Download Hypertensive Retinopathy

Hypertensive Retinopathy
Caliber Changes in Retinal Blood Vessels Following
Blood-Pressure Reduction and Inhalation of Oxygen
By P. S. RAMALHO, PH.D., M.D.,
AND
C. T. DOLLERY, M.B., M.R.C.P.
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SUMMARY
Caliber changes in retinal vessels of groups of hypertensive patients were measured
after the blood pressure had been lowered by successful renal surgery, posture with adrenergic blocking drugs, and parenteral hydralazine. The small arterioles dilated when
the pressure was reduced, whatever means were used. Larger arterioles dilated in
three younger hypertensive patients but in the remainder they were unchanged or narrowed by pressure reduction.
Inhalation of oxygen constricts normal retinal arterioles but the response in hypertensive patients was much less. A response to oxygen was restored in some small arterioles that dilated when the blood pressure was lowered.
As retinal arterioles have no adrenergic vasomotor supply, changes in their caliber
probably occur because of autoregulation. Narrowing caused by autoregulation during
a rise in systemic arterial pressure may become irreversible in long-standing hypertension because of structural changes in the vessel wall.
Additional Indexing Words:
Retinal circulation
Arteriolar reactivity
NARROWING of the retinal arterioles in
hypertension has been described for
many years.' 2 In 1914, Volhard and Fahr3
gave the name "angiospastic retinopathy" to
the changes that occur in this condition. The
retinal appearances in hypertension are particularly important because they correlate
better than any other single factor with the
prognosis of the untreated disease.4
Advances in drug treatment have allowed
hypotensive therapy to be used in many patients who are not acutely ill with accelerated
forms of the disease. The purpose of treatment
in patients with mild disease is to prevent
late vascular complications that now account
for most of the morbidity and mortality. This
type of treatment is based on the assumption
that reduction of blood pressure will prevent
or even reverse vascular complications of hypertensive disease.
Renal hypertension
Retinal vessels are the only ones in the body
that are readily accessible to direct and repeated examination in life. Their caliber can
be measured from well-focused retinal photographs.5 In this study caliber measurements
from retinal photographs have been used to
assess the response of the retinal arterioles
of hypertensive patients to a number of different methods of lowering the blood pressure.
Inhalation of oxygen at 1 atmosphere pressure
has been used as an alternative method of
assessing the vascular reactivity of retinal
blood vessels in hypertensive patients because it is known that oxygen causes severe
vasoconstriction in normal retinal vessels and
the
response
is reduced in hypertension.6, 7
Methods
Retinal photographs were taken with a Carl
Zeiss retinal camera with Kodachrome IH film.
The pupil was dilated with 0.5% cyclopentolate
and 10% phenylephrine. Two retinal cameras
were available, one mounted horizontally and
the other vertically, so that photographs could
From the Department of Medicine, Royal Postgraduate Medical School, London, England.
580
Circulation, Volume XXXVII, April 1968
HYPERTENSIVE RETINOPATHY
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be taken in both the erect and supine positions.
Blood pressure measurements were made with
a standard sphygmomanometer.
The studies with the use of oxygen were
carried out with the patient breathing the gas
from a Douglas bag through a low dead-space
respiratory valve box. Photographs were taken
between 5 and 15 minutes after beginning of
oxygen breathing, when the lung was completely
washed out with oxygen.
Method of Caliber Measurement
Retinal photographs were scrutinized after
processing and all those with imperfect focus
rejected. Even minor degrees of image blurring are unacceptable in this method. The
drawing of the retinal vessels was made by
projecting the color transparencies onto a sheet
of paper. Pairs of pictures of different areas
were selected, and their identity was concealed
by a code number. Caliber measurements were
made with a low-power microscope (x 30) with
a screw micrometer eyepiece. The site of each
measurement was identified with respect to vessel
branches and crossings and was marked on a diagram. Where possible, 10 arterioles and 10 veins
were measured in each patient studied. Care was
taken that these represented the whole range of
vessel sizes that could be measured. The largest
vessels near the optic disk are about 120 microns
in the normal eye, and the smallest that can be
identified clearly enough to be measured are about
30 microns. The results in this paper have been
expressed as arbitrary units, each of which
represents 1.25 ,u in an eye of normal length.5
There is an error in the measurement of
retinal vascular caliber by this method, even
when five measurements are averaged at each
site. The standard deviation of the mean value
obtained in this way is 2 units and is independent
of the diameter of the vessel measured. Because
of this variability we have preferred to look at
trends of caliber change either by calculating
regression lines of caliber change against initial
diameter or a paired t-test on the caliber changes
in all the vessels measured in one individual.
