STUDIES ON EXPERIMENTAL HYPERTENSION
XII.
T H E EXPERIMENTAL PRODUCTION AND PATHOGENESIS OF
HYPERTENSION D U E TO RENAL ISCHEMIA*
HARRY GOLDBLATT
From the Institute of Pathology, Western Reserve University, Cleveland, Ohio
The thought that human hypertension, in certain circumstances, may be of renal origin, is not new. Its origin is usually
assigned67, "• 142 to Richard Bright 11 ' 12 , because he suggested the
existence of a causative relationship between renal disease and
otherwise unexplained enlargement of the heart. Volhard153,
however, states that this relationship was suspected in China,
200 years B.C., and also finds suggestive references to it in the
Old Testament. Volhard151 •152 himself deserves much of the
credit for keeping this idea alive, despite much controversy,
especially as applied to the hypertension that is associated with
renal excretory insufficiency. Volhard154 is even willing to accept the view of a possible renal origin in some cases of hypertension that are associated with vascular disease of the kidney,
without impairment of renal excretory function, the benign phase
of essential hypertension. Ample support for this view was
given recently by Moritz and Oldt122 on the basis of an anatomical study of the incidence and distribution of arteriolar sclerosis
in various organs of patients with essential hypertension. They
concluded that a causative relationship exists between the renal
vascular disease and the hypertension despite the reports 47 •143 of
occasional cases of essential hypertension in which no renal vascu* Received for publication, November 30, 1939.
These studies were supported by the Beaumont Trust—L. D. Beaumont,
and the Josiah Macy, Jr. Foundation and aided by grants from Mr. Nathan
Dauby and Mr. Alex Wintner and Associates, of Cleveland.
Presented as part of a symposium on hypertension before the American
Society of Clinical Pathologists in St. Louis, Missouri, on April 12,1939.
40
EXPERIMENTAL
HYPERTENSION
41
lar disease is found. There are those, however, who still deny
the renal origin of hypertension under any circumstances105,106.
A more complete account of the historical background has been
given in a previous communication67, and an exhaustive treatment of it is given by Fishberg47. A review of the experimental
approach to this problem has also been given previously in some
detail 65 ' 67 .
The investigations to be described here were begun because it
was thought that the problem of the possible renal origin of the
type of hypertension that is associated with vascular disease of
the kidney, with or without accompanying renal excretory insufficiency, should be capable of solution by experiments on
animals. By postulating that if the vascular disease of the
kidney be responsible for initiating the hypertension, it must
precede the development of the hypertension, it became necessary in some way to reproduce the vascular disease in the kidney,
or to develop some method whereby the probable functional
disturbances of renal circulation caused by the vascular disease
could be reproduced. The effect of such vascular disease, it was
assumed, would be renal ischemia, and it was thought, therefore,
that a solution to the problem should be possible, if a method
for the production of renal ischemia in animals could be developed. It was thought also that if renal ischemia, with its consequences, be the sole determining factor in both the benign as
well as the malignant phase of so-called essential human hypertension associated with vascular disease of the kidneys, then it
should be possible to produce hypertension with or without accompanying renal excretory insufficiency, by varying the degree
of renal ischemia. If hypertension without significant renal
excretory insufficiency could be produced by renal ischemia,
then the probability of a renal origin of the benign phase of socalled essential human hypertension associated with vascular
disease of the kidney would be increased, since the only good
argument against its renal origin has always been the absence
of accompanying significant renal excretory insufficiency47.
For the production of renal ischemia in animals, an adjustable
clamp was devised whereby the main renal artery could be con-
42
HAREY GOLDBLATT
stricted to any desired degree. In 1932, the production of
persistent hypertension in dogs by renal ischemia was first reported,* and in 1934, the first paper on the subject was published62. The value of the method was soon confirmed36 • 123 •163,
and during the past six years, there have been many publications
in which the same device, or some modification, has been employed to produce renal ischemia and hypertension in dogs and
other animals. Most of the references in the appended bibliography are to studies designed to determine the mechanism of
this type of hypertension and the application of the results of
these studies to the problem of the pathogenesis and treatment
of human hypertension.
In the first publication62, to save space, full details about the
surgical operation for the production of renal ischemia were
not given. Because of the continued interest in the method and
the many requests for details, it is considered advisable to give
here a complete description of the procedures practiced for the
production of experimental hypertension by renal ischemia,
and to give only a brief summary of some of the results obtained
by the use of this method. These results have been published
in detail in other papers 63-72 . A full discussion of progress in
the study of the pathogenesis of the condition has also been
published65 •67 • 72, so only a brief summary will be included in
this paper.f
THE METHOD
This consists essentially of the production of renal ischemia by constriction
of the main renal arteries effected by means of a special clamp devised for the
purpose. The advantages of this clamp over any other device that was tried
and that can be employed for vascular constriction are that by this means
the artery can be constricted to any desired degree, the constriction increased
or decreased later, at will, and the clamp removed and normal circulation
to the kidney restored, provided not too long an interval elapses after its application. When the clamp has been on for a long time, scar tissue, which
* Preliminary communication before the Experimental Section of the Academy of Medicine, Cleveland, November 11, 1932.
t In this publication reference will also be made to publications that have
appeared since the symposium was held.
EXPERIMENTAL
43
HYPERTENSION
grows into all crevices, may make it difficult or impossible to remove the clamp
without injuring the renal artery.
The clamp
Full information about the nature and construction of the original clamp
and instruments used to aid its application was given in the first publication,
and will not be repeated in detail here. The original clamp (fig. 1) was made
of pure silver. It may be made of stainless steel128 or any other single metal
that is not irritating and does not rust or deteriorate in the body or cause un-
METRIC
I
T
i i x i 1 i 'f
2
i t i r "V I ' l l
31
I 1 I I TTT1
,
1 T'T ! ~
FIG. 1. CLAMP WITH MOVABLE AND REMOVABLE PLATES AND DOUBLE-ACTING
SCREW.
ORDINARY T Y P E
a, movable plate in open position; b, movable plate partly screwed down;
c, side view.
usual inflammatory reaction. The clamp can be made of a size to fit any vessel.
For dogs weighing between 10 and 20 kgm., a clamp 3 mm. square, in cross
section, and 6 mm. long has been found most satisfactory. For dogs weighing
less than 10 kgm., a clamp of the same length, but 2 mm. square, in cross section, and 5 mm. long is desirable. For dogs weighing much more than 20 kgm.,
similar but larger clamps have been employed. In our experiments, the 3 mm.
clamp has been used the most. For the application of this type of camp,
special instruments (fig. 2) were devised to facilitate and expedite the procedure.
In order to obviate the necessity of using the special instruments devised
dial 2
3:
ON
_j_
<;
• ui
55
Ixi
I
U
-LJ
I
- H
FIG. 2. CLAMP HOLDER FOB ORDINARY TYPE ("LAMP (FIG. 1)
a, holder without clamp; 6, holder with receptacle of clamp inserted; screw
stem pointing downward; c, holder with clamp inserted in position with screw
stem pointing upward and removable plate inserted to enclose artery; d, instrument holding removable plate in j aws; e, screw-driver for screw stem of clamp and
for set screw; /, screw on handle of clamp holder to release the part that holds
the clamp and allow it to turn over so that the screw of the clamp becomes
accessible; g, knob on top of clamp which when pressed down compresses a spring
on the inside of the handle and releases the part that holds the clamp; h, set
screw on part that holds clamp to fix it in position.
44
EXPERIMENTAL
45
HYPERTENSION
for the application of this type of clamp, a different clamp (fig. 3) has been
constructed which can be used for the renal or larger arteries, but was developed
mainly for the constriction of the aorta or large arteries. This clamp and the
method of its application to the aorta have been described in detail in a recent
publication71. It consists of a right angles U-shaped portion, the open recep-
I
ft
f.
FIG. 3. CLAMPS WITH UPRIGHT STEM SCREW CARRYING MOVABLE AND
REMOVABLE PLATES
a, 3 mm. clamp with screw stem and flexible cable for constriction of the
artery from the outside of the body; b~e, various types and sizes of clamps with
short upright screw- stem;/, 1 cm. clamp with long rigid screw stem for constriction of the aorta or large artery from outside the body.
tacle for the artery (fig. 4, b), and a removable portion consisting of a screw
stem carrying two plates (fig. 4, c). Screw stems of any length can be made
for this type of clamp. Some have been made with a long rigid stem (fig. 3, / ) ,
or a long stem consisting of a flexible cable (fig. 3, a). These have been made
of such a length that the constriction of the renal artery, and even of the aorta,
46
HARRY
GOLDBLATT
can be accomplished from the outside of the body. The upper plate of the
screw stem (fig. 4, c) slides into a groove on the inner sides of the U-shaped
a
i
L.1
FIG. 4. CLAMP HOLDER FOR CLAMPS OF TYPES d, e AND / IN F I G . 3
a, holder; b, receptacle; c, screw stem, carrying movable and removable
plates.
receptacle (fig. 4, 6) and serves to enclose the vessel. The lowermost, movable
plate of the double acting screw can be screwed down to constrict the vessel
to any desired degree. Special instruments for the application of this clamp
EXPERIMENTAL
HYPERTENSION
47
are not necessary, but one has been devised (fig. 4, a) for the purpose of holding
the U-shaped receptacle. This facilitates the insertion of the vessel into the
receptacle and serves to hold the latter fixed while the screw stem with two
plates is being inserted to enclose the vessel. The special instrument is not
necessary for the application of this type of clamp to the renal or any other
large artery, but it simplifies the application of the clamp to the abdominal,
and especially the thoracic, aorta.
