Download Autoregulation of blood flow in the capillaries of the human

Invest. Ophthalmol. Visual Sci.
June 1977
568 Reports
for other connective tissues verifies that the vitreous gel is of this class of tissue albeit very
highly hydrated.
The treatment of swelling tissue flow conductivity by Bert and Fatt 5 can be used to estimate
the pore space in the vitreous gel through which
water flows. Bert and Fattr> conclude that for very
highly hydrated swelling materials the pore radius is given very approximately by
i- = 8k
(5)
For the (k/?/)v values obtained for rabbit and
bovine vitreous gel equation 5 gives the pore
diameter as about 4,000 A. This large pore
diameter explains why some investigators of the
vitreous gel in vivo have been able to observe
flow in this tissue when using tracer particles as
large as 1,000 to 2,000 A.
I wish to thank Dr. Richard F. Brubaker for
making available unpublished data from his
vitreous gel studies.
From the School of Optometry and Department of Mechanical Engineering, University of
California, Berkeley. Submitted for publication
Oct. 25, 1976. Reprint requests: Dr. Irving Fatt,
7A, The Grove, Highgate Village, London N6
6JU, England.
Key words: vitreous gel, flow conductivity.
REFERENCES
1. Fatt, I., and Hedbys, B. O.: Flow of water in
the sclera, Exp. Eye Res. 10:243, 1970.
2. Fatt, I.: Flow and diffusion in the vitreous
body of the eye, Bull. Math. Biol. 37:85,
1975.
3. Brubaker, R. F., and Riley, F. C, Jr.: Vitreous
body volume reduction in the rabbit, Arch.
Ophthalmol. 87:438, 1972.
4. Pirie, A.: The vitreous body. In Davson, H.,
editor: The Eye, New York, 1969, Academic
Press, Inc., vol. I, pp. 273-297.
5. Bert, J. L., and Fatt, I.: Relation of water
transport to water content in swelling biological membranes. In Blank, M., editor: Surface Chemistry of Biological Systems, New
York, 1970, Plenum Press, Inc., pp. 287-294.
6. Maurice, D. M.: The cornea and the sclera.
In Davson, H., editor: The Eye, New York,
1969, Academic Press, Inc., vol. I, pp. 489600.
Autoregulation of blood flow in the capillaries of the human macula. CHARLES E.
RIVA AND MICHAEL LOEBL.
The entoptic phenomenon by which one can observe leukocytes flowing in one's own parafoveal
capillaries has been used to study the effect of
changes in perfusion pressure on blood flow. Out
measurements in humans with normal ocular fundi
indicate that the retinal circulation of the parafovea is autoregulated in relation to perfusion
pressure. The average time lag between a change
in blood flow and the beginning of the autoregulatory response was about 46 sec, and the
average duration of this response was about 48 sec.
At the end of the autoregulatory response, the
vascular resistance of the parafoveal segment was
about 50% lower than that at normal intraocular
pressure.
The maintenance of constant blood flow despite
changes in perfusion pressure (autoregulation) is
an intrinsic property of nearly all body tissues.1
A small number of studies showing that the
human retinal circulation responds actively to
changes in perfusion pressure suggest that the
retina also has an autoregulatory mechanism. For
example, Dobree- found that constriction of
arteries and veins occurs in patients with glaucoma after a decrease in the intraocular pressure
(IOP) by either drugs or operation. Russel3
demonstrated that retinal arteries dilate when the
IOP is increased by mechanical pressure on the
globe in patients with Horner's syndrome. He
attributed this effect to a homeostatic mechanism
in the retinal circulation in these patients with
oculosympathetic paralysis. Ernest'1 reported that
the visual threshold in the Bjerrum area is elevated with an increase in IOP, but with time
compensation takes place, reducing the visual
threshold toward normal.
None of these experiments, however, provides
quantitative data on the fundamental parameters
which generally characterize such physiological
feedback control mechanisms as blood flow regulation. These parameters are the time lag between a change in the blood flow and the beginning of the regulatory response, the duration
or time constant of the regulatory response, and
the open-loop gain of the feedback control system. The last-named is a measure of the efficiency
of the control mechanism in counteracting variations of blood flow from the normal state. Determination of these parameters requires measurements of blood flow as a function of the
perfusion pressure.
