio scale (Borg 1982). (0 = no pain, 3 = moderate pain, 5 = strong pain,
10 = very, very strong (almost intolerable).
Arterial pressures and heart rate
Arterial pressures were measured inside the chamber using two techniques. Systolic and
diastolic pressures were measured continuously in a finger using a volume-clamp technique
8
(Portapres, Model 2.0; TNO, Amsterdam, The Netherlands) and intermittently in the brachial
artery, using a sphygmomanometric technique. Heart rate (HR) was obtained from
electrocardiographic recordings using a bipolar precordial lead (Physiocontrol Lifepak 8,
Physiocontrol corp., Redmond, WA, USA). Arterial distending pressure (DP) was calculated
by adding the applied chamber pressure to the diastolic arterial pressure. Venous DP was
assumed to be equal to the chamber pressure (see also under methodological considerations
and in: Eiken & Kölegård 2001).
Vasodilatation
Brachial artery dilatory capacity was determined using the technique introduced by
Celermayer et al. (1992). Endothelium-dependent flow-mediated dilatation (FMD) and
endothelium-independent nitroglycerin-mediated dilatation (NMD) were determined
bilaterally, in a standard manner (Corretti et al. 2002). During each experiment, the subject
was supine on a guerney, equipped with 12.5 cm pneumatic tourniquets placed around the
most proximal portions of the forearms. After 10 min of rest, a baseline measurement of
brachial artery diameter was performed unilaterally using an ultrasound technique.
Thereafter, the brachial artery flow was occluded by pressurizing the tourniquet to 250
mmHg. The occlusion was released after 4.5 min and brachial artery diameter was recorded
continuously from 30 s before to 2 min following the release. The procedure was repeated
ipsilaterally after 10 min. Thereafter, FMD measurements were performed in the
contralateral arm. Subsequently, end-diastolic diameters, as synchronized from the ECG
trace, were determined 45, 60 and 75 sec after each tourniquet-pressure release. A mean of
the diameters recorded 45, 60 and 75 sec after the release was estimated for each
examination and, eventually, the average of the two FMD examinations performed in each
arm was used.
30 min after the last FMD examination, NMD was determined in the following manner: after
a baseline measurement of brachial artery diameter, 0.4 mg of nitroglycerin (Spray
Nitrolingual®, G-Pohl-Boskamp GmbH & Co, Germany) was administered sublingually,
and the brachial artery diameter was recorded continuously from 30 s before to 5 min
following the administration. Subsequently, peak dilatation, usually occurring 3.5-4.0 min
after administration of nitroglycerin, was determined bilaterally in a fixed order.
Experimental protocols
Study I. Vascular distensibilities in arm vs. leg
The protocol was designed to study the difference between forearm and lower leg regarding
pressure-distension relationships in arteries, arterioles and veins as well as with respect to
pain induced by increased intravascular pressure. Distensibility tests were performed in one
arm and in one leg; the order of the tests was alternated amongst the subjects and separated
by at least 24 hours.
9
Studies II-III. Vascular distensibilities as affected by prolonged reductions of local
intravascular pressures
Sustained recumbency (bedrest) was used as an intervention model to study the effect of
prolonged exposure to reduced intravascular pressure on pressure-distension relationship in
the vasculature of an arm and a lower leg.
Bedrest protocol
The subjects were maintained in a horizontal position for 35 days. They remained supine at
all times, including during transport and bathing/WC procedures. They could use only one
pillow and were not allowed to move their arms below the horizontal plane, while the legs
were kept in the horizontal plane at all times. Any kind of muscular exercise was prohibited
but to reduce bedrest-induced neck/back pain and stiffness of joints, each subject received
physiotherapy consisting of massage, passive stretching and assisted joint flexions at least
twice a week. Subjects were continuously surveilled by use of video cameras. Each subject
was screened for thrombosis in the popliteal and femoral veins twice a week using an
ultrasound/Doppler system. To evaluate the degree of bedrest-induced cardiovascular and
musculoskeletal deconditioning, criterion tests regarding orthostatic tolerance (study II),
aerobic capacity (Mekjavic et al. 2005), anthropometry and isometric muscle strength (Berg
et al. 2007) were performed before and within one week after bedrest. After bedrest, all
subjects participated in a 4-week active recovery regimen comprising lower body resistance
training (n=5) or cycle ergometry (n=5).
Vascular distensibility test
Vascular pressure-distension relationships were determined in the left arm and left leg
before, immediately after and 4 weeks after bedrest. On each occasion, the two trials were
separated by more than 1 hr, and the order of arm vs. leg was alternated among the subjects.
The pre-tests were performed during the week preceding bedrest and the post-tests were
conducted immediately after the 35 days of bedrest. After four weeks of active recovery the
subjects were tested again.
Studies IV-V. Distensibilities in precapillary vessels (IV) and veins (V) as affected by
intermittent elevations of local intravascular pressure (Pressure training; PT)
In these two studies the effects of five-week vascular pressure training (PT) protocols on
pressure-distension relationships in the vasculature in the arms were examined. The two
studies were conducted using similar protocols.
After a vascular distensibility test in one arm, a PT-regimen was performed in the
contralateral arm (test arm), three times per week during a five week period. Each training
session consisted of four 10-min pressure plateaus with 3-min pauses at atmospheric
chamber pressure in between. During the course of the PT, chamber pressure during the
plateaus was increased by 10 mmHg/week, from 65 mmHg during the first week to 105
mmHg during the last week.
After a PT-regimen, precapillary (study IV) or venous (study V) distensibilities were
investigated in both the pressure-trained arm and the control arm. In study IV vascular
10
distensibilities and IM-thickness three and five weeks after PT were also investigated, as
well as the dilatory capacity in the brachial artery before and after PT.
In both study IV and V, the order of the experiments (left arm vs. right arm) was alternated
among subjects but kept constant across the trials for each subject.
Study VI. Venous flow pattern during elevated venous pressure
Two different experimental series termed the main study and the supplementary study, were
performed. In the main study, flow characteristics in arm veins (brachial and cephalic veins)
were analysed at venous DPs up to +150 mmHg. Venous DP was increased stepwise every 4
min. During the last min at each pressure plateau, blood flow through the hand and wrist was
blocked, by applying suprasystolic pressure (>300 mmHg) in a pneumatic tourniquet placed
around the wrist. In the supplementary study venous flow characteristics in the posterior
tibial vein was analysed at DPs up to +240 mmHg.
Analyses
Threshold and gain determinations.
Linear functions were fitted to the initial four and the last three arterial diameter and arterial
flow data points. The DP corresponding to the intercept of the two regression lines was
defined as the threshold DP. The slope of the regression line of the last three points was
defined as the gain of the pressure distension.
Statistics
Two-tailed paired Student´s t-test or one or two-way analysis of variance for repeated
measures design (two-way ANOVA; Statistica 7.1, Statsoft Inc., Tulsa, OK, USA), preceded
by probability plots indicating normal distribution, were used to evaluate statistical
significance of differences. Greenhouse-Geisser correction of the critical F-value was
performed when necessary. Tukey´s HSD post hoc test was used to locate the differences
corresponding to the significant interactions in the ANOVA models. Ratings of pressureinduced pain were analysed with Friedmans two-way analysis of variance test and Wilcoxon
matched-pairs test. Unless otherwise stated, physiological variables are presented as mean ±
standard deviation (SD), ratings of perceived pain are presented as median and range.
