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Vasopressor role of ADH in the pathogenesis

of malignant DOC hypertension

JAN MijHRING, BARBEL MijHRING, MARIA PETRI, AND DORIS HAACK


Department of Pharmacology, University of Heidelberg, Heidelberg, Germany

M~HRING, JAN, BARBEL M~HRING, MARIA PETRI, AND the sympathetic nervous system or vasopressin, or both.
DORIS HAACK. Vasopressor role of ADH in the pathogenesis of Although no direct evidence has been presented so far
malignant DOC hypertension. Am. J. Physiol. 232(3): F260- to support the notion that endogenous vasopressin could
F269, 1977 or Am. J. Physiol.: Renal Fluid Electrolyte Physiol. act as a vasopressor hormone, Szczepanska-Sadowska
l(3): F260-F269, 1977. - During the onset of malignant hyper- (38) and Cowl ey et al. (8) have recently presented indi-
tension (MH) in rats treated with deoxycorticosterone trimeth- rect evidence that vasopressin-induced vasoconstriction
ylacetate (DOC), pi asma argini ne vasopressin (AVP) con-
might play an important role even in normal blood
centrations increase tenfold as a consequence of hypovolemia
and hyperosmolality. In benign hypertensive (BH) rats, pressure regulation. We did consider such a possibility
plasma AVP is increased threefold in comparison with control for the pathophysiological situation of malignant DOC
animals. Plasma renin is markedly suppressed in both BH and hypertension in rats. Here hypovolemia (14) and hy-
MH animals. In MH rats, biologically active AVP antiserum perosmolality (observation from an unpublished study)
lowers blood pressure (BP) transiently to normal or subnormal develop, both of which are the physiological stimuli for
levels; in BH rats, a small BP-lowering effect of the AVP vasopressin release (11). It has been repeatedly demon-
antiserum is seen. (Biologically active angiotensin II antise- strated since the early work of Byrom (ref. 4, p. 57-58)
rum does not lower BP in MH rats.) The relationship between that pharmacological doses of vasopressin might rapidly
the height of BP and plasma AVP concentration in DOC induce vascular damage (22, 25).
hypertensive rats indicates, when compared with that rela-
tionship in diabetes insipidus rats infused with AVP, a
marked enhancement of the vasopressor effect of AVP. These MATERIALS AND METHODS
findings and the earlier observation of vasopressin-induced
vascular damage by Byrom (F. B. Byrom, The Hypertensive General experimental protocol. Male Wistar rats (WU
Vascular Crisis. London: Heinemann, 1969) strongly suggest strain, Ivanovas) weighing 200-230 g were placed in
that ADH is involved as a vasopressor hormone in the patho- individual cages in a room with constant temperature
genesis of malignant DOC hypertension. (23 t 1°C) and humidity (60 t 5%) that was lighted
automatically from 6 A.M. to 6 P.M. The animals were
sodium; potassium; renin; renal failure; stroke fed a commercial diet (ssniff) containing 100 meq so-
dium/kg and 210 meq potassium/kg. Fresh demineral-
ized water was given every 2 days. After 5-7 days the
COULD VASOPRESSIN, i.e., the antidiuretic hormone rats were submitted to unilateral nephrectomy and
(ADH), play a role in the pathogenesis of malignant were subsequently offered, instead of water, 1% NaCl as
DOC hypertension similar to that ascribed to the renin- drinking fluid. Deoxycorticosterone trimethylacetate
angiotensin system in the pathogenesis of malignant (DOC) was injected subcutaneously at a weekly dosage
renal hypertension? Answering this question has been of 12.5 mg to one group of animals (n, 76), while the
the aim of the studies to be presented. other rats (n, 24) were injected with 0.5 ml of 0.9%
In both malignant renal and malignant deoxycorti- NaCl, the vehicle only. Systolic blood pressure (BP) was
costerone (DOC) hypertension the organism becomes recorded once or twice a week by ta il plethysmography
volume depleted (3, 14, 30). In spite of decreasing blood under light ether anesthesia. Body weight, saline and
volume, blood pressure remains high, indicating that food intake were measured every 2nd or 3rd day at 10
vasopressor systems are activated. It has been predicted A.M., and when the experiment progressed daily meas-
by systems analysis that in malignant hypertension urements were done.
volume depletion will activate vasopressor systems to Experiment I. When, during the 4th-7th wk after the
an extent that blood pressure will remain high (16). In start of DOC treatment, signs of malignant hyperten-
malignant renal hypertension increasing plasma renin sion (MH) had become apparent in some of the rats for
and angiotensin concentrations induce progressive vas- at least 3 days, i.e., systolic BP values of 170-190 mmHg
oconstriction, whereby high blood pressure levels are or above and weight loss (for details, see RESULTS), these
maintained (3, 9, 30). However, in malignant DOC hy- animals, as well as rats that did not exhibit such signs,
pertension the activity of the renin-angiotensin system i.e., benign hypertensive (BH) rats, and the control
remains markedly suppressed (14). Therefore, in this animals were decapitated at 9 A.M. (blood sampling was
latter situation vasoconstrictors other than the renin- performed in 38 hypertensive and in 1.2 control animals).
angiotensin system should become activated, such as Blood was collected in hepari .nized gl.ass capil laries and
F260
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VASOPRESSIN IN MALIGNANT DOC HYPERTENSION F261