Surgical procedure for the constriction of the main renal artery
The operation is usually performed under general anesthesia, with ether,
after a hypodermic injection of morphine and atropine, but it can also be performed easily under local anesthesia with 1 per cent procaine. To perform the
operation under local anesthesia, skin and subcutaneous tissue are first infiltrated with the anesthetic. The splitting of the muscle for the gridiron
incision seems to cause no pain, but it is better to inject a small amount of
procaine at the site where the split is to be made.
For the constriction of the main renal artery, an oblique incision about
6 cm. in length is made in the skin, below and parallel to the inferior costal
margin. On the right side, the incision is made about 1 cm., and on the left
side about 1.5 cm. below and parallel to the costal margin, beginning at the
costo-lumbar angle. On both sides, the external oblique muscle can be avoided
by pulling it out of the way, or split, and a gridiron incision made by also splitting the internal oblique and transversalis muscles in the line of their fibers.
This procedure is bloodless and reveals peritoneum, which is then pushed away
manually from its attachment to the lateral and posterior wall of the abdomen.
Care should be taken not to tear the peritoneum, or, if this happens, the tear
should be repaired before proceeding. A self-retaining retractor, with long,
thick wire blades, is then inserted to retract the wound and keep it open. The
main renal artery is usually seen pulsating behind some subperitoneal fat,
which, if abundant, hides the vessel. This fat is split, and, by blunt dissection,
with long tissue forceps, the main artery is dissected out for a length of about
1 cm., close to the aorta.
It is of great importance to make certain that the clamp is being applied
to the main renal artery, and also to ascertain whether there are any other main
arteries going to the kidney directly from the aorta. Two separate main renal
arteries are not uncommon, and rarely, three main renal arteries to one kidney
may be encountered. The length of the trunk of a single main renal artery also
varies greatly. In some dogs this portion is so short that there is insufficient
room for a clamp, so that separate clamps must be placed on the main branches
of the vessel. When the main renal artery has been dissected out at the site
where the clamp is to be applied (as close as possible to the origin of the aorta),
the vessel is then inserted into the receptacle of the clamp (fig. 2, 6) which is
held, by means of the clamp holder (fig. 2, a) in the first position, with the screw
of the clamp directed downward (fig. 2, b). The vessel is then enclosed in the
48
HAEEY GOLDBLATT
clamp by means of the removable plate held in the jaws of a special instrument
(fig. 2, d), which helps to slide the plate into the grooves on the inner sides
of the clamp. Care should be taken not to catch any portion of the vessel or
its surrounding tissue between the removable plate and the receptacle. This
is best avoided by pulling the clamp holder upward and compressing the vessel
moderately during the instant that is required to insert the plate. Then the
part holding the clamp is turned over, to make the screw of the clamp accessible
(fig. 2, c). This is done by releasing the screw on the handle (fig. 2, /), which
permits the part holding the clamp to turn at the hinge when the knob at the
top of the handle (fig. 2, g) is pressed down. When the part holding the clamp
reaches the vertical position, the knob on the handle is released and the spring
within the shaft pulls the part holding the clamp into the horizontal position
with the screw of the clamp facing upward (fig. 2, c). During this manoeuver,
if no portion of the vessel is caught between the removable plate and the receptacle, the artery turns freely within the clamp. The screw of the handle is
tightened again to fix the part holding the clamp in the horizontal position.
The clamp remains fixed in the holder, held by a small set screw. Now, by means
of a screw-driver (fig. 2, e), the movable plate is screwed down to constrict the
artery to any desired degree. This is best done by first tightening the screw of
the clamp until the movable plate occludes the vessel, and then turning the
screw back to release the pressure on the vessel and leave the desired constriction.
To release the clamp from the holder and leave it on the vessel, the set screw
(fig. 2, h) is turned back. The clamp then comes out, if the holder is lifted up,
or it can be pushed out of the holder easily by a little pressure on the screw
of the clamp.
To apply the other type of clamp (figs. 3 and 4), the renal artery is inserted
in the receptacle (fig. 4, b), and then enclosed in the clamp by the screw stem
(fig. 4, c) carrying the two plates, the upper one of which slides into the grooves
on the inner side of the receptacle. The lower plate is first screwed down, to
occlude the vessel, and then turned back to leave the desired constriction of the
vessel. For the application of the larger clamps of this type, especially to the
aorta, the insertion of the vessel into the receptacle of the clamp is facilitated
by fixing this part of the clamp in the special holder (fig. 4, o).
It is possible, by observation and palpation of the portion of the vessel
proximal and distal to the clamp, to estimate roughly to what degree it has
been constricted, but it is difficult to judge this accurately, and practically impossible to find a quantity either for the degree of constriction or the degree of
ischemia, because it is impossible to determine beforehand the amount of developed or potential natural accessory circulation to the kidney by way of the
renal pedicle or through the capsule. If well marked pulsation of the vessel
on the renal side of the clamp can be felt, the constriction is inadequate; but
when the constriction is great, it is often impossible, by palpation, to tell whether
the vessel is occluded or whether some blood is still entering the kidney. Our
method of recording the degree of constriction has been to state how many
EXPERIMENTAL
HYPERTENSION
49
turns it takes to occlude the vessel and how much of the screw is turned back.
It has been found by experience that with the 3 mm. clamp, in dogs weighing
between 10 and 20 kgm., it takes from about 2 | to 3 | turns to occlude the vessel,
and that from f to J of a full turn back, after occlusion of the vessel, usually
affords sufficient circulation to prevent necrosis of the kidney and produces
adequate renal ischemia to determine the development of hypertension. In
animals weighing around 15 kgm., a release of J of a full turn has been found
most satisfactory. With this degree of constriction, there is frequently no
significant accompanying renal excretory insufficiency detectable by the usual
renal function tests, including determinations of urea and creatinine clearance,
even if both main renal arteries are constricted at one time. In some of the
larger animals, however, weighing more than 20 kgm., this degree of constriction may be too great and may result in renal excretory insufficiency, which
may prove fatal, if both renal arteries are constricted at the same time. In such
animals, if both main renal arteries are constricted at one operation, it is better
to leave one at f of a turn and the other at i or even 1 full turn open, and increase
the constriction at a later operation.
THE E F F E C T OF CONSTRICTION OF ONE MAIN RENAL ARTERY
Adequate constriction of the main renal artery of one kidney
results in elevation of blood pressure which persists for a period
varying from weeks to months, and usually returns to normal
within four to six weeks 62 ' 66 ' " (fig. 1). The gradual return of
the blood pressure to normal is considered to be due in part
perhaps to the development of accessory circulation to the ischemic kidney, but mainly to the presence of the other normal
kidney. This is in agreement with the views of Katz and collaborators100, m . Just how the normal kidney effects this compensation has not been elucidated. If the constriction of one
main renal artery is excessive, there may be little or no rise of
blood pressure. Release of the constriction, removal of the
clamp or excision of the kidney62 •66 • 67 at the height of elevation
of blood pressure usually results in a drop to normal within
twenty-four hours, and the blood pressure remains normal66 (figs.
2 and 3). That unilateral renal disease may be responsible for
human hypertension in man is now recognized2 • 7 • 9 •16 •60, and
it has also been found that the removal of the kidney, usually
the seat of pyelonephritis and arteriosclerosis, or of ischemia
due to some other intrarenal or extrarenal abnormality, has resulted in a return of the blood pressure to normal in a number of
50
HARRY GOLDBLATT
cases 2 .». ». i»». "9. Recently Blalock, Levy and Cressman6
have shown that unilateral renal ischemia superimposed upon
intestinal ischemia results in a prolonged elevation of the arterial
blood pressure in a high percentage of the animals. The significance of this observation is not yet clear.
THE E F F E C T OF CONSTRICTION OF BOTH MAIN R E N A L
ARTERIES
The most common procedure has been to constrict one main
renal artery, and, after an interval of a week or more, to constrict
the main renal artery of the other kidney. This usually results
in persistently elevated blood pressure, and, if the constriction
of the vessels is not excessive, there is usually no significant
alteration of renal excretory function. In some animals the
blood pressure has remained elevated for more than five years67
(fig. 2). Release or removal of one of the clamps results in a
slow return of the blood pressure to normal66 (fig. 1). Release or
removal of both clamps also results in a prompt return of the
blood pressure to normal. Removal of the clamp after it has
been on the artery for a long time has not been accomplished
successfully for technical reasons.