In an attempt to perform such measurements,
Riehm, Podesta, and Bartsch5 have made use of
the entoptic phenomenon by which one can observe leukocytes flowing in one's own parafoveal
retinal capillaries. These authors used the number of leukocytes passing within 30 sec. in a capillary as a measure of blood flow. They found that
blood flow in the parafoveal capillaries decreased
linearly as the IOP was raised, up to about 40
mm. Hg. Thus no autoregulatory response was
observed within the 30 sec. following a decrease
in the perfusion pressure. The measurements of
L.
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Volume 16
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Reports 569
AA»RGTONOMfTER
RlCOROINtf 1O
Time (min)
Fig. 1. Typical recording of IOP as subject maintains leukocytes at constant reduced speed.
Pi = average IOP after initial sudden increase. IOP remains practically constant during
interval U, then increases during interval tr to reach saturation level Pi + SP.
Ffytche et al.,(i showing that dilatation of the
retinal vessels of the pig occurs only after the
IOP has been elevated for at least 1 min., suggest that the 30 sec. counting time chosen by
Riehm, Podesta, and Bartschr> mtiy have been
too short for autoregulation to take place. We
repeated this experiment, trying to count the
leukocytes for longer periods of time but found
it very difficult to count them reliably for more
than 30 sec.
On the basis of the above phenomenon, we
developed another method for studying the effect of changes in perfusion pressure on blood
flow in the parafoveal capillaries over a period
longer than 2 min. Our measurements indicate that
retinal blood flow in this region of the fundus
is autoregulated. They also provide quantitative
data on the time delay with which the autoregulatory system responds following an abrupt
change in perfusion pressure and on the time
course of the autoregulatory response.
Materials and methods. Seven healthy volunteers 22 to 39 years old, participated in this
study. IOP was measured prior to the experiment by Goldmann applanation tonometry, and
systemic blood pressure was measured by brachial
sphygmomanometry. Each subject was seated in
front of a standard slide projector, with his head
resting on a support. An interference filter centered at a wavelength of 430 ran, (bandwidth =
10 nm.) was mounted in front of the projection
lens, and an optical diffuser was placed in front
of the filter to provide a uniformly illuminated
field of observation. This setup permits an optimal visualization of the leukocytes.5 The fellow
eye of each subject was covered with a patch,
and the room was darkened.
To monitor and simultaneously measure the
IOP, the probe of a Mackay-Marg tonometer was
mounted on a micrometer slide and carefully
/>P(mm Hg)
25
10
20
30
40
Pi (mm Hg)
Fig. 2. Variation of 5P as a function of Pi obtained from 22 measurements in seven subjects.
placed perpendicular to the sclera of the subject's eye, close to the limbus. The signal from
the probe was continuously recorded by the Mackay-Marg strip chart recorder set at 1 mm./sec.
The subject was asked to raise his IOP quickly
by pressing the probe of the tonometer on his
eye until he saw that the leukocytes moved at
a reduced speed. Then he was told to adjust the
pressure of the probe to maintain this speed constant for about 2 min.
It has been shown that the Mackay-Marg
tonometer can provide a continuous and accurate
reading of IOP when the probe is applied to
the cornea.7 Therefore we compared the readings
taken with the probe close to the limbus with
conventional Goldmann applanation tonometry on
three subjects and found that when the MackayMarg probe was held against the sclera so as to
produce a constant reading for 2 to 3 min.,
Goldmann tonometry performed every Yz minute
during this time also indicated a constant IOP
(t 5%). Mackay-Marg readings taken in this
position were slightly higher than Goldmann mea-
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Invest. Ophthalmol. Visual Set.
June 1977
570 Reports
surements, but always by a constant amount and
not by more than 4 mm. Hg.
Results. Fig. 1 displays a typical recording of
the time course of the IOP as the subject maintained the speed of the leukocytes at a constant
reduced value. The curve shows that the IOP
increases abruptly when the subject first applies
pressure. After some initial oscillation while the
subject masters control, the IOP stabilizes around
an average value, P i ; and remains constant up
to a time t«i. After time t,i, the IOP increases up
to a value Pi + 5p, as the subject continues to
apply pressure to maintain the leukocytes at the
same reduced speed as before. This increase in
the IOP takes place during an interval of time t r .
In most of the experiments, after the IOP reaches
Pi + 8P, it remains relatively constant for the
rest of the experiment. In the others, however,
there is a further slow increase in IOP following t r , although the IOP usually appears to approach a maximum within 2 to *LVz min. The
average values for t,i and tr are 46 ± 21 sec.
and 48 ± 14 sec, respectively. A plot of 5p as
a function of Pi, based on 22 measurements, is
shown in Fig. 2.