Differences were considered to be significant at p < 0.05.
The normalized measure of dispersion of a probability distribution, coefficient of variation
(CV), was calculated as the ratio in % of SD to the mean.
11
RESULTS AND COMMENTS
All changes and/or differences given in the results chapter below are statistically significant
(p < 0.05), unless otherwise stated.
Arterial and arteriolar distensibility
In general, in response to slight and moderate elevations of intravascular pressure, changes
in arterial diameters and arterial flows were minute. Thus, baseline diameters and flows were
preserved at least up to an arterial DPs of about 150 mmHg for the arm vessels and 200
mmHg for the leg vessels. The pattern with preserved diameter and flow at slight and
moderate DPs was similar in all arteries studied: the brachial, radial and posterior tibial
arteries. Present experiments were not designed to study the low-pressure portions of the
DP-∆ diameter and DP-flow relationships in detail. Nevertheless, collapsed data from study
I, II and IV indicate that arterial DP elevations up to about 100 mmHg above baseline
pressure reduced arterial flows by about 5-10 %, but did not affect arterial diameters.
DP elevations greater than 100 mmHg increased the diameters of the brachial and radial
arteries, with no significant difference between these two arteries with respect to relative
diameter increases (study I). The posterior tibial artery was more pressure resistant than the
brachial artery, across the range of DPs investigated (brachial artery: 76 ± 9 to 269 ± 18
mmHg; posterior tibial artery: 69 ± 13 to 275 ± 23). It was also obvious that the threshold
DPs at which diameter and flow commenced to increase were higher for the posterior tibial
artery than for the brachial artery, and that once the diameters and flow had commensed to
increase, the gains (slopes) of the DP-∆ diameter and DP-flow relationships were
considerably higher for the brachial than the tibial artery (Table 4, study II).
In study VI, it was found that pressure-induced diameter increases in the brachial and radial
arteries prevailed during complete blocking of blood flow to the hand, suggesting that these
diameter increases reflected true distension rather than flow-mediated dilatation.
In study II, it was found that the 5-wk bedrest increased arterial pressure distension threefold
in the posterior tibial artery and by a third in the brachial artery. The pressure-induced
increase in tibial artery flow was more pronounced after (50 ± 39 ml/min) than before
bedrest (13 ± 23 ml/min), whereas the brachial artery flow response was unaffected by
bedrest. The bedrest-induced reductions of wall stiffness in arteries and precapillary
resistance vessels of the lower leg were due to both reduced DP thresholds and increased
gain for the DP-∆ diameter and DP-flow relationships. Bedrest did not change threshold or
gain for the pressure-induced brachial artery distension nor for the arterial flow response
(Table 4; Figure 4; Figure 5). After four weeks of recovery, all vessels had resumed prebedrest pressure-distension responses.
12
Study II
Diameter
gain (mm/mmHg)
threshold (mmHg)
Flow
gain
(ml/min/mmHg)
threshold (mmHg)
Study IV
Diameter
Flow
gain (mm/mmHg)
threshold (mmHg)
gain
(ml/min/mmHg)
threshold (mmHg)
Arm
pre BR
0.36 ± 0.31
168 ± 29
Arm
post BR
0.33 ± 0.18
150 ± 29
Leg
pre BR
0.21 ± 0.16
250 ± 31
Leg
post BR
0.33 ± 0.18
220 ± 37
3.34 ± 1.71
2.65 ± 1.00
0.427 ± 0.35
0.83 ±0.56
160 ± 19
153 ± 15
234 ± 16
230 ± 21
CNpre
0.311 ± 0.17
190 ± 26
PT
0.15 ± 0.10
199 ± 23
CNpost
0.310 ± 0.16
193 ± 21
6.3 ± 3.6
2.8 ± 2.6
6.2 ± 2.9
185 ± 20
202 ± 41
188 ± 21
Table 4. Pressure-diameter and pressure-flow relationships in the brachial and posterior tibial
arteries in terms of the DP thresholds and gains for the pressure responses (for detailed descriptions
see text). denotes difference (p<0.05) between: pre bedrest vs. post bedrest in study II, PT arm vs.
control arm (CN) pre and post in study IV.
30
a. brach.
25
gain n.s.
∆ diameter (%)
20
a. tib. post.
postBR
15
postBR
10
preBR
gain p<0.05
5
thresholds
0
n.s.
preBR
p<0.05
-5
75
100
125
150
175
200
225
Distending pressure (mmHg)
250
275
300
Figure 5. DP threshold and gain for the pressure-induced increase in diameter, before and after
bedrest in the brachial and posterior tibial arteries. The figure is schematic in the sense that the
minute differences in the slopes of the initial regressions (DPs below threshold) of the curve have
been omitted and values have been denoted 0 % change in diameter. Values are means. n=10.
13
a. brach
175
postBR
Flow (ml/min)
gain n.s.
preBR
125
75
a. tib. post
25
postBR
gain p<0.01
preBR
threshold n.s.
threshold n.s.
-25
70
90
110
130
150
170
190
210
Distending pressure (mmHg)
230
250
270
290
Figure 6. DP threshold and gain for the pressure-induced increments in arterial flow, before and
after bedrest. The figure is schematic in the sense that the minute differences in the slopes of the
initial regressions (DPs below threshold) of the curve have been omitted and values have been
denoted 0 % change in flow. Values are means. n=10.
In study IV, it was found that the 5-wk PT regimen decreased both pressure distension in the
brachial artery and pressure-dependent increments in arterial flow by about 50 %. The
reduced stiffness in the precapillary resistance vessels of the arm were due to a slight
increase in DP threshold and a marked decreased in the gain of the DP-flow relationship,
whereas the reduced distension of the brachial artery was due solely to reduced gain of the
DP-∆ diameter relationship (Table 4; Figure 6). No pressure-habituation effects were
observed in the vessels of the contra-lateral (control) arm. After 5 wks of recovery, the
pressure distension in the conduit artery and the resistance vessels had resumed pre-PT
responses.
20
CNpre
15
∆ diameter (%)
gain p<0.05
10
PT
5
0
Threshold
n.s.
-5
70
90
110
130
150
170
190
210
Distending pressure
230
250
270
290
Figure 7. DP threshold and gain for the pressure-induced increments in brachial artery diameter,
before (CNpre) and after (PT) the PT regimen. The figure is schematic in the sense that the minute
differences in the slopes of the initial regressions (DPs below threshold) of the curve have been
omitted and values have been denoted 0 % change in diameter. Values are means. n=11.
14
700
600
CNpre
Flow (ml/min)
500
400
gain p<0.05
300
200
PT
100
0
threshold p<0.05
-100
70
90
110
130
150
170
190
210
Distending pressure
230
250
270
290
Figure 8. DP threshold and gain for the pressure-induced increments in brachial artery flow before
and after the PT regimen. The figure is schematic in the sense that the minute differences in the
slopes of the initial regressions (DPs below threshold) of the curve have been omitted and values
have been denoted 0 % change in flow. Values are means. n=7.
Venous distensibility
A slight initial elevation of venous DP invariably resulted in a prompt increase in venous
diameter (study I; III; V). Such initial diameter increase is to a large extent attributable to a
venous filling phase during which the circular shape of a semi-collapsed vein is restored. At
DPs greater than about 20-25 mmHg the veins invariably exhibited circular cross-sections
and hence further increments in venous diameters were regarded to represent true distention
of their walls. Consequently, venous baseline diameters were determined at a DP of 30
mmHg, when possible (study I; V) and at 60 mmHg in study III, in which measurements
were not obtained at a DP of 30 mmHg. At DPs exceeding 30 mmHg venous diameters
increased steadily with increasing DP in an approximately linear manner (study I; V).