THE E F F E C T OF CONSTRICTION OF ONE MAIN RENAL ARTERY AND
REMOVAL OF THE OTHER
KIDNEY
If there is a significant elevation of blood pressure as a result
of the constriction of one main renal artery, a good procedure is
later to remove the other kidney. This usually results in persistent hypertension 4 - 67 (fig. 3)100. If the constriction of the
main renal artery is not very great, there may be no accompanying disturbance of renal excretory function. Unilateral nephrectomy before constriction of the main renal artery of the other
kidney can also be practiced, but it is a risky method, because
it is likely to be followed by renal excretory insufficiency and
fatal uremia if the constriction of the renal artery is too great.
In some animals in which the constriction of one main renal
artery results in only a slight or no rise of blood pressure, the
subsequent removal of the other kidney is usually followed by the
development of persistent hypertension. Unilateral nephrec-
EXPERIMENTAL HYPERTENSION
51
tomy alone produces no significant change in the blood pressure
of normal dogs and but little or no significant disturbance of
renal excretory function as measured by urea clearance tests.
THE EFFECT OF CONSTRICTION AND OF GRADUAL OCCLUSION OF
BOTH MAIN RENAL ARTERIES
The method that has been used most frequently for the production of persistent hypertension in the dog66 (fig. 7), monkey64
(fig. 1), and rabbit183 has been moderate constriction of the main
renal artery of both kidneys. The constriction of both arteries
may be accomplished at the same time, but usually an interval of
a week or more is allowed between the clamping of the two
arteries. This results in elevations of both systolic and diastolic
pressure84'1M which usually persist.
In some animals, after a variable period of hypertension,
due to moderate constriction of both renal arteries, the blood
pressure may subside to a lower level or even to normal. This
lowering of the blood pressure, under these circumstances, cannot be explained, as in the case of unilateral renal ischemia, on
the basis of the presence of normal kidney. The only reasonable
assumption is the development of collateral circulation adequate
to counteract the effects of the constriction of the main renal
artery. The degree of constriction of the vessels can then be
increased on one or both sides. In most instances this results
in re-elevation of the blood pressure, which persists62 (fig. 9).
When there is abundant natural or acquired accessory renal circulation, it has been found necessary in some animals to occlude
both main renal arteries in order to make the hypertension persist. In such animals, provided the occlusion of both renal
arteries is not produced too abruptly, there may be no resultant
renal excretory insufficiency. But some animals have developed
a chronic, mild or moderate renal excretory insufficiency, detectable only by one or other of the clearance tests and usually not
by accumulation of nitrogenous products in the blood. The constriction or occlusion of the blood supply to spleen and lower
limbs62, head, liver, intestinal tract and pancreas6 is not followed
by elevation of blood pressure.
52
HARRY GOLDBLATT
T H E E F F E C T O F SUDDEN EXCESSIVE CONSTRICTION O F BOTH MAIN
RENAL ARTERIES
The uremic, convulsive, malignant phase of this type of hypertension can be produced at will merely by excessive constriction
of the main renal arteries62 (figs. 5 and 6)66 (fig. 3)69, or of the
aorta just above the origin of both main renal arteries.71 If
both main renal arteries are occluded at the same operation66
(figs. 7, 8 and 9), or with a short interval between operations,
or if one renal artery is occluded and the other kidney is removed,
elevation of blood pressure, usually of moderate degree, results,
and the animal dies in uremia in from three to five days. Such
animals usually develop the degenerative, necrotizing and inflammatory lesions of the arterioles in many organs, but not in
the necrotic, ischemic kidney. A complete report of this phase
of the subject has already been published69. Similar findings
have also been reported by Child19. An increase of guanidine in
the blood of such animals has been reported 20 ' 62 , but the exact
mechanism of development of the arteriolar lesions has not yet
been elucidated. There are those19 •162 who claim that impairment of renal excretion is not a necessary condition for the development of the lesion, but their published data do not completely support their view, and their methods of determining
disturbance of renal function were not adequate. More work
is necessary and is being done in this laboratory to settle this
important point.
APPLICATION
OF
ORGANIC
MEMBRANE
AROUND
DECAPSULATED
KIDNEY AT T H E TIME OF CONSTRICTION OF R E N A L
ARTERY OR LATER
In order to decrease the naturally abundant potential accessory
circulation to the dog's kidney and to prevent the development
of new blood vessels, a membrane that does not induce much
scar formation can be placed around the decapsulated kidney.
This membrane can be applied at some time before, at the same
time, or at any time after the constriction of the main renal artery
by the clamp. This can be practised on one or both kidneys,
or on one kidney with the removal of the other. The type of
EXPERIMENTAL
HYPERTENSION
53
membrane used by Bell and Pedersen 3 ' m for the same purpose
was found most suitable. This is dried lamb's cecum (socalled "fish skin" condom), a cylindrical sac with one end
closed. The membrane can be sterilized by soaking in 10 percent formalin, 75 per cent ethyl alcohol, or 1:1500 phenyl mercury nitrate. A hole is cut in the side of the sac of sufficient
size to permit insertion of the kidney and a purse string suture
is placed around the opening. After decapsulation, the kidney
is inserted into the membrane through the hole in the side, the
purse string suture is drawn up and tied firmly around the hilus
of the kidney, but not tightly enough to constrict the renal vein.
The membrane is then drawn over to fit the kidney closely, the
part that includes the open end is then tied off with silk ligatures
close to the pole of the kidney, and the excess of the membrane is cut off close to the ligature. The only accessory circulation that remains, after the membrane is applied, comes by
way of the renal pedicle, probably along the ureter. This
procedure usually insures a persistent type of hypertension.
When practiced on kidneys that are already ischemic, but in
animals in which the blood pressure has returned to normal,
the blood pressure usually becomes re-elevated, and the hypertension persists. In animals in which both renal arteries have
been gradually occluded, renal excretory function may be greatly
disturbed after the membrane is applied, and death due to uremia
may result. The application of this type of membrane does not
result in the formation of a thick perirenal shell of scar tissue,
as is the case when a membrane of cellophane is wrapped around
the kidney129. By the latter method, the scar itself causes renal
ischemia, by compression of renal tissue, and it is easily possible
that the scar also causes constriction of the ureter and vessels of
the renal pedicle.
ANATOMICAL CHANGES IN KIDNEYS AND OTHER ORGANS OP
HYPERTENSIVE
ANIMALS
In various studies on experimental hypertension due to renal
ischemia produced by the methods described, more than six
hundred animals have been used. It has happened only excep-
54
HARRY GOLDBLATT
tionally that no elevation of blood pressure has followed the constriction of only one main renal artery, and rarely has there been
no response to the constriction of both main renal arteries. The
degree of elevation of blood pressure is not predictable, because
it is never possible to determine the exact degree of renal ischemia
produced, and certainly impossible to estimate the amount of
potential or established accessory circulation to the kidney. It
is of great interest and importance that in animals with hypertension due to renal ischemia, if there is no accompanying renal
insufficiency (the benign phase), the kidneys may show no significant gross or microscopic changes detectable by the usual
methods 62 ' 67 ' 100 . In some of these animals, if the artery of
one kidney has been excessively constricted, or even occluded,
there may be parenchymatous degeneration, focal or diffuse
necrosis, with or without hemorrhage, or atrophy of the kidney.
The changes in the tubules, glomeruli and blood vessels of a few
atrophic kidneys, mentioned in the first report62, were exceptional
and were the direct consequence of prolonged excessive ischemia.
It is to be emphasized that such anatomical changes are not
necessary conditions for the determination of the hypertension.
The minute alterations in the afibrillar muscle cells of the preglomerular arterioles in the moderately ischemic kidneys of hypertensive dogs, recently reported by Goormaghtigh and Grimson73
as the only detectable change, are of great interest. Their significance awaits elucidation.
In both kidneys of animals in the malignant phase of hypertension due to excessive constriction of the main renal arteries,
there may be found various changes from advanced parenchymatous degeneration to necrosis, with or without hemorrhage.
In other organs and tissues, except the eyes 102,1M , the only
change that has been noted67 in the smaller arteries and arterioles
of animals in the benign phase has been some thickening of the
media. No degenerative intimal changes to suggest the development of arterial or arteriolar sclerosis have occurred in any other
site except the eyeball102-103. It is not being assumed that even
at this site the cause of the arteriolar sclerosis is the hypertension. Certainly Fishberg's47 recent conclusion that widespread
EXPERIMENTAL
HYPERTENSION
55
arteriolar sclerosis has been produced by hypertension alone is
not justified by the publications on this subject. In the malignant phase, on the contrary, widespread fulminating arteriolar
necrosis and necrotizing arteriolitis occur in many organs and
are not distinguishable from similar lesions in the malignant
phase of human essential hypertension in man. Because these
lesions do not occur in the ischemic kidneys of these animals, nor
in any organs of animals with extreme azotemia, without hypertension, due to bilateral nephrectomy, nor in animals with great
hypertension but without accompanying disturbance of renal
excretory function, the conclusion has been reached that hypertension and impaired renal excretory function are at least two of
the necessary conditions for the determination of these arteriolar
lesions. The reports of others19 • m, which have minimized the
importance of disturbance of renal excretory function in the
production of the arteriolar lesions, are not convincing because
their methods for the determination of renal function were not
adequate. In the malignant phase the media of the aorta frequently shows edema and degeneration or destruction of elastica.
Moderate enlargement of the heart has been reported in animals with persistent hypertension due to renal ischemia21 •6B •67.