The IOP's of the seven subjects were between
14 and 21 mm. Hg. Their brachial artery blood
pressure ranged between 110/65 and 120/85
mm. Hg. The average mean ophthalmic artery
pressure, taken as two thirds of the mean systemic pressure, was about 56 mm. Hg. In two
subjects we measured the brachial blood pressure
before and at the end of the experiment. We
found no significant difference between initial
and final pressures.
Discussion. The present study was undertaken
to determine the effect of raised IOP on the
blood flow in the parafoveal capillaries over periods of time longer than 30 seconds. For this
purpose, a method based on the entoptic observation of leukocytes in the parafoveal capillaries was developed.
With our method the subject raises the IOP
in such a way that he sees the leukocytes moving in a pulsatile mode consisting of two phases.
One is a fast forward movement (systole), and
the other a slower forward movement (diastole).
The latter may even become a pause at high
values of Pi. Each subject is able to choose
various flow speeds that he feels capable of maintaining. This explains the various initial pressure
steps of Pi which range between 22 and 46 mm.
Hg.
In each experiment the subjects had to raise
their IOP by an amount Sp in order to keep the
speed of the leukocytes constant. This increase
in IOP indicates that a feedback mechanism is
operative, acting to increase the blood flow
towards its initial rate. The effect of this mechanism is first observed at time t,i and is effective
only for a time t,. The works of Dobree2 and
Russell1 suggest that this mechanism reduces the
vascular resistance by causing dilatation of the
retinal arteries and possibly of the veins also.
An estimation of the decrease in this resistance
that occurs during the time interval tr can be
obtained from our data. Let P(t) represent the
perfusion pressure of the parafoveal vascular system and R(t) the vascular resistance of this
system at time t. The corresponding rate of blood
flow is given by the relation
F(t) = P ( t ) / R ( t )
(1)
Since the pressure in the central retinal vein is
only slightly above the IOP, one can write as
a good approximation, P(t) = PA - IOP(t),
where P.* is the mean pressure in the parafoveal
arterioles, which we assume to be practically the
same as that in the larger retinal arteries and
to remain constant during the experiment. The
sudden increase of the IOP to a value Pi causes
the rate of blood flow to decrease by an amount
AF and to become
F, = F.N - A F = ( P A - P I ) / R . N
(2)
where FN and R.\ are the values of F and R at
normal IOP. If this vascular system autoregulates,
a feedback process acts to decrease the resistance
R and thus to reduce AF toward zero. As a result, the leukocytes start flowing faster.
However, at time T = t,i + t r the IOP usually
does not need to be raised further to maintain
a constant reduced flow. At this time, R(t) has
reached a minimal value R ( T ) , and the corresponding flow is F ( T ) = [PA - (P. + 8 P ) ] / R ( T ) .
Since F ( T ) = F l ; it follows that
[PA - (P, + « P ) ] / R ( T ) =
(PA - P,)/Rx (3)
After rearrangement of the terms of equation 3
and expressing [ R ( T ) - RlN]/Rx as AR/RX> this
equation can be rewritten as
AR/RN, = -8P/(P A - P,)
(4)
AR/RN. represents the total relative change in
the vascular resistance occurring during t r . Using,
as an approximation for PA, the average ophthalmic artery pressure of our subjects, i.e., 56
mm. Hg, and for Sp an average value of 15.5
mm. Hg, one finds from equation 4 that in the
range of Pi between 24 and 30 mm. Hg, the
relative decrease in resistance AR/RN, that occurs during autoregulation lies between 45% and
60% of the normal value RN. Identical calculations show that for an initial elevation of IOP
to a value Pi between 40 and 46 mm. Hg, this
decrease is somewhat larger.
Our average value of t,i is smaller than the
one found by Ffytche et al.G in their experiments
with pigs. The retinal vessels of these animals did
not start to dilate until about 1 min. following
an increase in IOP. The difference between these
data and ours may be species related, but they
could also be explained by the fact that the
retinal vessels must dilate by at least 5% before
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Volume 16
Number 6
one can detect a change in their caliber by
fluorescein fundus photography. Since a 5%
change in caliber represents a 20% change in
flow, it is quite probable that our method is more
sensitive to changes in blood flow.
Our results indicate that the retinal circulation
supplying the parafovea is autoregulated in relation to perfusion pressure. It provides quantitative information on the time interval between a
change of perfusion pressure and the response
of the autoregulation mechanism and on the duration and time course of the response. This method
in its present stage does not permit the determination of the open-loop gain of the feedback mechanism; that is, how close to its initial rate does
the flow of blood return after a change in perfusion pressure.