in heparinized plastic tubes. The collected blood was tubes within 3-5 min. In the plasma samples AVP con-
centrifuged, and the hematocrits and plasma sodium centrations were determined. 4) To two DI rats prepared
and urea concentrations were determined; osmolalities as described above, 5-isoleucine-angiotensin II was in-
were measured by freezing-point depression (Knauer fused at a rate of 0.45 and 0.6 pg/h (2.0 and 2.7 r_Lg/kg
osmometer). Arginine vasopressin concentrations were per h), which increased BP by 35 and 45 mmHg. When
estimated in 2 ml of plasma by a recently developed the BF had stabilized, 0.2 ml of an angiotensin II antise-
radioimmunoassay (26). After blood collection, the kid- rum was injected. After the BP had returned to the
neys were excised, fixed in 10% Formalin, and thin preinjection level for 15 min, 0.2 ml of the AVP antise-
paraffin sections were stained with periodic acid-Schiff rum Erwin was given.
and examined. Experiment ZZZb. In 15 rats exhibiting malignant
Experiment ZZ. Seven control, seven BH, and seven DOC hypertension, in 9 rats with benign DOC hyper-
MH rats were submitted to the same protocol as in tension, and in 5 control rats one PE-10 catheter was
experiment I, except that blood sampling was performed placed in the femoral artery and another catheter in the
in a different way: the animals were anesthetized with femoral vein. Two or three hours after surgery, the
ether and 1 ml of blood was taken from the cut tail for arterial catheter was connected to a Statham trans-
the measurement of hematocrit and plasma renin con- ducer; 20 min later the experiment was started by inject-
centration (33). Then a catheter was placed in the jugu- ing the various rabbit serums. Of the AVP antiserum
lar vein for further blood sampling, and plasma sodium Erwin, 0.2 ml were injected into six MH rats, and 0.4 ml
and potassium concentrations were determined. into five other MH animals. Two BH rats were given 0.2
Experiment ZIIa. In order to assess a possible vasocon- ml of the antiserum Erwin, and seven BH rats as well as
strictor effect of plasma arginine vasopressin (AVP) in five control animals were injected with 0.4 ml of this
rats with benign and malignant DOC hypertension, AVP antiserum. Four of the MH rats and two of the
rabbit serums containing specific AVP antibodies were control rats were given 0.4 ml angiotensin II antiserum
used. Prior to such studies, the biological activity of either before or after the injection of the AVP antise-
these antiserums [antiserum “Erwin,” “Kaspar,” and rum. In addition, 0.4 ml of an angiotensin I antiserum
“Oskar” according to the names of the immunized rab- (titer l/1,000) was injected into two MH rats. Finally,
bits (26)] were evaluated. The biochemical characteris- 0.4 ml serum of a normal rabbit was given to three of the
tics of AVP antibody Erwin were as follows: titer, l/ MH rats, to four of the BH rats, and to three of the
6,000; KtI = 0.9 x 10” l/mol; cross reactivity with lysine control animals. Angiotensin I and II antiserums as
vasopressin lOO%, with oxytocin < O.Ol%, with arginine well as the control serum were injected either before or
vasotocin < O.Ol%, with angiotensin I < O.OOOl%, and after the injection of the AVP antiserum. To two of the
with angiotensin II < 0.0001%. The antiserum Kaspar four remaining MH rats 0.4 ml of the AVP antiserums
had a titer of l/3,750 and the Kcl equaled 1.3 x 10” l/mol; Kaspar and Oskar was given.
the respective values for AVP antiserum Oskar were l/ At the end of these studies, the animals were anesthe-
9000 and Ku = 0.7 x 10” l/mol. The angiotensin II tized with ether, the kidneys were excised and fixed in
antiserum had a titer of l/160,000, and the Ku equaled 1 10% Formalin for histological examination.
x 10" l/mol. Rats with hereditary hypothalamic diabe- Statistics. All values in the text and figures are
tes insipidus (DI) (39) were nephrectomized under ether means t SE. The significance of difference between
anesthesia, and one PE-10 catheter was placed in the mean values was evaluated by the Student t test.
left femoral artery while two other PE-10 catheters were Regression equations and . correla tion coeffi cien .ts were
inserted into the left femoral vein. The catheters calculated by the method of least squares.
emerged at. the neck. Three to four hours after surgery
the arterial catheter was connected to a Statham trans-
RESULTS
ducer (P23Db), and the BP was recorded continuously in
the conscious animal which could move freely in its cage In all rats treated with DOC blood pressure increased
and did so. Then the following experiments were per- progressively. In most of those rats in which systolic BP
formed: reached a level of 170-190 mmHg during the 4th-7th
1) To two DI rats, which received no further treat- experimental wk weight started to decline and the gen-
ment, 0.4 ml of the AVP antiserum Erwin was injected. era1 condition deteriorated in most of these rats. In the
2) To four DI rats an infusion of arginine vasopressin other hypertensive animals body weight continuously
(kindly supplied by Dr. Eva Sedlakova, Academy of increased, as in untreated control rats. In 34 of the 41
Science, Prague) was infused at a rate of 37.5 or 60 rig/h hypertensive rats that exhibited weight loss [ which re-
(about 150-260 rig/kg per h), which increased the BP by fleets sodium and water depletion accordi .w to the bal-
25-50 mmHg. When the BP had stabilized for at least 15 ante studies of Gavras et al. (14) 9 signs of malignant
min, 0.2 ml of antiserum Erwin was slowly injected. nephrosclerosis were found, such as arteriolosclerosis,
Twenty to 30 min later, 0.4 ml serum of a normal rabbit fibrinoid insudation of the vascular wall, and fibrinoid
was injected. To two other DI rats, each infused with necrosis. However, the degree of histological alterations
AVP, 0.4 ml of antiserum Kaspar or 0.4 ml of antiserum varied remarkably, being moderate in some of these
Oskar was injected. 3) To seven DI rats, AVP was animals. Furthermore, during the daily handling period
infused at a similar rate as described above. When the it was observed that in most of the weight-losing rats
BP had stabilized for at least 30 min, 4 ml of blood were the eyes became remarkably pale. Eighteen of the 41
collected from the arterial catheter into heparinized weight-losing rats showed signs of a cerebral vascular