The failure of these animals to develop very large hearts is
worthy of further investigation.
SUMMARY OF STUDIES ON T H E PATHOGENESIS OF HYPERTENSION
DUE TO R E N A L ISCHEMIA
In any "a priori" consideration of the possible mechanism
whereby hypertension can result from renal ischemia, at least
three main possibilities come to mind. The first is a teleological
explanation and has to do with the purposeful increase of peripheral vascular resistance in order to elevate the pressure and improve the blood flow through the ischemic kidney. This explanation is not susceptible to experimental investigation or to
proof, and is merely mentioned because similar reasoning has
been used by Fahr42 and others to explain the elevation of blood
pressure that accompanies human arteriolar nephrosclerosis.
There are therefore but two possible mechanisms, susceptible of
56
HARRY GOLDBLATT
investigation, whereby the increase of peripheral resistance can
be induced by the ischemic kidney. The one is a nervous reflex from the ischemic kidney, which affects the vasomotor
apparatus, and the other is a humoral mechanism initiated in
some way by the ischemic kidney and resulting in the formation
or accumulation in the blood of a substance which, by direct
action on the contractile elements of the arterioles, or indirectly,
by affecting the nervous vasomotor apparatus, constricts these
peripheral vessels. It is also possible, of course, that such a
substance might act by neutralizing some natural depressor
substance which prevents the arterioles from being in a constant
state of spasm. Such a depressor substance has never been
demonstrated.
That the ischemic kidneys are directly responsible in some
way for the development of this type of experimental hypertension has been shown by the following experiments: If the
main renal artery of one kidney is constricted, and the ischemic
kidney is removed some time later, when the blood pressure is
still elevated, the blood pressure falls within about twenty-four
hours to the original normal level66 (figs. 2 and 14). If one main
renal artery is constricted, and the blood pressure becomes elevated, the release or removal of the clamp is also followed by a
prompt return of the blood pressure to normal. The same holds
true if both renal arteries are constricted, and both clamps are
later released or removed. If both main renal arteries are first
constricted, and only one clamp is released, the blood pressure
also falls eventually to a lower level, but it takes a longer time65
(fig. 1). In these circumstances, the blood pressure remains
elevated for about the time that it does when only one renal artery is constricted67 (fig. 1). If one kidney is transplanted to the
neck31 or inguinal region66 •67, and the other kidney removed, constriction of the blood supply to the transplanted kidney results
in the development of elevated blood pressure. Bilateral nephrectomy is not followed by the development of persistent
hypertension66 (fig. 4, and for other references, see 67).
All these results point to the kidney as the site of origin of the
elevation of the blood pressure, and show that the deficient irri-
EXPERIMENTAL
HYPERTENSION
57
gation of the kidney with blood is the determining factor that
produces the hypertension. That there is a reduction of the
blood flow through the kidney immediately after the constriction of the renal artery was shown in the first publication on the
subject62, and that this may continue has also been shown. It
is of the greatest interest in this connection that recently Smith
and collaborators144 have found by indirect methods, an indication of reduced blood flow through the kidneys in practically
all cases of essential hypertension which they investigated.
All experiments that have been performed by the author and
collaborators as well as others, up to the present time, have
tended to eliminate a nervous reflex from the kidney as the
mechanism responsible for the increased peripheral resistance.
In dogs, denervation of the renal pedicle21 •65 •123, section of the
splanchnic nerves and excision of the lower four thoracic sympathetic ganglia63, section of the anterior nerve roots from the
sixth dorsal to the second lumbar inclusive66, excision of the celiac
and upper lumbar ganglia4, excision of the entire sympathetic
nervous system in the thorax and abdomen, including cardiac
denervation 1 , 4 9 ' 7 8 ' 9 1 , and even pithing of the animal60 have
failed to prevent, or permanently to reduce hypertension produced by constriction of the main renal arteries. If one kidney
is removed and the other is transplanted to the neck or to the
inguinal region, and its main renal artery is then constricted,
elevated blood pressure also develops31 •66 •67. In such animals
there is certainly no direct connection between the kidney and
the nervous system. These studies, therefore, eliminate a nervous reflex from the ischemic kidney as a possible mechanism in
the production of persistent hypertension and leave only a
humoral mechanism as a probable explanation of the phenomenon. These experiments do not exclude the possibility that
in human essential hypertension stimuli from the central nervous system may play an accessory, or, in some cases, even a
primary part in elevating blood pressure. It has been suggested
by the author 70 that this factor may be the one which is influenced by the usual medical treatment of essential hypertension
and accounts for any fall of blood pressure that occurs.
58
HARRY GOLDBLATT
Up to the present time, all the published studies that have dealt
with the pathogenesis of this type of experimental hypertension
indicate the probability that a humoral mechanism of renal origin
is responsible for the increased peripheral vascular resistance that
produces the elevation of the blood pressure. A few of the pertinent findings that justify this conclusion are as follows: Removal of both kidneys does not result in elevation of blood
pressure, although fatal azotemia develops. The fleeting hypertension reported101 as occurring soon after bilateral nephrectomy
in dogs has been considered of neurogenic origin, because even
unilateral nephrectomy was found to cause a similar rise. Although great constriction or occlusion of both renal arteries
may also result in fatal uremia, yet the animal does develop hypertension. It is known that occlusion of both renal arteries
does not eliminate all circulation to the kidneys, and this would
indicate that a chemical substance might still enter the renal
venous circulation. That this is probably the case is shown by
the failure of hypertension to develop when both main renal veins
are occluded at the same time that the main renal arteries are
constricted or occluded65 (figs. 8, 9, 10). Presumably this is due
to the interference with the entrance of a hypothetical chemical
substance into the blood stream. Just how this substance is
elaborated has not been elucidated by any studies up to the
present. If the substance does exist, it is not known whether it
is excreted or secreted by the ischemic renal parenchyma,
whether it is formed anew or accumulates in the blood as it
flows through the ischemic kidney, and whether it requires an
activator to make it effective. It is not even known that the
effective factor does not represent a physical rather than a chemical change in the blood or some part of it.
Houssay and collaborators96 • 98 have reported that transplantation of the ischemic kidney from one animal to the neck of a
nephrectomized animal results in elevation of the blood pressure
of the latter, in a few minutes after the ischemic kidney is irrigated with blood. The transplantation of a normal kidney does
not have a similar immediate effect on the blood pressure. This
work has not yet been confirmed. This result is interpreted as
EXPERIMENTAL HYPERTENSION
59
indicating that some chemical substance present in the ischemic
kidney is washed into the circulation of the recipient animal and
produces an almost immediate pressor effect. The existence of
such a hypothetical substance and its nature have not yet been
demonstrated. Houssay and collaborators44' 46, 9 6 > 97, 98' 146' 147
have also reported vasoconstrictor properties in venous blood
plasma from the ischemic kidneys of hypertensive dogs and little
or none in the venous blood plasma from normal kidneys. Mason
and Rozzell117 have failed to corroborate these findings, but they
did not employ exactly the same variety of test animal and tested
serum instead of plasma.
In 1871 Tiegerstedt and Bergmann demonstrated that the saline
extract of a normal kidney has pressor properties which they
attributed to a substance that they named renin. The work was
confirmed at the time (for bibliography, see 67), and then the
subject was neglected. Recently several investigators82 •132 •135 •137
have again confirmed this work and have reported the presence
of a larger amount of pressor substance in the saline extract of
ischemic kidneys of animals with experimental hypertension,
and also of the kidneys of hypertensive human beings, than in
similar extracts of normal kidneys. Extracts of other kinds
made from normal or ischemic kidneys have also been prepared
and found effective. Recently a relatively pure pressor substance has been isolated by several investigators26 • 87 •107 • 146.
Page130 has shown that renin by itself is not vasoconstrictor, but
requires activation by some substance present in normal plasma.
There are some studies that have drawn attention to the possible
part played by adrenal cortical hormone on the action of renin160.
All this does not constitute proof that renin is the pressor
principle involved in the production of hypertension which
follows constriction of the main renal arteries or of essential
hypertension in man. Most of the attempts to demonstrate a
direct pressor substance in the blood or extracts of blood of
animals with experimental hypertension due to renal ischemia
have failed100'126 (for additional bibliography, see 67), so that
there is no conclusive proof that a pressor substance is present
in the blood of such individuals. Thus, although the results
60
HAREY GOLDBLATT
of most of the experimental work point directly to a humoral
mechanism as responsible for hypertension due to renal ischemia,
yet there is no conclusive proof of the existence of this mechanism, and the nature of the substance responsible has not yet
been elucidated.
If the mechanism involved in the pathogenesis of hypertension
due to renal ischemia be a humoral one, it may still be possible
that the endocrine organs play some part. It is even possible
that some substance from the kidney might stimulate the outpouring of an unusual amount of a known pressor substance from
such organs. It has been shown by Page and Sweet124' 126 that
although the removal of the hypophysis has little or no influence
in preventing this type of hypertension, yet hypophysectomy in
hypertensive dogs is followed by reduction of the hypertension
or a return to the normal level in some of the animals. Also, the
hypertension due to renal ischemia reached by hypophysectomized dogs did not tend to last as long as hypertension produced by the same method in normal animals. Both results may
be due, in part at least, to the development of adequate accessory circulation to the kidneys and may not actually be due to
the hypophysectomy.