This method should prove useful for investigating autoregulation in the normal retina under
various physiological conditions and in the retina
of patients with diseases such as vascular occlusions, systemic hypertension, diabetic retinopathy, ocular hypertension, and glaucoma.
The authors wish to thank Drs. G. Feke and
F. Delori for helpful suggestions concerning this
work, W. P. Roberts and M. D. Gonzalez for
technical help, and A. Seidman and S. F. Blackwell for editorial assistance.
From the Department of Retina Research, Eye
Research Institute of Retina Foundation, Boston,
Massachusetts. This work was supported by the
Massachusetts Lions Eye Research Fund, Inc. and
by the Morton Adler Foundation. Submitted for
publication Dec. 10, 1976. Reprint requests: Editorial Services Unit, Eye Research Institute of
Retina Foundation, 20 Staniford St., Boston, Mass.
02114.
Key words: perfusion pressure, intraocular pressure, blood flow, autoregulation, macular circulation, entoptic phenomenon, leukocytes.
REFERENCES
1. Guyton, A. C., Jones, C. E., and Coleman,
T. G.: Circulatory Physiology: Cardiac Output and its Regulation,, ed. 2, Philadelphia,
1973, W. B. Saunders Co., chap. 19.
2. Dobree, J. H.: Calibre changes in retinal vessels occurring in raised ocular tension; circulatory compensation in chronic glaucoma,
Br. J. Ophthalmol. 40:1, 1956.
3. Russell, R. W.: Evidence for autoregulation
in human retinal circulation, Lancet 2:1048,
1973.
4. Ernest, J. T.: Pathogenesis of glaucomatous
optic nerve disease, Trans. Am. Ophthalmol.
Soc. 73:366, 1975.
5. Riehm, E., Podesta, H. H., and Bartsch, C :
Untersuchungen iiber die Durchblutung in
Netzhautkapillaren bei intraokularen Drucksteigerungen, Ophthalmologica 164:249, 1972.
6. Ffytche, T. J., Bulpitt, C. J., Kohner, E. M.,
Reports 571
et al.: Effect of changes in intraocular pressure on the retinal microcirculation, Br. J.
Ophthalmol. 58:514, 1974.
7. Moses, R. A.: Constant pressure applanation
tonography with the Mackay-Marg tonometer,
Arch. Ophthalmol. 76:20, .1966.
Choroidal and cerebral blood flow in baboons measured by the external monitoring of radioactive inert gases. R.
STRANG,* T.
M. WILSON,** AND E.
T.
MACKENZIE. * * *
Quantitative measurements of blood flow using
xenon-133 to measure cerebral blood flow and
krypton-85 to measure choroidal blood flow were
made in 12 anesthetized baboons (Papio anubis).
Analysis of tlie clearance curves of krypton from
the eye and studies of the diffusion of krypton
in the eye show that the inert gas-clearance
method measures choroidal blood flow only. The
mean choroidal blood flow at normocapnia in
this group of baboons is 463 ± 44 ml./100 gm./
min., and the mean cerebral blood flow is 46 ±
5 ml./100 gm./min. (mean ± 1 S.D.).
The quantitative measurement of cerebral blood
flow by the external monitoring of the clearance
of radioactive inert gas from the brain was established by Lassen and his co-workers.1"3 For a
homogeneous tissue the clearance of inert gas is
monoexponential. For tissue of unit density, blood
flow is related to the exponential rate constant by
the following equation:
(1)
F = 100 x k x p
where F = blood flow (ml./lOO gm./min.),
p = the partition coefficient (i.e., the ratio of
the solubility of the inert gas in 1 gm. of tissue
to its solubility in 1 ml. of blood), and k = exponential rate constant (min.- 1 ).
The clearance of xenon-133 from the brain can
be analyzed into two exponential components.
The faster component is representative of gray
matter flow, and the slower component representative of white matter flow. An estimate of the
average blood flow through the gray and white
matter can be obtained from the height-over-area
method of analysis.4
Friedman, Kopald, and Smith/1 using the betaemitting inert gas krypton-85, applied the inert
gas-clearance method to the measurement of
ocular blood flow. They obtained clearance curves
with four exponential components from both rabbits and primates. They initially believed that the
exponential rate constant of the first component
obtained by exponential curve stripping was representative of choroidal blood flow. However, they
subsequently stated,0 without proof, that it was
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