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F262 MGHRING, MGHRING, PETRI, AND HAACK

crisis, such as twitching movements, uncoord inated mo- weight increased steadily, and saline and food intake
tor activity, convulsions, etc. [described in detail bY showed minor fluctuations. In the other animal (rat 12),
Byrom (4)]; four other rats died during the dark period. BP increased to higher levels, and when it had reached
All these observations demonstrated that in the weight- a range of NO-190 mmHg, daily weight gain stopped
losing animals the course of high blood pressure had and then started to fall. During the first 3 days of weight
become malignant. Therefore, these animals are called loss, food intake remained constant, but subsequently
mali gnant hypertensive rats, while the other hyperten- also declined. Such a reduction of food intake by at least
sive animals are referred to as benign hypertensive 3 g had been observed in 8 of the 15 MH rats included in
rats. Fig. 1. When weight started to decline, saline intake
In five hypertensive rats, in which BP was as high as slightly decreased in 12 of the 15 MH rats by 10 to 25 ml
in MH rats, but in which body weight did not fall for 2-10 days. At day 33 of the experiment shown in Fig.
continuously during the days prior to blood sampling, 2, the MH animal started to recover. Daily weight gain
arteriolosclerosis in the kidney was pronounced, but no and food intake normalized,and saline intake increased
fibrinoid insudations or fibrinoid necrosis could be de- remarkably (such an increase was seen in four of the six
tected after repeated examination. Since these animals MH rats in which a similar recovery occurred within the
seem to represent a group of “borderline cases” with period of observation). During the last 2 experimental
respect to malignant hypertension, they will be de- days, rat 12 (Fig. 2) started to lose weight again, i.e., a
scribed separately at the end of this section. In addition, second malignant phase became apparent. Food intake
the data of four rats, in which at the day prior to blood again showed a tendency to decline, but now saline
collection BP was rather low in comparison with the intake remained increased (this was seen in four of the
other MH rats, and which exhibited most severe signs of six MH rats exhibiting a second malignant phase).
malignant hypertension, will also be summarized sepa- As can be seen in Fig. 3, the plasma arginine vaso-
rately . pressin concentrations of the MH rats were increased
Expe riment 1. One or two days before the end of the tenfold in comparison with the control animals. The
studies, systolic BP levels of the MH rats were higher plasma AVP concentrations of MH rats decapitated dur-
(range, 170-200 mmHg) than in the BH animals (range, ing a second malignant phase (six rats) fell into the
130-165 mmHg), as may be seen from the data presented range of those values obtained from MH rats during the
in Fig. 1. Body weight fell in the MH rats, while in the first malignant phase (nine rats). In the BH animals,
BH animals daily weight gain was almost similar to plasma AVP concentrations were increased threefold
that of the controls. Saline intake was significantly (Fig. 3).
increased in the BH animals when compared with con- Osmolality was moderately elevated in the BH ani-
trol rats (Fig. l), while food intake was similar. In the mals as compared with the control rats (P < 0.05). In
MH rats, saline intake was further increased during the the MH rats it increased further (Fig. 3; P < 0.01).
last 3 days prior to blood collection and food intake was Plasma sodium concentrations were 139.9 t 0.7 meq/
reduced (Fig. 1). liter in controls, 141.8 t 0.7 meq/liter in BH rats (P <
In Fig. 2 a typical case report is given for an MH rat 0.02 in comparison with controls), and 146.6 t 1.5 meq/