The part played by the adrenals has also been studied by a
number of investigators. Bilateral adrenalectomy without supportive or substitution therapy interferes with the development
of hypertension due to renal ischemia65 (fig. 11) and also causes
previously reduced hypertension to fall to normal or to a subnormal
level66 (fig. 12). The result is the same even when-supportive
treatment in the form of sodium chloride and sodium bicarbonate
or sodium citrate are given to the adrenalectomized animals66
(fig. 13). When, however, presumptive substitution therapy in
the form of cortical extract, as well as supportive treatment, is
given, some of the animals do develop elevated blood pressure66
(fig. 17) despite the absence of both adrenals. This work has
been confirmed by several investigators4,23> m . Rogoff, Stewart
and Nixon139 found that in three hypertensive animals, adrenalectomy did not cause an immediate fall of blood pressure to the
normal. From this they have concluded that the adrenal cortex
EXPEBIMENTAL HYPEBTENSION
61
plays no part in this phenomenon. That it is the cortex, and not
the medulla, of the adrenals that is important in this connection, is shown by experiments in which one adrenal was completely removed, the medulla of the remaining medulla destroyed,
and the entire cortex62 (fig. 15), or a small portion of it, was left
just sufficient to maintain life66 (fig. 19). In such animals the
blood pressure became elevated in the usual way when the main
renal arteries were constricted. Just how the cortical hormone
acts, if it does, is not elucidated by these experiments. It may
do so by playing only its usual part in the physiological mechanisms and by insuring a normal reactive state of the blood vessels
of the animal. It may act by sensitizing the blood vessels to
the action of the hypothetical effective substance of renal origin
or the two substances may act in combination. These are points
that still remain to be studied.
The influence of removal of other endocrine organs has been
pancreatectomy
investigated 58 ' 101 . Thyroparathyroidectomy,
and gonadectomy do not prevent or cause a significant persistent
lowering of hypertension due to renal ischemia.
Thus it appears to be established beyond reasonable doubt
that the hypertension which develops after constriction of the
main renal arteries, or as a result of renal ischemia produced by
any method, is due to some humoral mechanism of renal origin.
Evidence is accumulating to justify the conclusion that the results
of these studies on animals may be directly applicable to the
pathogenesis of both the benign and malignant phases of essential
hypertension in man, which is associated with the presence of
intrarenal or extrarenal vascular or other disease that can produce renal ischemia. Further knowledge of the pathogenesis
and perhaps treatment of this condition will depend upon the
establishment of this conclusion.
REFERENCES
(1) ALPERT, L. K., ALVING, A. S., AND GRIMSON, K. S.: Effect of total
sympathectomy on experimental renal hypertension in dogs. Proc.
Exper. Biol. & Med., 37: 1 (Oct.) 1937.
(2) BARKER, N. W., AND WALTERS, W.: Hypertension associated with unilateral chronic atrophic pyelonephritis: Treatment by nephrectomy.
Proc. Staff Meet. Mayo Clin., 13: 118 (Feb.) 1938.
62
HABKY GOLDBLATT
BELL, E. T., AND PEDEHSEN, A. H.: The causes of hypertension.
Ann.
Int. Med., 4: 227 (Sept.) 1930.
BLALOCK, A., AND LEVY, S. E.: Studies on the etiology of renal hypertension. Ann. Surg., 106: 826 (Nov.) 1937.
BLALOCK, A., AND LEVY, S. E.: Gradual complete occlusion of the coeliac
axis, the superior and inferior mesenteric arteries, with survival of
animals: Effects of ischemia on blood pressure. Surgery, 6: 175
(Feb.) 1939.
BLALOCK, A., LEVY, S. E., AND CHESSMAN, R. D.: Experimental hyper-
tension. The effects of unilateral renal ischemia combined with
intestinal ischemia on the arterial blood pressure. J. Exper. Med.,
69: 833 (June) 1939.
BLATT, E., AND PAGE, I. H.: Hypertension and constriction of the renal
arteries in man: Report of a case. Ann. Int. Med., 12: 1690
(April) 1939.
BotrcKAERT, J. J., ELATJT, L., AND HEYMANS, C : Vasomotor carotid
sinus reflexes in experimental hypertension produced by renal
ischemia. J. Physiol, 89: 3p, 1937.
BOYD, C. H., AND LEWIS, L. G.: Nephrectomy for arterial hypertension.
J. Urol., 39: 627 (May) 1938.
BOYLSTON, G. A., M C E W E N , E. G., AND IVY, A. C.: A pressor substance
is not present in the perfusate of ischemic kidneys. Proc. Soc.
Exper. Biol. & Med., 39: 559 (Dec.) 1938.
BRIGHT, R.: Cases and observations illustrative of renal disease accompanied with the secretion of albuminous urine. Guy's Hosp.
Rep., 1: 338, 1836.
BRIGHT, R.: Tabular view of the morbid appearance in 100 cases connected with albuminous urine. Guy's Hosp. Rep., 1: 380, 1836.
BROTCHNER, R. J.: Hypertension from obstruction of the aorta. Proc.
Soc. Exper. Biol. & Med., 40: 264 (Feb.) 1939.
BROTCHNER, R. J.: Etiology of hypertension resulting from coarctation
of the aorta. Arch. Path., 28: 676 (Nov.) 1939.
BUTLER, A. M.: Chronic pyelonephritis and arterial hypertension.
J. Clin. Invest., 16: 889 (Nov.) 1937.
CASH, J. R., AND WOOD, J. E., J R . : Observations upon blood pressure
of dogs following changes in body weight. South. M. J., 31: 270
(March) 1938.
CHILD, C. G., AND GLENN, F . : Experimental hypertension in dogs by
constricting the artery of a single transplanted kidney. Proc. Soc.
Exper. Biol. & Med., 37: 217 (Oct.) 1937.
CHILD, C. G., AND GLENN, F . : Effect of passing renal blood through
liver in dogs with experimental hypertension. Arch. Surg., 36:
376 (March) 1938.
CHILD, C. G.: Observations on pathological changes following experi-
EXPERIMENTAL HYPERTENSION
63
mental hypertension produced by constriction of renal arteries.
J. Exper. Med., 67: 521 (April) 1938.
(20) CHILD, C. G.: The guanidine bases in the blood of dogs with experimental hypertension produced by constriction of the renal arteries.
J. Clin. Investigation, 17: 301 (May) 1938.
(21) COLLINS, D. A.: Hypertension from constriction of the arteries of denervated kidneys. Am. J. Physiol., 116: 616 (Aug.) 1936.
(22) COLLINS, D. A., AND HOPFBAUER, F. W.: Effect of transfusion of blood
from dogs with experimental renal hypertension into normal dogs.
Proc. Soc. Exper. Biol. & Med., 35: 539 (Jan.) 1937.
(23) COLLINS, D. A., AND WOOD, E. H.: Experimental renal hypertension
and adrenalectomy. Am. J. Physiol., 123: 224 (July) 1938.
(24) CORCORAN, A. C, AND PAGE, I. H.: Observations on the relation of
experimental hypertension to renal clearance and renal ischemia.
Am. J. Physiol., 123: 43 (July) 1938.
(25) CORCORAN, A. C, AND PAGE, I. H.: The effects of Renin, Pitressin and
Atropine on renal blood flow and clearance. Am. J. Physiol.,
126: 354 (June) 1939.
(26) CRESSMAN, R. D., AND BLALOCK, A.: Experimental Hypertension.
Effects of Kieselguhr Injection and of Splanchnic Stimulation. Proc.
Soc. Exper. Biol. & Med., 40: 258 (Feb.) 1939.
(27) DICKER, E.: Existence de substances hypertensives dans le sang du
chien pendant la compression permanente des arteres resales.
Compt. rend. Soc. de biol., 122: 476 (Apr.) 1936.
(28) DICKER, E.: Recherches sur la pathogenic de I'hypertension. II. Une
lesion resale peut determiner une eleVation de la pression sanguine.
Acta med. Scandinav., 93: 265, 1937.
(29) DICKER, E.: A propos de I'hypertension arterielle consecutive a une
entrave de la circulation r£nale. Compt. rend. Soc.de biol., 125:
1046 (May) 1937.
(30) DICKER, E.: Un rein en voie d'autolyse donne naissance a des produits
hypertenseurs. Compt. rend. Soc. de biol., 126: 88 (June) 1937.
(31) DICKER, E.: Resultats de l'anastomose de reins normaux au cou de
chiens hypertendus par compression de leurs arteres resales.
Compt. rend. Soc. de biol., 126: 912 (Oct.) 1937.
(32) DICKER, E.: Recherches experimentales concernant le m6canisme de
I'hypertension d'origine resale chez le chien. Arch. Internat. de
meU exper., 13: 27, 1938.
(33) DILL, L. V., AND ERICKSON, C. C : Eclampsia-like syndrome occurring
in pregnant dogs and rabbits following renal artery constriction.
Proc. Soc. Exper. Biol. & Med., 39: 362 (Nov.) 1938.