Results
Response of Normal Retinal Vessels
In the study of hypertensive patients we
made use of changes in the inspired oxygen
pressure and postural change as maneuvers
to bring about changes in the caliber of retinal vessels. It was necessary first to establish
the normal reaction of retinal vessels to these
maneuvers. It is well known that retinal arterioles constrict in response to increases in
Circulation, Volume XXXVII, April 1968
581
inspired oxygen pressure6' 7especially the
smallest arterioles less than 50 microns in
diameter.8 Previous data on the reactions of
the smaller retinal arterioles in nornal subjects breathing oxygen were obtained in
young men under the age of 35 years. As the
hypertensive patients were usually older than
this, studies were made in a group of normal
subjects embracing a larger span of years.
Effects of Breathing Oxygen at 1 Atmosphere
Thirteen normal subjects with ages ranging
from 19 to 62 years were studied while
breathing air and oxygen at I atmosphere pressure. Retinal photographs were taken during
air breathing and again after at least five
minutes of oxygen breathing. One hundred
and fifty-seven arterioles and 139 venules
were measured at the same sites while breathing air and again while breathing oxygen.
The average reduction of caliber for all arterioles was 13.5% and for all venules 16.3%.
The arterioles measured ranged in size from
30 to 124 units and the veins from 35 to 171
units. Variations in the reactions in individual
vessels were large. The smallest reduction in
the caliber of an arteriole was 3.8% and the
largest 22.6%. Similar figures for veins were
3.4% and 24.9%.
When the average results for each individual were plotted against age there was clear
evidence of a relationship. The older the
individual was, the less the reduction in diameter with oxygen. A similar trend was evident in both arterioles and venules (fig. 1).
Effects of Postural Change in Normal Subjects
Six normal subjects, average age 28 years
(range 21 to 36), were photographed in both
the standing and lying positions. Their blood
pressures were taken with a standard sphygmomanometer during photography. Seventy
arterioles and 61 veins were measured on
these photographs. Changes in diameter were
measured against the initial diameter of each
vessel when each subject was lying flat. Although there was a wide scatter of results,
there was a small but significant tendency
for the smallest arterioles to dilate and the
largest ones to constrict when these subjects
RAMALHO, DOLLERY
582
ARTERIOLES
30
20
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y 34,278-0,4818x
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AGE (years)
Figure
1
Percentage changes in caliber of retinal arterioles and veins during oxygen breathing of 13
normals ranging in age from 19 to 62 years.
moved from the recumbent to the upright
position. There was also a change in the diameter of the veins, as all except the smallest
showed a significant reduction in diameter
on standing (fig. 2). The mean blood pressure,
taken as the diastolic plus one third of the
pulse pressure, rose from 85.5 mm in recumbency to 94 mm on standing. Cardiac
output changes were not measured in this
study (fig. 2).
ference between normal and hypertensive
subjects is not so great as it appears by eye
and also because the major narrowing of
arterioles takes place more peripherally than
15 _
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15
DIAMETER WHEN ov--
Vascular Responses in Hypertensive Retinal
Vessels
Hypertensive vascular disease leads
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to nar-
rowing, irregularity, and sclerosis of retinal
arterioles. We attempted to derive an index
of arteriolar narrowing by measuring the diameter of all veins and arterioles on the edge
of the optic disk. Neither the crude ratio of
the sum of arteriolar diameters over the sum
of vein diameters nor the ratio of sums of
squares of diameters gave a satisfactory separation between normal and hypertensive
subjects. This may be partly because the dif-
15r_
10
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.