The great saphenous vein was stiffer than the cephalic vein (study I, Figure 9). Prolonged
bedrest increased pressure distension in both the brachial and the posterior tibial veins,
although the bedrest-induced distensibility increase was considerably greater in the posterior
tibial vein than in the brachial vein (study III, Figure 10). The PT regimen reduced the
distensibility in both the deep and the superficial veins (study V, Figure 11).
Before PT, distensibility in the brachial vein was greater at the site of the valve than
proximal to the valve, whereas in the cephalic vein, pressure distension was similar at the
site of the valve as proximal to the valve (study V). In the brachial vein, PT reduced the
pressure distension more at the site of the valve than outside the valve; the cephalic vein
showed no PT effects on distensibility at the site of the valve.
15
Arm
cephalic vein
80
Leg
great saphenous vein
70
∆ diameter (%)
60
*
50
40
30
20
10
0
Figure 9. Relative changes in diameter in the cephalic and great saphenous veins in response to an
increase in DP from 60 to 150 mmHg. *denotes statistical difference (p<0.05). Values are means
(SD). n=11 (study I).
30
25
∆ diameter (%)
20
Arm
brachial vein
preBR
postBR
*
Leg
posterior tibial vein
recovery
*
15
preBR
*
10
recovery
postBR
*
5
0
Figure 10. Relative changes in diameter in the brachial and posterior tibial veins in response to an
increase in DP from 60 to 150 mmHg, before (preBR) and immediately after (postBR) and 4 wks
after (recovery) bedrest. *denotes statistical difference (p<0.05). Values are means (SD). n=10
(study III).
Arm
brachial vein
25
∆ diameter (%)
20
15
CNpre
CNpost
PT
*
*
10
5
0
Figure 11. Relative changes in diameter in the brachial vein in response to an increase in DP from
60 to 150 mmHg in control arm before (CNpre) and after (CNpost) PT and in the PT arm. *denotes
statistical difference (p<0.05). Values are means (SD). n=11 (study V).
16
Forearm and lower-leg tissue impedance
In both the forearm and the lower leg, tissue impedance decreased with increasing
intravascular pressure. At the highest intravascular pressure levels, tissue impedance
dropped at an increasing rate, most likely as a consequence of distension of the precapillary
resistance vessels, thus increasing the capillary filtration pressure and consequently the rate
of the tissue edema formation (Figure 12 A and B). The pressure-induced decrease in tissue
impedance was, in relative terms, considerably greater in the arm than in the lower leg at any
given level of markedly elevated intravascular pressure (study I). Five weeks of bedrest
increased the rate of change, at high intravascular pressures, of lower-leg tissue impedance
(study II). Conversely, the 5–wk PT regimen reduced the rate of change of forearm
impedance at high intravascular pressures (study IV).
0
A
30
60
Applied pressure (mmHg)
90
120
150
180
210
240
0
∆ Impedance (%)
-5
Lower leg
-10
-15
Forearm
-20
-25
Applied pressure (mmHg)
B
0
30
60
90
120
150
180
210
240
0
∆ Impedance (%)
-5
-10
Forearm
Lower leg
-15
-20
-25
Figure 12. Relative change in impedance in the forearm and lower leg as a function of applied
chamber pressure. Figure A is adapted from study I (n=11) and figure B is adapted from preBR,
study II (n=10).
17
Intima-media thickness
In study II, the tibial artery intima-media cross-sectional area (IMCSA) tended to be smaller
(p=0.07) after bedrest than before bedrest (Table 5). The thickness of the arterial IM, and the
lumen to IM-thickness ratio (L/IMT), respectively, were similar after bedrest as before
bedrest. In the brachial artery, bedrest had no effect on IMT, IMCSA or L/IMT (Table 5).
In study IV, there was a similar IMT, IMCSA and L/IMT in the PT arm as in the control arm
before and after PT (Table 5).
Study II
IMT (mm)
IMCSA (mm2)
L/IMT
Study IV
IMT (mm)
IMCSA (mm2)
L/IMT
Arm
pre BR
0.49 ± 0.05
6.59 ± 0.93
7.89 ± 1.16
Arm
Post BR
0.47 ± 0.06
6.36 ± 1.16
8.29 ± 1.00
Leg
pre BR
0.47 ± 0.05
4.11 ± 0.73
4.94 ± 0.81
Arm
CNpre
0.53 ± 0.04
7.79 ± 0.62
7.76 ± 0.72
Arm
PT
0.52 ± 0.04
7.51 ± 1.28
7.80 ± 0.50
Arm
CNpost
0.51 ± 0.04
7.42 ± 0.86
7.97 ± 0.51
Leg
post BR
0.45 ± 0.05
3.68 ± 0.58
4.84 ± 0.72
Table 5. Intima-media thickness (IMT), intima-media cross-sectional area (IMCSA) and lumen-toIM-thickness ratio (L/IMT), in the brachial artery (Arm) and the posterior tibial artery (Leg), (for
detailed descriptions see text). denotes a tendency of difference (p=0.07) between pre-bedrest and
post-bedrest. Values are means. n=10 for study II and n=11 for study IV.
Vasodilatation
The PT regimen did not affect endothelium-dependent flow-mediated dilatation or
endothelium-independent nitroglycerin-mediated dilatation (study IV).
Pressure-induced pain
Exposure to high intravascular pressures induced pain in both the arm and the lower leg
(study I-VI). Pain increased progressively with increasing pressure and was stronger in the
arm than in the lower leg at any given pressure elevation (study I). The pressure-induced
pain was rated as moderate at intravascular pressure elevations of about 90 to 100 mmHg for
the arm, and of about 120 to 130 mmHg for the lower leg. Prolonged bedrest augmented the
pressure-induced pain in both the arm and the leg (study II; III). The PT-regimen induced an
opposite effect, with reduced pain ratings in the pressure-trained arm compared to the
control arm. PT also induced a smaller, but still substantial, reduction of pressure-induced
pain in the control arm (study IV; V).
18
Venous flow pattern at high distending pressures
Flow characteristics in peripheral veins, as influenced by increased DP were investigated in
study VI. At markedly elevated DPs, both deep and superficial veins showed antegrade,
pulsatile, arterial-like flow patterns. The occurrence of pulsatile flow increased with
increasing intravascular pressure. At markedly elevated intravascular pressures (+100 to
+150 mmHg) flow in the arm veins remained pulsatile even during complete blocking of the
blood flow to the hand.
Arterial pressures and heart rate
During the course of an intravascular pressure provocation, arterial pressures, systolic as
well as diastolic, showed slight increments, whereas heart rate remained relatively stable.
Coefficient of variation (CV) for ultrasound/Doppler measurements
The coefficient of variation (CV) for the brachial artery diameter measurements was 1.8 %
in study I, which compares well with subsequent results (1.7 %, Gustafsson et al. submitted
for publication) and 2.4 % and 1.9 % respectively for the radial and posterior tibial artery
diameter measurements (study I). CV for the average brachial artery flow velocity
measurement is usually about 8 % (Gustafsson et al. submitted for publication). The
coefficients of variation for the lumen diameter measurements were 1.7 % for the cephalic
vein and 2.7 % for the great saphenous vein (study I).