(34) DILL, L. V., ISENHOUR, C. E., AND CADDEN, J. F.: The effect of quantitative reduction of renal bloodflowupon the pregnant rabbit. J. Clin.
Investigation, 18: 641 (Nov.) 1939.
64
HABRY GOLDBLATT
(35) DEURT, D. R.: The production by a new method of renal insufficiency
and hypertension in the rabbit. J. Exper. Med., 68: 693 (Nov.)
1938.
(36) ELATJT, L.: Influence de Innervation resale sur 1'hypertension expdrimentale chronique chez le chien. Compt. rend. Soc. de biol.,
119: 318 (April) 1935.
(37) ELAUT, L.: Hypertension art^rielle chronique chez le chien par isch^mie
renale. Compt. rend. Soc. de biol., 122: 126 (March) 1936.
(38) ELAUT, L.: Observations concernant 1'hypertension chronique expeYimentale du chien par constriction de l'artere r6nale. Compt. rend.
Soc. de biol., 123: 1244 (Nov.) 1936.
(39) ENGEE, R.: Experimentelle Untersuchungen iiber die Pathogenese des
renalen Hochdrucks. Verhandl. d. deutsch. Gesellsch. f. inn.
Med., 50: 268, 1938.
(40) ENGEE, R., AND GEESTNER, H.: Der Einfluss der Niere auf den Blutdruck
nach ihrer volligen Losung aus dem Gewebszusammenhang des
Organismus. Ztschr. f.d. ges. exper. Med., 102: 413, 1938.
(41) ENGEE, R., LINDEB, F., AND SAREE, H.: Die Erzeugung eines renalen
(42)
(43)
(44)
(45)
Hochdruckes bei hypophysen—und bei nebennierenlosen Hunden.
Ztschr. f.d. ges. exper. Med., 104: 10 (Aug.) 1938.
FAHE, T H . : Pathologische Anatomie des Morbus Brightii. Handbuch
der speziellen pathologischen Anatomie und Histologie, V I / I Niere,
(156- 472).
FASCIOLO, J. C : Acci6n del rin6n sano sobre la hipertensi6n arterial
por isquemia renal. Rev. Soc. argent, de biol., 14: 15 (April) 1938.
FASCIOLO, J. C : Papel de las glandulas adrenales en la genesis de la
hipertension arterial por isquemia renal. Rev. Soc. argent, de
biol., 14: 25 (April) 1938.
FASCIOLO, J. C , AND CEAMEE, F. K.: Las lesiones oculares en la hipertensidn arterial por isquemia renal. Rev. Soc. argent, de biol.,
14: 393 (Sept.) 1938.
(46) FASCIOLO, J. C , HOUSSAY, B. A., AND TAQUINI, A. C.: The blood pressure
(47)
(48)
(49)
(50)
raising secretion of the ischaemic kidney. J. Physiol., 94: 281
(Dec.) 1938.
FISHBEEG, A. M.: Hypertension and Nephritis. Lea and Febiger,
Philadelphia, 4th ed., 1939.
FREEMAN, N . E., AND PAGE, I. H . : Hypertension produced by constriction of the renal artery in sympathectomized dogs. Surgery,
2: 487 (Sept.) 1937.
FREEMAN, N. E., AND PAGE, I. H.: Hypertension produced by constriction of the renal artery in sympathectomized dogs. Am. Heart J.,
14: 405 (Oct.) 1937.
FEEEMAN, G., AND HARTLEY, G.: Hypertension in a patient with a
solitary ischemic kidney. J. A. M. A., I l l : 1159 (Sept.) 1938.
EXPERIMENTAL
HYPERTENSION
65
(51) FRIEDMAN, B., ABRAMSON, P. I., MARX, W.: Pressor substance in the
cortex of the kidney. Am. J. Physiol., 124: 285 (Nov.) 1938.
(52) FRIEDMAN, B., AND PRINZMETAL, M.: Vasomotor effects of blood in
patients with hypertension and animals with experimental hypertension. Ann. Int. Med., 12: 1617 (April) 1939.
(53) FRIEDMAN, M., AND KATZ, L. N.: Renal insufficiency following Trypsin
injection into the renal arteries. J. Exper. Med., 68: 485 (Oct.)
1938.
(54) GEER, W. A., AND DRAGSTEDT, L. R.: Studies on renal hypertension:
The effect of deviating urine into the blood stream and intestines
of dogs. Ann. Surg., 108: 263 (Aug.) 1938.
(55) GIBSON, J. G., AND ROBINSON, R. W.: Blood volume, cardiac size and
renal function in dogs with hypertension produced by Goldblatt
technic. Proc. Soc. Exper. Biol. & Med., 39: 497 (Dec.) 1938.
(56) GLENN, F., CHILD, C. G., AND HEUER, G. J.: Production of hypertension
by constricting the artery of a single transplanted kidney. Ann.
Surg., 106: 848 (Nov.) 1937.
(57) GLENN, F., CHILD, C. G., AND HEUER, G. J.: Hypertension experi-
mentally produced by constricting artery of single transplanted
kidney; additional observations. Ann. Surg., 107: 618 (April)
1938.
(58) GLENN, F., AND LASHER, E. P . : Effect of total thyroidectomy upon
production and maintenance of experimental hypertension. Proc.
Soc. Exper. Biol. & Med., 38: 158 (Feb.) 1938.
(59) GLENN, F., AND CHILD, C. G.: Lumbar approach to renal artery for
application of Goldblatt clamp. Arch. Surg., 36: 373 (March)
1938.
(60) GLENN, F., CHILD, C. G., AND PAGE, I. H.: Effect of destruction of
spinal cord on hypertension artificially produced in dogs. Am. J.
Physiol., 122: 506 (May) 1938.
(61) GLENN, F., AND LASHER, E . P.: The effect of destruction of the spinal
cord on the artificial production of hypertension in dogs. Am. J.
Physiol., 124: 106 (Oct.) 1938.
(62) GOLDBLATT, H., LYNCH, J., HANZAL, R. F., AND SUMMERVILLE, W. W.:
Studies on experimental hypertension. I. The production of persistent elevation of systolic blood pressure by means of renal ischemia.
J. Exper. Med., 59: 347 (March) 1934.
(63) GOLDBLATT, H., GROSS, J., AND HANZAL, R. F . : Studies on experimental
hypertension. I I . The effect of resection of splanchnic nerves on
experimental renal hypertension. J. Exper. Med., 65: 233 (Feb.)
1937.
(64) GOLDBLATT, H.: Studies on experimental hypertension. I I I . The
production of persistent hypertension in monkeys (Macaque) by
renal ischemia. J. Exper. Med., 65: 671 (May) 1937.
66
HARRY GOLDBLATT
(65) GOLDBLATT, H.: Studies on experimental hypertension. V. The pathogenesis of experimental hypertension due to renal ischemia. Ann.
Int. Med., 11: 69 (July) 1937.
(66) GOLDBLATT, H., AND WARTMAN, W. B.: Studies on hypertension.
(67)
(68)
(69)
(70)
VI.
The effect of section of anterior spinal nerve roots on experimental
hypertension due to renal ischemia. J. Exper. Med., 66: 527 (Nov.)
1937.
GOLDBLATT, H.: Experimental hypertension induced by renal ischemia.
The Harvey Lectures, 1937-38, pages 237-275. Reprinted in Bull.
New York Acad. Med., 14: 523 (Sept.) 1938.
GOLDBLATT, H., AND KAHN, J. R.: Experimental hypertension: Constriction of the aorta at various levels. J. A. M. A., 110: 686 (Feb.)
1938.
GOLDBLATT, H.: Studies on experimental hypertension. VII. The
production of the malignant phase of hypertension. J. Exper.
Med., 67: 809 (May) 1938.
GOLDBLATT, H.: Experimental observations on the surgical treatment
of hypertension. Surgery, 4: 483 (Oct.) 1938.
(71) GOLDBLATT, H., KAHN, J. R., AND HANZAL, R. F . : Studies on experi-
(72)
(73)
(74)
(75)
(76)
(77)
(78)
mental hypertension. IX. The effect on blood pressure of constriction of the abdominal aorta above and below the site of origin of
both main renal arteries. J. Exper. Med., 69: 649 (May) 1939.
GOLDBLATT, H.: Experimental observations on the pathogenesis of
essential hypertension. Tr. & Stud., Coll. Physicians, Philadelphia,
6: 5 (June) 1938.
GOORMAGHTIGH, N., AND GRIMSON, K. S.: Vascular changes in renal
ischemia. Cell mitosis in the media of arteries. Proc. Soc. Exper.
Biol. & Med., 42: 227 (Oct.) 1939.
GOVAERTS, P., AND DICKER, E.: Mise en Evidence de propriety hypertensives dans le liquide cdphalo-rachidien et dans le sang de
n6phr6tiques hypertendus. Bull. Acad. roy. de m6d. de Belgique
1: 141, 1936.
GOVAERTS, P., AND DICKER, E.: Les substances vasopressives pr^sentes
dans le se>um des n6phr6tiques hypertendus existent-elles dans le
serum des sujets normaux? Compt. rend. Soc. de biol., 122: 807
(May) 1936.