0-
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4
.
15 _-
Figure 2
Caliber changes in retinal arterioles and veins of
normal subjects on standing upright. Each point
represents the change in diameter at a single point
on an individual vessel.
Circulation, Volume XXXVII, April 1968
HYPERTENSIVE RETINOPATHY
583
the disk edge. It is difficult to make such
the more peripheral parts
of the retina because of the variability of the
vessel branching pattern.
measurements in
change in diameter during oxygen breathing
arteriolar segments, even in patients
with grade 3 or grade 4 hypertensive retinopathy, showed a significant constriction during
oxygen breathing.
some
Effects of Oxygen
Thirteen hypertensive patients ranging in
age from 15 to 63 years and with mean blood
pressure readings between 147 and 173 mm
Hg were studied while breathing air and oxygen at 1 atmosphere pressure. One hundred
twenty-seven arterioles and 142 venules
measured. Reduction of caliber of arterioles produced by oxygen breathing was
much less in the hypertensive than in the
normal subjects with the same range of ages.
In the hypertensive patients the reactivity
was almost independent of age, except for the
youngest patient (table 1). The over-all percentage reduction of arteriolar caliber was
3.3% (normal 13.5%). The reaction of veins
to oxygen breathing was much less reduced
than that of the arterioles. The over-all reduction in diameter averaged 11.6% (normal
16.3%). In five of the 13 hypertensive patients
the caliber reduction of arterioles during
oxygen breathing was not statistically significant but, surprisingly, these five subjects all
showed a significant reduction in the diameter
of the veins. Although there was little over-all
were
Effect of Pressure Changes on Caliber of Retinal
Vessels in Hypertensive Patients
Posture and Sympathetic Blockade
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Six treated hypertensive patients, average
48 years (range 35 to 53 years), were
selected because they were known to have
a substantial fall in pressure when they stood
up. The mean arterial pressure of the group
was 144.6 mm Hg in recumbency and 114.6
mm on standing. All were being treated with
drugs that are known to interfere with transmission at some point on the sympathetic
vasomotor pathway. Seventy arterioles and
51 venules were measured on photographs
taken while the patient was lying down and
again at the same sites while he was standing
upright. The initial diameter of the arterioles
ranged from 28.8 to 114 units and the veins
from 38 to 158 units. A plot of the change in
diameter against the initial diameter of arterioles in the recumbent position showed that
there was a significant increase in the diameter
of the smallest arteriole and a decrease in
diameter of the larger ones (fig. 3).
age
Table
Percentage Reduction of Diameter of Retinal Arterioles and Venules in Thirteen
Hypertensive Patients While Breathing Oxygen
Age
Sex
15
20
31
33
46
47
F
M
M
M
M
M
M
F
M
F
M
M
M
52
53
57
58
60
62
63
Mean
*P > 0.05.
Circulation, Volume XXXVII, April 1968
Mean BP
(mm Hg)
147
170
167
153
157
150
153
173
163
167
167
163
157
Grade of retinopathy4
2
2
3
3
4
4
3
3
3
3
3
3
3
Percentage change of diameter
Venules
Arterioles
-12.0
- 2.9
- 1.5*
-
3.7
+ 1.1*
- 1.8*
3.0
4.7
- 7.4
- 3.2
- 3.0
+ 0.7*
-
-
1.5*
- 3.31
-19.1
-16.9
-12.5
-16.3
- 3.3
-11.7
-15.1
- 7.5
-14.8
-11.1
-10.2
- 1.8
-10.4
-11.59
.X1~ -r A
RAMALHO, DOLLERY
584
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120
100
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140
BP reduction
144 6-1146mmHg
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INITIAL DIAMETER
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168 -121 mmrnHg
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Figure 4
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Figure 3
Caliber change in retinal arterioles and veins of
hypertensive patients on adrenergic blocking drugs,
who had a large postural fall in blood pressure on
standing.
retinal arterioles and veins in
Caliber changes
hypertensive patients treated with parenteral hydralin
azine.