19
DISCUSSION
The present studies deal with certain adaptive responses to prolonged or intermittent
pressure changes that enable vessel walls to withstand action of local pressure perturbations.
It supplies information on the in vivo regional differences in vascular stiffness as reflected in
pressure-distension relationships of arteries, arterioles and veins.
Arterial and arteriolar distensibility
In study I, it was demonstrated that the precapillary vessels are more pressure resistant in the
lower legs than in the arms (publication I, Figure 1, 3, 4), supporting the theory that a lifelong exposure to intermittent elevations of intravascular pressures in the lower body, induced
by assuming upright position, results in greater stiffness in dependent blood vessels (cf.
Folkow 1982; Dobrin 1983; Rowell 1993). Thus, in longitudinally oriented blood vessels,
gravity-dependent hydrostatic pressure components substantially influence local pressures in
erect posture. In a normotensive adult human who is standing erect, diastolic pressure is
about 150-200 mmHg in the posterior tibial artery at ankle level, and about 80-100 mmHg in
the brachial artery at elbow level. Our results suggest that intermittent exposure to such
pressure differences, i.e. 70-100 mmHg between the tibial and brachial arteries, while in the
upright position, is a sufficiently large difference in pressure stimulus to induce substantial
differences in the distensibility of both arteries and arterioles.
That precapillary vessels in the legs are stiffer than those of the arm is supported by studies
in which qualitative changes in skin blood flow have been estimated using a calorimetric
method (Coles & Greenfield 1956) and (Coles 1957), and by a study in which precapillary
stiffness was approximated from measurements of arterial pulse-wave velocity (McDonald
1968). Moreover, it appears that vascular vasoconstrictor and vasodilator responses differ
between the arms and legs. In a resting subject, there was a larger relative increase in arterial
flow to intra-arterial infusions of vasodilators in the arm than in the leg (Newcomer et al.
2004). Conversely, the sympathetically mediated vasoconstrictor response was greater in the
legs than in the arms (Pawelczyk & Levine 2002). It should also be noted that it appears
likely that the present pressure-induced increments in arterial diameters (study I; II; IV; VI)
represented true distension rather than dilatation elicited by increased shear stress on the
arterial wall resulting from increased flow (for reviews see Melkumyants et al. 1995,
Resnick et al. 2003), since pressure-induced diameter increments remained also during
blocking of blood flow (study VI).
The main question addressed in studies II and IV was whether the differences between arms
and legs, as regards the precapillary distensibilities observed in study I, are permanent or
whether precapillary distensibility is a plastic modality, that may change in response to
changes in local intravascular pressures. It was demonstrated that within 5 weeks, both
arteries and arterioles change their distensibility to meet the altered demands imposed by
sustained pressure reductions (study II) and by intermittent pressure elevations (study IV).
20
A transition from upright to recumbent body position reduces the DP in precapillary vessels
of the lower leg by 80-110 mmHg. Judging from the results in study II, it appears that
reducing pressure by such magnitude during a 5-week period constitutes a sufficiently large
stimulus withdrawal to markedly increase precapillary distensibility. This suggests that the
high pressure resistance observed in leg vessels is not inherent, but constitutes an acquired
characteristic that even after life-long adaptation to intravascular pressure differences
associated with upright body position, depends on regular exposures to pressure elevations.
The finding that bedrest did not induce similar distensibility increments in the
arteries/arterioles of the arm (Publication II, Figure 1, 2) implies that the distensibility
changes in the leg vessels were not caused by any systemic effect of prolonged bedrest. The
aforementioned notion that intermittent pressure elevations may significantly affect the
mechanical properties of precapillary vessel walls was confirmed in study IV, which
demonstrated that fifteen 40-min (i.e. in total 10 hrs) exposures to moderately increased
pressure, administered over a 5-week period (c:a 840 hrs), is a sufficiently strong pressure
stimulus to markedly reduced arterial and arteriolar distensibility. This may suggest that
arterial pressure peaks, rather than the average arterial pressure, serve as the primary stimuli
for inducing arterial and arteriolar stiffness. That the PT regimen did not affect pressure
distensibility in the vessels of the control arm indicates that the training effects were not
humorally mediated.
Mechanisms that may underlie local changes of the in vivo stiffness of blood vessels are
either altered external counter pressure exerted by tissues surrounding the vessel or intrinsic
changes in the vessel wall of the myogenic activity and/or the passive mechanical properties
(Folkow 1991; Berk 2001; Jacobsen 2008). That the changes in precapillary distensibility
induced by the bedrest and PT regimens were due to pressure changes in the tissues
surrounding the vessels seems highly unlikely. Thus, although bedrest induced substantial
skeletal muscle atrophy in the legs (Berg et al. 2007) it can be assumed that the atrophy did
not significantly affect the pressure-distension relationship in the tibial artery, since the
vessel was examined outside the muscle compartments. Moreover, the impedance
measurements indicated increased pressure-induced edema formation in the lower leg
following bedrest, and reduced pressure-induced edema formation in the forearm following
PT; assuming that tissue pressure is governed by the degree of edema, such changes may
have served to reduce vascular pressure distension following bedrest and to increase it
following PT.
Whether the local changes in arterial and arteriolar distensibility, in response to the bedrest
and PT regimens, are attributable to changes in the pressure responsiveness of the smooth
muscle layer or to changes of the passive mechanical properties of the wall, or to a
combination of these factors, cannot be conclusively discerned from the present results.
According to Folkow and co-workers (Folkow & Sivertsson 1968; Folkow 1990) changed
myogenic reactivity is likely to predominatly affect the pressure threshold at which flow
commences during a DP-flow provocation, whereas a change in the thickness of the
arteriolar media layer is expected to change the gain of the DP-flow response. Since the
bedrest and PT interventions affected both the gain and the pressure threshold of the DPflow relationship (Figures 5-7), it must be considered that the distensibilty changes induced
by these interventions were of mixed origin, i.e. functional and structural. Several
21
mechanisms may alter the pressure responsiveness of the smooth muscles. Changes in the
prevailing pressure may alter the myogenic response to transmural pressure (cf. Osol et al.
2002). It is also possible that the myogenic pressure responsiveness was altered by changes
in the pressure-induced local release of vasoconstrictive/vasodilatory substances. Local
release of vasoactive substances in response to increased intravascular pressure may be
mediated by several mechanisms, including shear stress and vascular tension (Pourageaud et
al. 1997; Berk 2001; Ohura 2003). Gravity-dependent changes in vascular responsiveness
observed in long-term tail-suspended rats have been shown to be associated to changes in
nitric oxide (NO) availability (Jasperse et al. 1999; Vaziri et al. 2000). Our observation that
flow-mediated vasodilatation was unaffected by PT training does not necessarily exclude the
possibility that the PT affected endothelial NO function since the technique may not be
sensitive enough to detect minor changes in endothelial function (Sorensen et al. 1995).