GOVAERTS, P., AND DICKER, E.: Production intrar^nale de substances
hypertensives par ligature ou pincement de l'artere resale. Compt.
rend. Soc. de biol., 122: 809 (May) 1936.
GOVAERTS, P . : Note rectificative a propos de publications anteiieures
concernant la mise en Evidence de propri^tds hypertensives dans le
liquide cdphalo-rachidien et le sang des n£phr6tiques hypertendus.
Bull. Acad. roy. de m<5d. de Belgique., 2: 34 (Jan.) 1937.
GRIMSON, K. S.: Restoration of blood pressure and peripheral resistance
EXPERIMENTAL
HYPERTENSION
67
in sympathectomized dogs. Proc. Soc. Exper. Biol. & Med., 34:
235 (March) 1936.
(79) GRIMSON, K. S.: The onset of renal ischemia hypertension induced by
readily adjustable renal artery clamps. J. Physiol., 95: 45 p.
(March) 1939.
(80) GROSSMAN, E. B.: Preparation of extracts of the renal pressor substance.
Proc. Soc. Exper. Biol. & Med., 39: 40 (Oct.) 1938.
(81) GROSSMAN, E. B., AND WILLIAMS, J. R.: Relation of age to renal pressor
substance. Arch. Int. Med., 62: 799 (Nov.) 1938.
(82) HARRISON, T. R., BLALOCK, A., AND MASON, M. F . : Effects on blood
pressure of injections of kidney extracts of dogs with renal hypertension. Proc. Soc. Exper. Biol. & Med., 35: 38 (Oct.) 1936.
(83) HARRISON, T. R., MASON, M. F., RESNIK, H., AND RAINEY, J.: Changes
in blood pressure in relation to experimental renal insufficiency.
Tr. A. Am. Physicians, 51: 280, 1936.
(84) HARRISON, T. R., BLALOCK, A., MASON, M. F., AND WILLIAMS, J. R.:
Relation of kidneys to blood pressure: Effects of extracts of kidneys
of normal dogs and of dogs with renal hypertension on blood pressure
of rats. Arch. Int. Med., 60: 1058 (Dec.) 1937.
(85) HELMER, O. M., AND PAGE, I. H.: Guanidine-like substances in the
blood of normal and hypertensive dogs. Proc. Soc. Exper. Biol. &
Med., 37: 680 (Jan.) 1938.
(86) HELMEH, O. M., KOHLSTAEDT, K. G., AND PAGE, I. H.: The isolation
of nicotine from human urine. Am. Heart J., 17: 15 (Jan.) 1939.
(87) HELMER, O. M., AND PAGE, I. H.: Purification and some properties of
Renin. J. Biol. Chem., 127: 757 (March) 1939.
(88) HESSEL, G.: Uber das Renin. Ein experimenteller Beitrag zur Pathogenese des renalen Hochdrucks. Arch. f. exper. Path. u. Pharmakol., 190: 180, 1938.
(89) HESSEL, G.: Uber Renin. Klin. Wchnschr., 17: 843 (June) 1938.
(90) HESSEL, G.: Aussprache. Verhandl. d. deutsch. Gesellsch. f. inn.
Med., 50: 272, 1938.
(91) H E Y M A N S , C , B O U C K A E R T , J. J., E L A U T , L., BAYLESS, F., A N D S A M A A N ,
A.: Hypertension art&ielle chronique par isch^mie resale chez
le chien totalement sympathectomise\ Compt. rend. Soc. de biol.,
126: 434 (Sept.) 1937.
(92) HEYMANS, C., AND BOUCKAERT, J. J.: Vasoconstrictor properties in
blood of hypertensive dogs. Proc. Soc. Exper., Biol. & Med.
39: 94 (Oct.) 1938.
(93) HOLMAN, D. V., AND PAGE, I. H.: The cardiac output in arterial hypertension. I I . A study of arterial hypertension produced by constricting the renal arteries in unanesthetized and anesthetized
(pentobarbital) dogs. Am. Heart J., 16: 321 (Sept.) 1938.
(94) HOIJSSAY, B. A., AND FASCIOLO, J. C : Demostracion del mecanismo
68
HARRY GOLDBLATT
humoral de la hipertensi6n nefrogena. Bol. Acad, nac de med. de
Buenos Aires, 34: 342 (Sept.) 1937.
(95) HotrssAY, B. A., AND FASCIOLO, J. C.: Secrecion hipertensora del rinon
isquemiado. Rev. Soc. argent, de biol., 13: 284 (Oct.) 1937.
(96) HOUSSAY, B. A., AND TAQUINI, A. C : Accion vasoconstrictora de la
sangre venosa del rinon isquemiado. Rev. Soc. argent, de biol.,
14: 5 (April) 1938.
(97) HOUSSAY, B. A., AND TAQUINI, A. C : Especificidad de la accion vasoconstrictora de la sangre venosa del rinon isquemiado. Rev. Soc.
argent, de biol., 14: 86 (May) 1938.
(98) HOUSSAY, B. A., AND FASCIOLO, J. C : S6cr6tion hypertensive du rein
isch&nie. Compt. rend. Soc. de biol. (Paris), 127: 147 (Oct.) 1938.
(99) KAESNEE, H. T.: Recent advances in the study of hypertension. Internal Clin., 2: series 48 (June) 1938.
(100) KATZ, L. N., MENDLOWITZ, M., AND FRIEDMAN, M.: A study of factors
concerned in renal hypertension.
37: 722 (Jan.) 1938.
Proc. Soc. Exper. Biol. & Med.,
(101) KATZ, L. N., FRIEDMAN, M., RODBARD, S., AND WEINSTEIN, W.: Obser-
vations on the genesis of renal hypertension.
334 (March) 1939.
Am. Heart J., 17:
(102) KEYES, J. E. L., AND GOLDBLATT, H.: Experimental hypertension.
IV.
Clinical and pathologic studies of the eyes: a preliminary report.
Arch. Ophth., 17: 1040 (June) 1937.
(103) KEYES, J. E. L., AND GOLDBLATT, H.: Experimental hypertension.
VIII. Vascular changes in the eyes. Arch. Ophth., 20: 812 (Nov.)
1938.
(104) KOHLSTAEDT, K. G., HELMER, O. M., AND PAGE, I. H . : Activation of
renin by blood colloids. Proc. Soc. Exper. Biol. & Med., 39: 214
(Oct.) 1938.
(105) KYLIN, E.: Uber Hypertonie und Nierenkrankheit. Zentralbl. f. inn.
Med., 42: 441 (June) 1921.
(106) KYLIN, E.: On the etiology of essential hypertension. Acta med.
Scandinav., Supp. 16: 282, 1925.
(107) LANDIS, E. M., MONTGOMERY, H., AND SPARKMAN, D.: Effects of pressor
drugs and of saline kidney extracts on blood pressure and skin
temperature. J. Clin. Investigation, 17: 189 (March) 1938
(108) LASHER, E. P., JR., AND GLENN, F . : Effects on kidney and blood pressure
of artificial communication between renal artery and vein. Arch.
Surg., 38: 886 (May) 1939.
(109) LEADBETTER, W. F., AND BURKLAND, C. F . : Hypertension in unilateral
renal disease. J. Urol., 39: 611 (May) 1938.
(110) LEITER, L.: The non-specific r61e of pressor substances in the plasma of
hypertensive patients. Arch. Int. Med., 57: 729 (April) 1936.
(111) LEITER, L.: Unusual hypertensive renal disease. (1) Occlusion of renal
EXPERIMENTAL HYPERTENSION
arteries. (2) Anomalies of urinary tract.
(Aug.) 1938.
69
J. A. M. A., I l l : 507
(112) LEVY, S. E., LIGHT, R. A., AND BLALOCK, A.: The blood flow and oxygen
consumption of the kidney in experimental renal hypertension.
Am. J. Physiol, 122: 38 (April) 1938.
(113) LEVY, S. E., AND BLALOCK, A.: Experimental attempts to prevent or
abolish the hypertension that is associated with renal ischemia.
Surgery, 3 : 899 (June) 1938.
(114) LEVY, S. E., ROBINSON, C. S., AND BLALOCK, A.: The effect of altering
the renal blood pressure and blood flow on the glomerular filtration
of a transplanted kidney in unanesthetized dogs. Am. J. Physiol.,
123: 383 (Aug.) 1938.
(115) MANSFIELD, J. S., W E E K S , D. M., STEINER, A., AND VICTOR, J.: Reduc-
tion of experimental renal hypertension of pexis of spleen or omentum to the kidney. Proc. Soc. Exper. Biol. & Med., 40: 708 (April)
1939.
(116) MASON, M. F., AND BLALOCK, A.: Renal oxygen utilization of dogs with
experimental hypertension. Proc. Soc. Exper. Biol. & Med., 36:
819 (June) 1937.
(117) MASON, M. F., AND ROZZELL, J. D . : Attempts to demonstrate vasopressor properties in the serum of hypertensive dogs. Proc. Soc.
Exper. Biol. & Med., 42: 142 (Oct.) 1939.