Effect of Surgery in Patients with Unilateral Renal
Disease
Effect of Hydralazine
Sympathetic blocking drugs are thought
to lower blood pressure on standing chiefly
by preventing the normal adjustment of peripheral resistance that takes place when the
cardiac output falls on standing. For comparison we selected a group of six severely
hypertensive patients, average age 51 (range
36 to 66) years, who were to have treatment
initiated with parenteral hydralazine, a drug
that has -a direct vasodilator action on systemic
arterioles. The drug was administered by slow
intravenous injection (less than 1 mg/minute),
while the patients were lying flat. The average
of the mean blood pressures fell from 168 to
121 mm Hg after administration of an average
dose of 37 mg of hydralazine intravenously.
Sixty-one arterioles and 50 venules were measured. The response was different from that
seen in patients taking sympathetic blocking
drugs. Almost all arterioles dilated after administration of drugs and the average increase was 12.3%. Small caliber arterioles dilated to a greater extent than large ones.
The venules also dilated but in this case the
greatest increase in diameter occurred in the
largest veins. The average increase in diameter in veins was 13.5% (fig. 4).
The closest approach to
a cure
of hyper-
tension is successful renal surgery. Eleven
patients with unilateral renal disease were
studied before and between 4 and 40 weeks
after operation. Eight of the patients had
stenosis of the main renal artery and one of
a branch artery. The remaining two had hy-
dronephrosis and a pyelonephritic kidney,
respectively. Four of the patients had no
significant change in their pressure after surgery and there was no significant change in
the caliber of either arterioles or venules in
their retinae. Five of the remaining patients
had their blood pressure reduced to near normal levels and in two others it was significantly reduced from preoperative levels. All
these patients showed dilatation of the
.20
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Figure 5
Caliber changes in retinal arterioles of seven
whose blood pressure was reduced by renal
patients
surgery.
Circulation, Volume XXXVII, April 1968
HYPERTENSIVE RETINOPATHY
585
Hg before treatment and 98 mm Hg after
treatment.
CALIBRE CHANGES IN 3 YOUNG HYPERTENSIVES
B. P 138 mmHg - 9 rmmHg
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.
Response to Oxygen before and after Blood Pressure
Reduction in Hypertensive Patients
20
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Figure 6
Caliber changes in retinal arterioles of three young
hypertensive patients who showed a general dilatation
of arterioles.
Downloaded from http://circ.ahajournals.org/ by guest on June 17, 2017
smallest retinal arterioles whereas the response of the larger arterioles was variable
(fig. 5).
General Increase in Arteriolar Caliber
During this investigation we observed three
young patients, average age 18 (range 15
to 21) years, who showed a general increase
in arteriolar caliber when the blood pressure
was reduced (fig. 6). In two instances the
patients were treated with guanethidine and
the third had a successful nephrectomy for
renal artery stenosis (fig. 7). The average of
the three mean blood pressures was 138 mm
After blood pressure reduction many hypertensive patients in this study showed dilatation
of some arterioles of small caliber. The vasoconstrictor response of these small vessels
to oxygen was found to have increased after
reduction of the blood pressure.
In five hypertensive patients with retinopathy and high levels of blood pressure (mean
pretreatment pressure 157 mm Hg) the reaction to oxygen breathing was studied in
the sitting position before and after lowering
the blood pressure to a value of 109 mm Hg
for 2 to 6 weeks by treatment with adrenergic
blocking drugs. These patients' retinal arterioles showed a similar change in caliber
to that observed in patients treated by renal
surgery or posture after adrenergic blockade
(fig. 8). One patient had no increase in his
response to oxygen after pressure reduction
but in the remaining four there was a significant increase in the vasoconstrictor response.
The unreactive patient showed a small reduction in the caliber of his arterioles when the
Figure 7
Retinal photograph of patient J.M. aged 15 (left) before and (right) after nephrectomy. There
is a general increase in the diameter of arterioles.
Circulatioon, Volume XXXVII, April 1968
RAMALHO, DOLLERY
586
.-
az
a)
.e
E
co
-C'
of blood pressure allowed the arterioles to
dilate; this degree of dilatation could be reversed by oxygen breathing.