In a recent study, using the same experimental set-up as in the present studies, we observed
that elevated DP induced local release of the vasoconstrictive substances endothelin-1 (ET1) and angiotensin II (AT-II) (Gustafsson et al. submitted for publication). To what extent
sustained or repeated changes of DP will affect pressure-induced release of these substances
remains to be investigated. Conceivably, both ET-1 and AT-II may take part in long-term
changes in arterial/arteriolar stiffness. AT-II administration induces numerous processes
affecting the long-term function and structure of peripheral vessels (Berk 2001; Mehta
2007), such as smooth muscle growth, thickening of the wall, and increase in the arterial
media-to-lumen ratio (Daemen 1991; Moreau 1997). ET-1 has, beside the strong
vasoconstrictor function, a variety of physiological effects including regulation of other
vasoactive substances and stimulation of smooth muscle growth (Miyauchi & Masaki 1999).
As regards the possibility that the observed changes in precapillary distensibility are
attributable to changes in the mechanical properties of the vessel walls, the bedrest
intervention induced a small reduction of the cross-sectional area of the tibial artery wall,
whereas the PT regimen did not induce any measurable changes related to wall thickness.
Whether the bedrest and/or PT-intervention affected wall thickness in arterioles cannot be
discerned from present results. Moreover, we cannot exclude a slight PT-induced
hypertrophy of the brachial artery wall, since changes in wall thickness less than about 0.1
mm may not be detected using the ultrasound technique (Schmidt & Wendelhag 1999;
Åstrand et al. 2003).
Although the concept has been a matter of considerable debate (for review see Prewitt et al.
2002), a plethora of data seem to support that arteries and arterioles may undergo
morphological changes in response to changes in transmural pressure. It is commonly stated
that in healthy humans, the mechanical properties of the walls of precapillary vessels differ
along the body (Folkow 1982; Rowell 1993; Dobrin 1983). This statement is partly based on
the finding that in adult humans, walls are thicker in leg veins than in arm veins (von
Kügelgen 1955; Sveijcar et al. 1962). Individuals suffering from chronic hypertension
exhibit hypertrophic wall thickening in arterioles (Aalkjaer et al. 1987) and increased arterial
wall thickness-to-lumen ratio, resulting in increased flow resistance for a given smooth
muscle activity (Folkow et al. 1958; Folkow & Sivertsson 1968). It has been shown that
regional flow resistance in the forearm is higher in hypertensive than in normotensive
22
subjects, even during maximal dilatation induced by nerve blockade (Folkow et al. 1958).
The increased resistance has been attributed to changes in vascular wall design such as
media hypertrophy and fibrosis, and also to rearrangements of protein structures (Folkow
1982; Intengan et al. 1999; Intengan & Schiffrin 2000).
With regards to experiments in other species, the giraffe has been used as a model to
demonstrate adaptive responses to increased arterial pressure gradients. It is well known that
extrapolation of results from experiments on the giraffe to human vascular function/structure
must be done with caution, since the two species differ regarding, for example, tightness of
the skin and fascie surrounding the blood vessels (Hargens et al. 1987; 1988). Nevertheless,
the walls of dependent arteries are thicker in the adult than in the younger giraffes (Hargens
et al. 1988). In rats, prolonged decrement in arterial pressure reduces the wall thickness in
arterioles (Folkow et al. 1971) and also in arteries, with the medial layer showing a greater
decrease than the adventitial layer (Li et al. 2002). Conversely, prolonged pressure elevation
induces arterial thickening due to increased collagen, elastin and smooth muscle contents
(Wolinsky 1970; Fridez et al. 2003).
Venous distensibility
The present results demonstrated that with regard to superficial veins, distensibility was
greater in the arm than in the leg (study I), and that 5 weeks of horizontal bedrest increased
venous distensibility, especially in the legs (study III), whereas 5 weeks of vascular PT
reduced venous distensibility (study V). The results suggest that not only precapillary
vessels, but also veins adapt their distensibility to meet local pressure demands, and that the
intravascular pressure difference of about 70 mmHg between veins in the arm and in the
lower leg, apparent during daily life activities in upright position, is large enough to result in
a considerable difference in local venous wall stiffness. It is noteworthy that even though it
has been suggested repeatedly in the past that gravity-dependent intravascular pressure
components affect venous wall stiffness in humans (Gauer & Thron 1963; Alexander 1963;
Hargens 1983; Rowell 1986; 1993), conclusive experimental evidence supporting this
concept is scant. To determine distension of vein walls using ultrasound-guided diameter
measurements, the distension phase should be distinguished from the initial filling phase of
the pressure-volume relationship, since the cross-section of the vein cannot be assumed to be
circular during the filling phase (cf Öberg 1967). Therefore, and due to the different
experimental pressure-provocation protocols in the present studies, comparison of venous
distensibility between the individual studies was performed at the DP range 60 to 150 mmHg
(Figures 9-11).
Several studies support our finding that prolonged bedrest increases venous compliance in
the lower body (Menninger et al. 1969; Convertino et al. 1989; Savialov et al. 1990; PaivyLe Traon et al. 1999). However, results from these studies are not directly comparable with
present findings since in the previous studies, venous compliance has been determined using
different plethysmographic methods, which include the filling phase as a major component
in the determinations of pressure–vein volume relationships. Thus, under baseline conditions
after prolonged bedrest (i.e. while venous DP is about 0 mmHg), veins are commonly
23
collapsed since the circulating blood volume decreases by about 0.5-0.6 l in a 5-wk bedrest
(Fortney et al. 1996). There are no longitudinal studies reported in the literature on the
influence of sustained or intermittent pressure elevations on the in vivo distensibility in
human veins.
As regards mechanisms underlying the bedrest- and PT-induced changes in venous
distensibility, it can in conformity with the above conclusions on precapillary distensibility,
be ruled out that the changes were mediated via humoral factors, since PT did not affect
venous distensibility in the control arm and bedrest induced considerably larger changes in
the leg veins than in arm veins. As also mentioned previously, it appears unlikely that the
bedrest- and PT-induced vascular distensibility changes were attributable to changed counter
pressure exerted by tissues surrounding the vessels. Notably, bedrest-induced increments of
lower body venous compliance are commonly attributed to reduced counter pressure
resulting from concomitant skeletal muscle atrophy (Buckey et al. 1988, Convertino et al.
1999) and dehydration (Thornton et al. 1987). During the course of an intravascular pressure
provocation, tissue counter pressure in the test limb of a relaxed subject can in principle only
be increased by capillary filtration resulting in tissue edema formation or by transmission of
pressure from distending blood vessels. In the present experiments, the examined veins were
located outside any muscle compartment, and hence, pressure transmission from the veins to
the surrounding tissue was presumably minute (cf. Wells et al. 1938; Mayerson & Burch
1939). Therefore, and since pressure-induced edema formation was exaggerated by bedrest,
it appears that the increased venous distensibility following the present bedrest intervention
can be attributed to changes in the venous walls per se; in general, such a mechanism may
contribute to bedrest-induced increments in lower body venous compliance.
Presumably, the observed training and deconditioning effects on venous distensibility
reflected local changes in either intramural smooth muscle tone and/or passive elastic
properties of the vessel walls. The passive mechanical properties of the vein walls are, as the
precapillary vessel walls, mainly determined by the amounts of elastin, collagen and smooth
muscles, and also by the arrangements of fibrous material in the wall (Intengan & Schiffrin
2000). The notion that the mechanical properties of the venous walls will adapt in response
to intermittent or sustained local pressure changes (Gauer & Thron 1963; Alexander 1963;
Hargens 1983; Rowell 1986; 1993) is supported indirectly by the findings that the wall
contents of smooth muscle cells and elastin and collagen are greater in dependent veins than
in proximal veins in adults (von Kügelgen 1955; Sveijcar et al. 1962) but not in infants (von
Kügelgen 1955). Patients suffering from varicose veins in the legs may exhibit hypertrophic
smooth muscle layer in the walls of the affected veins (Kockx et al. 1998). Although the
cause of varicose veins is probably multifactorial, the condition is characterized by
insufficient venous valves resulting in increased pressure in dependent veins (Meissner et al.