(118) M C E W E N , E. G., HARRISON, S. P., AND IVY, A. C : Tachyphylaxis to
Renin. Proc. Soc. Exper. Biol. & Med., 42: 254 (Oct.) 1939.
(119) MCINTYRE, D. W.: Unilateral chronic pyelonephritis with arterial
hypertension. Apparent cure after nephrectomy. J. Urol., 4 1 :
900 (June) 1939.
(120) MERRILL, A., WILLIAMS, J. R., AND HARRISON, T. R.: The site of action
of the renal pressor substance.
Am. J. M. S c , 196: 18 (July) 1938.
(121) MERRILL, A., WILLIAMS, R. H., AND HARRISON, T . R.: The effects of a
(122)
(123)
(124)
(125)
(126)
pressor substance obtained from the kidneys on the renal circulation of rats and dogs. Am. J. M. S c , 196: 240 (Aug.) 1938.
MORITZ, A. R., AND OLDT, M. R.: Arteriolar sclerosis in hypertensive
and non-hypertensive individuals. Am. J. Path., 13: 679 (Sept.)
1937.
PAGE, I. H.: Relationship of extrinsic renal nerves to origin of experimental hypertension. Am. J. Physiol., 112: 166 (May) 1935.
PAGE, I. H., AND SWEET, J. E.: Extirpation of pituitary gland; effect on
arterial blood pressure of dogs with experimental hypertension.
Proc. Soc. Exper. Biol. & Med., 34: 260 (March) 1936.
PAGE, I. H.: Vasopressor action of extracts of plasma of normal dogs and
dogs with experimentally produced hypertension. Proc. Soc. Exper.
Biol. & Med., 36:112 (Oct.) 1936.
PAGE, I. H., AND SWEET, J. E.: Effect of hypophysectomy on arterial
70
(127)
(128)
(129)
(130)
(131)
(132)
HAKKY GOLDBLATT
blood pressure of dogs with experimental hypertension. Am. J.
Physiol., 120: 238 (Oct.) 1937.
PAGE, I. EL: Nature of hypertension. Bull. New York Acad. Med.,
13: 645 (Nov.) 1937.
PAGE, I. H.: The effect of bilateral adrenalectomy on arterial blood
pressure of dogs with experimental hypertension. Am. J. Physiol.,
122: 352 (May) 1938.
PAGE, I. H.: A method for producing persistent hypertension by cellophane. Science, 89: 273 (March) 1939.
PAGE, I. H . : On the nature of the pressor action of renin. J. Exper.
Med., 70: 521 (Nov.) 1939.
PEDERSEN, A. H.: A method of producing experimental chronic hypertension in the rabbit. Arch. Path., 3: 912 (May) 1927.
PICKERING, G. W., AND PRINZMETAL, M.: Some observations on renin,
a pressor substance contained in normal kidney, together with a
method for its biological assay. Clin. S c , 3: 211 (April) 1938.
(133) PICKERING, G. W., AND PRINZMETAL, M.: Experimental hypertension
of renal origin in the rabbit.
Clin. S c , 3: 357 (Dec.) 1938.
(134) PRINZMETAL, M., FRIEDMAN, B., AND ROSENTHAL, N . : Nature of periph-
eral resistance in arterial hypertension. Proc. Soc. Exper. Biol.
& Med., 34: 545 (May) 1936.
(135) PRINZMETAL, M., AND FRIEDMAN, B.: Pressor effects of kidney extracts
from patients and dogs with hypertension. Proc. Soc. Exper.
Biol. & Med., 35: 122 (Oct.) 1936.
(136) PRINZMETAL, M., FRIEDMAN, B., AND OPPENHEIMER, E. T.: Failure to
demonstrate pressor properties in extracts of blood from hypertensives. Proc. Soc. Exper. Biol. & Med., 38: 493 (May) 1938.
(137) PRINZMETAL, M., FRIEDMAN, B., AND ABRAMSON, D . I.: The nature of
arterial hypertension with special reference to the r61e of the kidney.
Ann. Int. Med., 12: 1604 (April) 1939.
(138) ROGOFF, J. M., MARCUS, E., AND WASSERMAN, P . : Experiments on the
supposed relation of epinephrine secretion to hypertension.
Soc. Exper. Biol. & Med., 38: 199 (March) 1938.
Proc.
(139) ROGOFF, J. M., NIXON, E. N., AND STEWART, G E O . N . : The adrenals in
(140)
(141)
(142)
(143)
experimental hypertension. Proc. Soc. Exper. Biol. & Med.,
4: 57 (May) 1939.
RTTAND, D. A.: Pathogenesis of arterial hypertension in coarctation of
the aorta. Proc. Soc. Exper. Biol. & Med., 38: 10 (Feb.) 1938.
RYTAND, D. A.: The renal factor in arterial hypertension with coarctation of the aorta. J. Clin. Investigation, 17: 391 (July) 1938.
SCOTT, R. W.: Hypertension a century after Bright. J. A. M. A.,
I l l : 2460 (Dec.) 1938.
SHAPIRO, S.: Report of a case of essential hypertension of more than
EXPERIMENTAL HYPERTENSION
71
twenty-five year's duration showing no renal arteriolar changes at
autopsy. J. Lab. & Clin. Med., 24: 60 (Oct.) 1938.
(144) SMITH, H. W., GOLDRING, W., CHASIS, H., AND RANGES, H. A.: Observa-
tions on the effective renal blood flow and functional excretory mass
in man, with special reference to essential hypertension. Am. J.
Physiol., 123: 189 (July) 1938.
(145) SWINGLE, W. W., TAYLOR, A. R., COLLINGS, W. D., AND HAYS, H. W.:
(146)
(147)
(148)
(149)
(150)
Preparation and bio-assay of Renin. Am. J. Physiol., 127: 768
(Nov.) 1939.
TAQUINI, A. C.: Liberacion de substancia hipertensora en el rinon completamente isquemiado. Rev. Soc. argent, de biol., 14: 422 (Oct.)
1938.
TAQUINI, A. C : Produccion de substancia vasoconstrictora renal en
diversas circumstancias. Rev. Soc. argent, de biol., 14: 456 (Nov.)
1938.
TIEGERSTEDT, R., AND BERGMANN, P. G.: Niere und Kreislauf. Skandinav. Arch. f. Physiol., 8: 223, 1898.
VERNEY, E. B., AND VOGT, M.: An experimental investigation into hypertension of renal origin with some observations on convulsive
"uraemia." Quart. J. Exper. Physiol., 28: 253 (Nov.) 1938.
VOGT, H.: Untersuchungen uber vasopressorische Stoffe bei der essentiellen Hypertonic und beim Kaolinhochdruck des Hundes. Klin.
Wchnschr., 17: 1148 (Aug.) 1938.
(151) VOLHARD, F., AND FAHR, T H . : Die Brightscht Nierenkrankheit.
(152)
(153)
(154)
(155)
(156)
J.
Springer, Berlin, 1914.
VOLHARD, F . : Die doppelseitige Nierenerkrankungen. Handbuch der
inn. Medizin, J. Springer, Berlin, Zweite Auflage, 1931.
VOLHARD, F . : Blutdruck und Niere. Uit Vlaamsch Geneeskundig
Tijdschrift, 25: 1, 1936.
VOLHARD, F . : Personal communication. 1939.
WAKERLIN, GEO. E., AND CHOBOT, GEO. R.: Does renin play a rdle in
the maintenance of normal blood pressure? Proc. Soc. Exper. Biol.
& Med., 40: 331 (March) 1939.
WAKERLIN, G. E., AND YANOWITZ, M . : Effect of normal and renal hypertensive dog plasmas on surviving arterial rings. Proc. Soc.
Exper. Biol. & Med., 41: 51 (May) 1939.
(157) WILLIAMS, J. R., HARRISON, T. R., AND MASON, M. F . : Observations
on two different pressor substances obtained from extracts of renal
tissues. Am. J. M. S c , 195: 339 (March) 1938.
(158) WILLIAMS, J. R., J R . , AND GROSSMAN, E. B . : The recovery of an adren-
alin-like substance from the kidney.
(Aug.) 1938.
Am. J. Physiol., 123: 364
(159) WILLIAMS, J. R., WEGRIA, R., AND HARRISON, T. R.: Relation of renal
72
HARRY
GOLDBLATT
pressor substance to hypertension of hydronephrotic rats.
Int. Med., 62: 805 (Nov.) 1938.
Arch.
(160) WILLIAMS, J. R., DIAZ, J. T., BURCH, J. C , AND HARRISON, T. R.:
The relation of the adrenal glands to the action of the renal pressor
substance. Am. J. M. S c , 198: 212 (Aug.) 1939.
(161) WILSON, C , AND PICKERING, G. W.: Acute arterial lesions in rabbits with
experimental renal hypertension. Clin. Sc., 3 : 343 (Aug.) 1938.
(162) WILSON, C , AND BYROM, F . B.: Renal changes in malignant hyperten-
sion.
Lancet, 1 (No. 3): 136, (Jan.) 1939.
(163) WOOD, J. E., AND CASH, J. R.: Experimental hypertension—observations
on sustained elevation of systolic and diastolic blood pressure in
dogs. J. Clin. Investigation, 16: 543 (Sept.) 1936.