CALIBRE CHANGES AFTER LONG TERM
MEDICAL TREATMENT
20
Arterioles
*
+10 [
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CI a
-?k-,
a
*-
0
S..
m0
-10
Mean BP reduction
-159-114mmHg
y= 10G69-02x
)I
20
0
20 40 60 80 100 120
ORIGINAL DIAMETER BEFORE TREATMENT
Figure 8
Caliber changes in retinal arterioles of five patients
whose blood pressure was reduced by several weeks
of treatment with adrenergic blocking drugs.
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blood pressure was reduced. The four with
increased reactivity to oxygen had dilatation
of their smaller blood vessels when blood
pressure was lowered. Study of 13 individual
arterioles, which dilated after pressure reduction, showed that the average diameter was
65 units before and 71.5 units after the blood
pressure was lowered (table 2). There was no
net change in diameter in response to oxygen
before the pressure was lowered but average
reduction in diameter of 5.4 units with oxygen
after the blood pressure had been lowered
and the vessels had dilated. Thus, reduction
Discussion
The retinal arterioles of hypertensive patients are often narrowed. Reversal of the
narrowing by sustained and general increase
in diameter following treatment was found
in only a small group of younger patients.
General arteriolar dilatation also occurred in
patients given intravenous hydralazine, during the period of drug action, but some of
the patients had retinal arterioles that appeared abnormally narrow even when the
blood pressure was near normal levels.
Other methods of lowering blood pressure
such as the postural change with adrenergic
blocking drugs or successful renal surgery
more often brought about a small reduction
in the diameter of the larger retinal arterioles
than an increase. These patients were middleaged and had long-standing hypertension.
The vasoconstrictor response to oxygen was
much reduced in hypertensive patients and
a similar although less striking reduction in
reactivity occurred in older, normotensive
persons. The loss of response may be due to
structural changes in the arteriolar wall which
are, at least in the short-term, iLrreversible.
Table 2
Changes in Thirteen Arteriolar Segments Which Showed Increased Reactivity to Oxygen after Lowering the Blood Pressure with Adrerergic Blocking
Drugs
Initial diameter
(units)
Mean
37
40
42
43
30
115
56
74
40
81
38
38
42
52
Caliber changes
on
100% oxygen
+1
+1
0
+2
+1
0
-1
+1
-1
-2
+2
-1
-2
+0.08
Diameter after
hypotensive treatment
39
51
48
49
42
125
59
76
44
82
43
41
45
57.3
Caliber changes on
100% oxygen after
treatment
-8
-8
-6
0
-7
-7
-5
-1
-1
-3
-5
-2
-3
-43
Circulation, Volume XXXVII, April 1968
HYPERTENSIVE RETINOPATHY
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The degree of vasodilatation to be expected
with blood pressure reduction must depend
on the degree of constriction that occurred
when the blood pressure rose. It has not
proved possible to derive a satisfactory quantitative expression of the degree of arteriolar
narrowing, and this places a limitation upon
the interpretations that can be made.
The most consistent response was the dilatation of small arterioles when the blood
pressure was lowered, whatever means were
used. The change in transmural pressure in
the retinal arterioles during some of these
maneuvers was large. Blood flow through the
eye is opposed by the intraocular pressure
of 16 to 20 mm Hg and, in the erect position,
by the hydrostatic height of the column of
blood from heart to eye (also 16 to 20 mm
Hg). A fall in mean arterial pressure from 144
mm in recumbency to 114 mm on standing is
equivalent to a reduction of retinal arteriolar
transmural pressure from 124 to 74 mm Hg,
a fall of over 40%.
There is strong evidence that retinal arterioles do not have an adrenergic nerve supply,9-11 so that there must be another mechanism controlling arteriolar diameter. Such
a mechanism is autoregulation, which is
known to play an important part in regulating
flow through many other organs. It is difficult
to find any other explanation for dilatation
of small arterioles in the face of reduced
blood pressure in such varied circumstances.