2007). In fact, in patients with chronic venous valvular insufficiency, and hence presumably
with increased venous pressure in the legs in upright posture, it was observed that the
femoral and popliteal veins were less compliant than in individuals with normal venous
valve function (Neglen & Raju 1995). Experiments on rabbits showed that sustained
pressure elevations induced venous hypertrophy (Hayashi et al. 2003). Monos et al. (1989),
who studied rats, did however not find altered venous wall thickness as an effect of sustained
pressure elevation.
24
Evidence supporting the notion that the prevailing pressure may affect myogenic
responsiveness in the vein walls is scant. Augmented pressure-dependent myogenic tone and
increased sympathetic innervation density have been observed in rats exposed to long-term
increased intravenous pressure (Monos et al. 1989; 2001). It is not known whether such a
mechanism contribute to venous pressure adaption also in humans.
One exception to the finding that vein walls adapt their distensibility to cope with the
prevailing pressure was the valve region in the cephalic vein, which did not respond to PT.
Whether this reflects a reduced adaptive capacity of superficial veins in general to increase
their wall stiffness at the regions of the valves in response to long-term pressure elevations,
and hence constitute one underlying mechanism in the development of valvular
insufficiency, remains to be established.
Habituation effects on vascular distensibilities; implications for circulatory control
In the present studies, pressure distension of both arteries and arterioles in the lower leg
occurred at transmural pressures of about 250 mmHg. In erect posture, arterial pressure in
the lower leg is about 200 mmHg. Therefore, and because it was found that arterial and
arteriolar distensibilities are not permanent but highly adaptable modalities, it appears that
the wall stiffness in precapillary leg vessels may be gauged so as to prevent a drop in local
peripheral resistance upon a transition from supine to upright. Since flow resistance in the
leg vasculature is a crucial determinant for orthostatic tolerance (Buckey et al. 1996, Cooper
& Hainsworth 2002) the capacity to develop high pressure resistance in dependent
precapillary walls may represent an important adaptation to life in erect posture. Orthostatic
tolerance is not merely dictated by arterial flow resistance but also by the distribution of
blood volume in the capacitance vessels. Thus, the orthostatic intolerance observed after
long-term exposure to bedrest or microgravity has to a large extent been attributed to excess
pooling of blood in dependent veins (Menninger et al. 1969; Buckey et al. 1988; Convertino
et al. 1989; Louisy et al. 1990). Present findings suggest that the increased compliance in leg
veins following prolonged bedrest/space journeys, may not merely be a consequence of
lower limb skeletal muscle atrophy, resulting in reduced intramuscular fluid pressure
(Buckey et al. 1988; Convertino et al. 1989), but also be due to increased intrinsic
distensibility in the vein walls of the lower body.
The capacity of dependent blood vessels to adapt their pressure resistance to meet increasing
demands may be of particular importance for circulatory control in pilots flying highperformance aircraft. An individual’s ability to withstand high gravitoinertial forces in the
head-to-foot direction whilst relaxed (G tolerance) is governed by his/her capacity to
maintain/increase arterial pressure (Wood & Lambert 1952; Newman et al. 1998; Convertino
1998; Eiken et al. 2003). In a seated, relaxed pilot, pressure in dependent blood vessels will
increase in direct proportion to the head-ward acceleration. Even though there is a
considerable inter-individual variability as regards relaxed G tolerance, it can be estimated
that pressure in precapillary blood vessels at G tolerance loads (3-5 G), correspond with the
pressure range in which precapillary vessels in the lower body distend (200-300 mmHg). It
is well known that repeated exposures to high G loads will increase pilots’ relaxed G
25
tolerance (Hallenbeck 1944; Wojtkowiak 1991; Convertino 2001). The G-training effects are
partly attributable to increased arterial baroreflex sensitivity (Newman et al. 1998), but it
appears likely that increased peripheral arterial flow resistance, resulting from decreased
distensibility in dependent precapillary vessels, might also contribute to training-induced
improvements in G tolerance. The notion that stiffness in precapillary leg vessels may
determine G tolerance is supported by the finding that arterial/arteriolar distensibility in the
lower leg was considerably higher in a group of individuals with low G tolerance than in a
matched group of individuals with high G tolerance (Eiken et al. 2003).
Even though the capacity to develop high pressure resistance in the walls of dependent blood
vessels may be an important adaptation to life in erect posture, it should be noted that such a
feature reflects a positive feed-back mechanism that may constitute a component in the
pathogenesis of primary hypertension. Namely, systemic elevation of arterial/arteriolar
pressure may increase arteriolar stiffness, which will increase peripheral flow resistance,
which may increase arterial pressure etc. Thus, present findings support the notion that local
load serves as “a prime mover” in the development of vascular changes in hypertension
(Folkow 2004).
Pressure-induced pain
In the present investigations (study I-VI), high DP induced deep aching pain locally in the
test limb. Pain increased progressively with increasing intravascular pressure, commencing
at pressure elevations of about 90 mmHg in the arm, and of about 140 mmHg in the lower
leg. Pain was less pronounced in the leg than in the arm, at any given level of high
intravascular pressure. The pressure-induced pain was aggravated by prolonged recumbency,
especially in the lower leg, and attenuated by the PT regimen.
The pain reported by our test subjects is presumably of similar vascular origin, as the arm
pain commonly experienced by pilots flying high-performance fighter aircraft (Macloskey et
al. 1990; Lewis et al 1995; Linde & Balldin 1998; Eiken et al. 2000). The arms of fighter
pilots are usually unprotected even when anti-G garments are used. During exposure to high
gravitoinertial forces in the head-to-foot direction (+Gz), intravascular pressure in the arms
may increase markedly. The degree of pressure elevation in the arm vessels will depend on
several factors including the type of anti-G suit used, whether the pilot is exposed to positive
airway pressure or performs anti-G straining maneuvers and also on the position of his/her
arms; at G loads between +7Gz and +9Gz pressure in arm vessels may be elevated by 200300 mmHg (cf. Green 1997; Eiken et al., 2000). When reducing the transmural vascular
pressure by lifting the arms or applying a counter pressure over the arms, the G-induced arm
pain is alleviated (Watkins et al. 1998; Eiken et al. 2000). The G-induced arm pain has been
suggested to be caused by venous overdistension (Wood 1990; Linder 1992; Prior 1996;
Green 1997; Watkins et al. 1998; Eiken & Kölegård 2001). Connoly & Wood (1954) clearly
showed that distension of a local vein induces pain, a finding that has been verified by
several research groups (Ernsting 1966; Frustorfer & Lindblom 1983; Davenport &
Thompson 1987; Arndt & Klement 1991). Veins are innervated by unmyelinated or thinly
myelinated afferent fibers connected to slowly adapting and rapidly adapting
26
mechanoreceptors that respond to stretch and to direct mechanical stimulation of the vessel
(cf. Davenport & Thompson 1987).