These studies suggest an explanation for
the widely varying degree of retinal arteriolar
narrowing seen in different patients with comparable degrees of pressure elevation. If arteriolar narrowing is an autoregulatory response, the amount of narrowing will depend
upon the height of the blood pressure and
the capacity of the vessel to react. Unreactive vessels in older patients or patients with
long-standing mild hypertension might constrict less for a given pressure elevation than
the arterioles of a young patient with a rapid
rise in blood pressure. Arterioles with a
greater degree of constriction are more likely
to show substantial vasodilatation when the
pressure is lowered.
Circulation, Volume XXXVII, April 1968
587
It is interesting to compare our studies of
the human retina in hypertension with those
of Byrom'2 in rats with experimental malignant hypertension. Byrom found that focal
retinal arteriolar constriction in rats during the
early stages of malignant hypertension could
be reversed by deepening the level of ether
anesthesia. In animals with long-standing hypertension this maneuver did not result in
vasodilatation, although removing the renal
clip that had caused the hypertension reversed
the changes. These results are comparable
with our findings in a small group of younger
patients but our older patients seemed to
have developed irreversible retinal changes
in most of their retinal arterioles. Our results
provide some support for those who advocate
early treatment to minimize hypertensive vascular disease.
Changes in the diameter of the veins also
require explanation. Both normal and hypertensive subjects show considerable venoconstriction during oxygen breathing and in the
latter group this sometimes occurred when
there had been little change in the diameter of
the visible arterioles. The veins in the normal
eye became slightly narrower in the upright
position and they dilated in the hypertensive
subjects when the blood pressure was lowered
with hydralazine. As there is little evidence
of smooth muscle in the walls of small retinal
veins,'3 they would not be expected to show
vasomotor responses. Many of the caliber
changes can be explained as purely passive.
The pressure relations of the thin-walled retinal vein resemble those of the collapsible
tubing of the resistor of a Starling heart-lung
preparation. At the outflow of the eye there
is a zone of rapid change of pressure similar
to that in the Starling resistor and sometimes
referred to as a "vascular sluice"' or "waterfall."14 If the intraocular tension exceeds the
.downstream venous pressure, which it must
do under all physiological circumstances, a
constriction will tend to form in the veins at
the outflow from the eye. The pressure in the
retinal veins will then be the intraocular
pressure plus a small transmural pressure
RAMALHO, DOLLERY
588
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linearly related to the flow. Changes in venous pressure downstream will not affect
either pressure or flow in the eye unless
the venous pressure reaches or exceeds the
intraocular pressure. Most of the changes in
the caliber of the retinal veins can be explained on the basis of retinal blood flow.
Thus, the small constriction that occurs on
standing in normal subjects may be a reflection of the reduction in cardiac output that
normally occurs in this position. Dilatation
with hydralazine can be explained by the
increase of blood flow which probably takes
place with this drug. Constriction with oxygen may result from the reduction of blood
flow following arteriolar constriction. The
difficulty with this explanation is that it
scarcely explains why venoconstriction occurs
in response to oxygen in hypertensive patients
whose arterioles do not respond. It is still
possible that arterioles too small to be measured from color photographs do constrict
in these patients but we have no direct evidence of this.
Acknowledgment
This work was supported by the Medical Research Council. We thank the patients and normal
volunteers who consented to take part in this investigation.
References
1. GOWERS, W. R.: State of the arteries in Bright's
disease. Brit Med J 2: 743, 1876.
2. MOOR, R. F.: Retinitis of arterio-sclerosis, and its
relation to renal retinitis and to cerebral vascular disease. Quart J Med 10: 29, 1916.
3. VoLHARD, F., AND FAHR, K. T.: Brightsche
Mirenkrankeit: Klinik, Pathologie und AUas.
Berlin, Springer-Verlag, 1914, p. 8.
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Circulation, Volume XXXVII, April 1968
Hypertensive Retinopathy: Caliber Changes in Retinal Blood Vessels Following
Blood-Pressure Reduction and Inhalation of Oxygen
P. S. RAMALHO and C. T. DOLLERY
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Circulation. 1968;37:580-588
doi: 10.1161/01.CIR.37.4.580
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