Evidence is less conclusive regarding the causal relationship between arterial overdistension
and pain. Patients undergoing arterial puncture may experience a dull aching pain (Bazett &
McGlone 1928). Anectdotal evidence suggests that overdistension of the aorta may induce
pain in humans (Wooley et al. 1998). Martin & Gorham (1938) studied pain reactions in
dogs, in response to manipulations of their coronary arteries, and reported that pain was
elicited by stretching the arteries in ways that did not alter coronary flow, a finding that has
been confirmed (Malliani & Lombardi 1982). Lim et al. (1962) showed that arteries are
innervated by free nerve endings in the adventitia and proposed that the nerves are activated
by chemical mediators (e.g. prostaglandins and bradykinins) released from surrounding
tissues. Bahns et al. (1987) reported that the aorta and inferior mesenteric artery contain
afferent mechanosensitive fiber-endings.
Thus, it appears likely that the present findings of pain in the test limb induced by marked
elevations of local intravascular pressures predominantly stemmed from venous
overdistension. It cannot be excluded that overdistension of precapillary vessels also
contributed to the pain, but the finding in study IV that without evoking pain, the diameter
increase in the brachial artery was more pronounced during nitroglycerin-induced dilatation
than during pressure distension, suggests that arterial overdistension was not a major pain
inductor in the present studies.
That pressure-induced pain was alleviated by PT and aggravated by bedrest most likely
predominantly reflect the concomitant changes in venous distensibility. The possibility that
these changes in pain responses were due to adaptations of sensory receptors in the vessel
walls seems more remote since the predominant local adaptation to pain is hyperalgesia
rather than hypoalgesia (for review see Cervero 1994). The observation that the PT regimen
reduced pressure-induced pain to a certain degree also in the control arm (study IV) suggests
that a central mechanism is also involved. Afferent signals from nociceptors reach several
areas of the cortex including the somatosensory cortex, the motor cortex and other areas
deep in the parietal and temporal regions of the cortex (Derbyshire et al. 1997; Price 2000;
Rainville et al. 1997). Perception of pain can be attenuated on a CNS-level by repeated
stimulations of nociceptors (Heinricher et al. 2009).
Irrespective of the underlying mechanisms, the present findings that pain induced by
markedly increased intravascular pressure is alleviated by a habituation procedure during
which the blood vessels are exposed to gradually increasing pressure, have practical
implications. Namely, that pilots who experience intolerable arm pain while being
introduced to high-performance aircraft, can be advised to fly in a manner so as to gradually
increase the peak +Gz loads during the initial weeks of flying.
27
Venous flow characteristics
In conjunction with a previous study (Eiken & Kölegård 2001), and also the first of the
present studies (study I), we observed pulsatile flow in veins at moderate and marked
elevations of local intravascular pressures. Since we were not able to find any description in
the literature of such venous flow pattern in humans, we conducted study VI, in which we
demonstrated pressure-induced antegrade, arterial-like, pulsatile flow, in deep and
superficial arm veins and in leg veins. It must be assumed that a key determinant for the
pulsatile venous flow pattern was the engorgement of blood in the pressurized veins. Thus,
in highly distensible vessels, such as collapsed or semi-collapsed veins, pressure waves are
rapidly damped out (Spencer & Denison 1963).
Two ways should be considered by which propagation of pressure waves from arteries to the
veins may occur: via the capillary network or via arteriovenous anastomses (AVAs). At high
DP (Wiederhielm et al. 1963), or during maximal dilatation of precapillary resistance vessels
(Smaje et al. 1980), cardiogenic pulse waves may reach the level of the capillaries. In study
VI the occurrence of venous pulse waves coincided with a prompt increase in arterial flow.
Thus, it cannot be excluded that the venous pulse waves were propagated from the arteries
via distended arterioles and capillaries. To account for the prominent waves in the veins, it
must also be assumed that minute waves at the level of the capillaries/venules were
augmented in the large veins due to cumulative flow effects as the venous network
converged. The alternative explanation for the observed pressure-induced venous flow
pattern is that AVAs were forced open at high DP, accommodating a substantial share of the
arterial flow. AVAs are pre-dominantly located in the dermis of the hands and feet, where
they serve thermoregulatory functions (Burton & Taylor 1939; Lossius et al. 1993). In study
VI, pulsatile flow was also observed in the arm veins while flow was blocked through the
hands, suggesting either that the pulsations were not propagated via AVAs, or that such
anastomoses exist in the forearm to a high degree. There have been reports that AVAs exist
in anatomical regions other than the palms of the hands and soles of the feet, namely in
skeletal muscle, skeletal joints, and forearm dermis, but the prevalence and function of
AVAs in these locations are not known (for review see Zweifach & Lipowsky 1963).
Nevertheless, it cannot be ruled out that propagation via AVAs contributed to venous pulse
waves in the present studies.
Methodological considerations
Pressure transmission and distending pressures
In trial experiments (unpublished data) concerning transmission of pressure from the
hyperbaric chamber to the vasculature of the test limb, we found that pressure elevations in
the chamber were transmitted virtually without distortion to the arteries in the test limb
(Figure 13). Likewise, Green et al. (2007), using the same technique to increase pressure in
arm vessels as that employed in the present studies, evaluated pressure transmission from the
chamber to the limb vessels by measuring pressure in an antecubital vein of the test arm, and
noted a pressure transmission from the chamber to the vein of almost 100 %. Wiederhielm et
al. (1979), who used a chamber model to pressurize vessels in a bat wing by up to +100
28
mmHg, found that pressure was transmitted to arteries and veins in the non-pressurized wing
more or less undistorted.
200 mmHg
Arterial pressure in the control arm
100 mmHg
200 mmHg
+30 mmHg change in chamber pressure
100 mmHg
+30 mmHg change in test arm arterial pressure
0 mmHg
Heart rate
Figure 13. This figure is describing arterial pressure in the test arm (lower arterial pressure
registrations) and in the control arm (upper arterial pressure registrations). Pressure elevations in
the chamber were transmitted virtually without distortion to the arteries of the test arm.
It thus appears that transmural pressure in the vasculature of the test limb increases in direct
proportion to the applied chamber pressure. Consequently, it seems justified to, as in the
present studies, calculate arterial DP in the test limb by adding applied chamber pressure to
arterial pressure and to assume that venous DP in the test limb equals pressure applied in the
chamber. In the present studies, also changes in arterial flow were examined as functions of
arterial DP. Since arterial flow in a test limb is predominantly controlled by local vascular
resistance it would be more correct to treat flow as a function of arteriolar than arterial DP.
Mean arteriolar DP is however not readily determined and hence flow patterns were
evaluated by treating them as functions of peak arteriolar DP, assumed to correspond to
arterial DP.
Non-invasive measurements of vascular distensibility
During the present pressure-distension determinations, static pressure loads were applied to
the test-limb vasculature. Also during hypertension are the walls of precapillary vessels
exposed to high static pressure loads, and a transition from supine to upright induces static
pressure loads to dependent vessel walls, not only of the arteries and arterioles, but also of
the veins. The rationale of using the present chamber-pressure model to study vascular
distensibilites is, as mentioned, that it allows investigations of arterial, arteriolar and venous
distension in response to graded changes of the static pressure load. In vivo distensibility of
29
conduit arteries is commonly evaluated by tracking dynamic diameter changes during the
course of a pulse-pressure wave (Arndt et al. 1968; Hokansson et al. 1972; Gennser et al.
1981; Ahlgren et al. 1995; Cinthio et al. 2010). It remains to be elucidated if, and in what
manner, results obtained with such techniques relate to the present findings. Notably, based
on results from echo-tracking of systolic/diastolic diameter variations in the popliteal artery,
Shoemaker and coworkers (personal communication) found that prolonged bedrest decreases
arterial distensibility, a finding which contrasts present results.
Conventional methods used to determine venous distensibility, are commonly based on
plethysmographic techniques to evaluate volume changes, for example in a lower limb in
response to orthostasis or to application of lower body negative pressure (Sjöstrand 1953;
Wolthuis et al. 1975; Lindenberger et al. 2008). The advantage of such techniques is that
they give an estimate of the overall compliance of regional veins, which may be critical to
evaluate hemodynamic effects of certain interventions. On the other hand, in contrast to such
plethysmographic techniques, the current method permits determinations of wall
distensibilities in individual veins and of venous distension at high DPs.
Diameter and intima-media measurements
Arterial and venous lumens were measured during end-diastole and in all investigated
vessels the diameter exceeded the theoretical axial resolution of the ultrasound system (0.20.3 mm). The limitation for diameter measurements was therefore less than 0.1 mm
(Schmidt & Wendelhag 1999). It should, however, be noted that 0.1 mm corresponds to
about 20 % of the arterial intima-media thickness and hence it cannot be excluded that
considerable thickness changes in the smooth muscle layer of the arterial wall in response to
the PT regimen and/or bedrest intervention may have remained undetected in the present
studies.
30
SUMMARY AND CONCLUSIONS
The studies presented in the present thesis investigated in vivo vascular wall stiffness in
healthy humans, and the ability of this modality to adapt to changes in the prevailing
intravascular pressure. Thus, pressure-distension relationships were determined in arteries,
resistance vessels and veins, across a wide range of vascular pressures.
To get information on vascular wall adaptation to the prevailing intravascular pressure we
examined the vascular stiffness by three different approaches. 1) A cross-sectional
comparison between leg and arm vasculature with the hypothesis that leg vessels are stiffer
than the corresponding arm vessels, due to higher intravascular pressures in the legs in erect
posture. 2) A longitudinal 5-week bedrest study, reducing vascular pressures in the legs with
the hypothesis that bedrest would reduce stiffness in the leg vasculature. 3) A longitudinal 5week “pressure training” (PT) regimen of the arm vasculature, which was intermittently
exposed to moderate pressure elevations. Here the hypothesis was that PT would increase
wall stiffness in the vasculature. Finally, we conducted a study designed to more thoroughly
investigate a previously observed pulsatile arterial-like venous flow pattern at high
intravascular pressures. One hypothesis for the cause of these observations was that the
pulsatile flow in arm veins was due to pressure-induced opening of arteriovenous
anastomoses in the hand.
The main findings and conclusions of this thesis were:
• The walls of precapillary vessels and veins are stiffer in the arm than in the lower leg,
suggesting that the vascular wall stiffness adapts to cope with long-term demands imposed
by gravity-dependent pressure gradients along the vessels. For the precapillary vessels, the
pressure threshold at which distension commenced was higher and the gain of the pressure
distension was lower in the lower leg than in the arm, which might suggest that both the
intramural myogenic reactivity and the mechanical stiffness was higher in the leg vessels.
• Five weeks of bedrest reduced stiffness in arteries, resistance vessels and veins of the lower
leg and to a lesser degree also in the arteries and veins of the arm, suggesting that the high
vascular wall stiffness in dependent vessels constitutes an acquired feature that depends on
regular pressure exposures. In addition, the results suggest that decreased wall stiffness in
dependent blood vessels may in part account for the reduced tolerance to orthostasis and
headward acceleration following prolonged exposures to bedrest or microgravity. The
mechanisms underlying the bedrest-induced reductions in the stiffness of dependent vessels
cannot be discerned from the present studies, but in the resistance vessels, the reduced
stiffness mainly reflected increased gain of the pressure-distension relationship, which might
suggest changes of the mechanical wall properties as the predominant underlying
mechanism.
• The PT-regimen increased stiffness in arteries, resistance vessels and veins, confirming the
notion that the vessel wall stiffness constitutes a plastic modality, and showing that it may
change considerably in response to a limited number of pressure increments of moderate
31
magnitudes and durations. The study did not provide any conclusive results as regards
underlying mechanisms. As in the bedrest experiments, PT affected the gains of the
pressure-distension relationships of the precapillary vessels predominantly. That increased
intraarteriolar pressure leads to increased arteriolar wall stiffness supports the notion that
local pressure load may serve as a “prime mover” (cf. Folkow 2004) in the development of
vascular changes in hypertension.
• Pain induced by markedly increasing intravascular pressure was more pronounced in the
arm than in the lower leg. Bedrest increased pain at any given intravascular pressure
elevation, especially in the leg, whereas PT reduced the pressure-induced pain, especially in
the pressure-trained arm, but to some degree also in the control arm. The results suggests
that pain induced by markedly elevated intravascular pressure is to a large extent attributable
to vascular distension, presumably mainly to the degree of venous distension. That pressureinduced pain increases by vascular deconditioning and decreases by PT may not solely
reflect concomitant changes in venous distensibility, but in part also a habituation effect at
central nervous level.
• Moderate to marked elevations of intravascular pressures changed the flow-profile in the
veins to pulsatile and arterial like, suggesting that under such conditions pulse waves may be
propagated from the arteries to the veins either via the capillaries or by shunting of blood
through arteriovenous anastomoses that are forced open by the high intravascular pressure.
32
ACKNOWLEDGEMENTS
I wish to express my sincere gratitude and appreciations to all colleges, friends and relatives
who helped me to realize this thesis and in particular to:
First of all Ola Eiken. I am deeply grateful to my supervisor, under whose guidance I have
the great privilege to work, for stimulating discussions and constructive criticism, for
generous friendly support in numerous ways during these years, and for sharing your great
knowledge in physiology, science and writing.
My co-supervisor and co-author Igor Mekjavic for showing me how a great scientist, with a
brilliant mind, do research and for many hard working hours during the Valdoltra bedrest
study at the Adriatic coast, interspersed by many, many funny hours.
My co-supervisor Dag Linnarsson, head of the section Environmental Physiology
department at Karolinska Institutet, for always showing enthusiasm.
Bertil Lindborg for excellent engineering and for a calm and friendly attitude.
The FOI/KTH STH, Environmental Physiology group: Ulf Bergh, Mikael Gennser, Arne
Tribukait Mikael Grönkvist, Gerard Nobel and Oskar Frånberg Björn Johannesson,
Lena Nordin, Eddie Bergsten and Ulf Danielsson for all support and the never ending,
very scientific and unscientific discussions.
Thomas Gustafsson for collaborations and friendship.
Lars-Åke Brodin, Ewa Wigaeus Tornqvist and Eva-Rut Lindberg at KTH STH.
The former members of the Environmental Physiology group at KI: Patrik Sundblad, Peter
Lindholm, Malin Rhodin, Stephanie Montmerle, Lars Karlsson and Bo Tedner.
The former members of the Muscle Physiology group at KI: Per Tesch, Björn Alkner and
Lena Norrbrand.
Jan Kowalski for giving important statistical advices.
All subjects for serious and dedicated participation.
My family: Marie, Caroline and Calle.
The studies included in this thesis were financially supported by grants from the Swedish
Armed Forces.
33
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