and compared with the case report of a BH animal. It liter in MH animals (P < 0.01). Plasma urea concentra-
may be seen that in both animals the BP increased tions of these three groups were 7.7 t 0.2 mM, 7.1 * 0.2
progressively after the start of DOC administration at mM (P < 0.05), and 10.0 t 0.9 mM (P < O.Ol), respec-
da-y- 0. In rat 7, BP leveled off between 160 and 170 tively. Hematocrit values were 44.1 t 0.5% in controls,
mmHg during the 5th-6th experimental wk; body 44.2 t 0.3% in the BH rats, and 42.0 t 1.7% in the MH
animals. However, in those nine MH rats sacrificed
m m Hg g Iday ml /day g iday during the first malignant phase, i.e., during the onset
200 of the malignant course of DOC hypertension, the he-
18, matocrits were significantly higher than in BH and
16, control rats (46.3 t 0.8%, P < 0.01). In each of the other
six animals, hematocrit values were below the lowest
14.
150 normal value measured in control rats (i.e., below
12. 42.2%), the mean value being 35.3 t 2.2% (range, 26.1-
10. 41.4%).
When the values of plasma AVP concentrations were
8.
100 plotted against the respective values of plasma osmolal-
6, ity for all groups studied (i.e., control rats, benign and
c
blood pressure weight gain saline intake food intake
malignant hypertensive rats, and the borderline cases)
a statistically significant correlation was obtained (r =
FIG. 1. Systolic blood pressure, weight gain, and intake of 1% 0.52; P < 0.001). Such a correlation was also found
NaCl and food in normotensive control rats (open columns, n, 12) and between plasma AVP and sodium concentrations (r =
in rats with benign and malignant DOC hypertension (hatched and 0.64; P < 0.001) and between blood pressure and plasma
black columns; n, 10 and 15, respectively). Values are means + SE; AVP (r = 0.67; P < 0.001). However, within each of the
*P < 0.05, **P < 0.01, as compared with control or benign hyperten-
sive rats. Blood pressure values indicated were recorded 1 or 2 days
experimental groups no such correlations existed. In
before end of studies. Values of weight gain and saline and food fact, in the group of MH rats plasma AVP could be
intake were calculated for last 3 experimental days. rather low although hematocrit, osmolality, and plasma

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VASOPRESSIN IN MALIGNANT DOC HYPERTENSION F263

6 . G--T lJo 7 i. . .

40 days
280

260
240 FIG. 2. Systolic blood pressure, body
weight, and intake of 1% NaCl and food
220 240 of an animal with benign course (rat 7)
and a rat developing a malignant
200 course (rat 12) of DOC hypertension.
At day 0, animals were submitted to
unilateral nephrectomy; subsequently,
0) 8o
Ym they were given 1% NaCl as drinking
fluid and injected with 12.5 mg DOC SC
g $ 60
at weekly intervals. For further details
see text.
.-g; 40
z-m
20

6 - i0 * 20 . jo ’ 4b days

sodium were relatively high (e.g., 4.6 pg/ml, 50.8%, 318


mosmol/kg, and 150.1 meq/liter); and the opposite pat-
tern could be also found (e.g., 11.5 pg/ml, 45.0%, 305
mosmol/kg, and 143.7 meqlliter).
Five ra& with DOC hypertension in which kidney
arteriolosclerosis was pronounced but in which no fibri- .
noid insudation or necrosis could be detected after re- IO,
peated examination were regarded as borderline cases .
with respect to malignant hypertension. Systolic BP 8.
was 180 _t 4 mmHg (range, 165-190 mmHg). During the
300 6
last 5-12 days of the study weight increased or decreased
from day to day (maximum t 5 g), the mean daily *
4 *
weight gain being + 1.7 +_ 0 . 1 g; saline intake was 44.7 295
t 5.0 ml/day, and food intake 17.1 t 1.0 g/day. Hemato- 2
crit was 43.9 t O.l%, plasma sodium concentration 143.3 : (--
t 1.1 meq/liter, plasma urea concentration 8.1 t 0.7
mM, plasma osmolality 300.2 t 1.1 mosmol/kg, and osmolality vasopressin
plasma AVP concentration 6.7 t 0.7 pg/ml (P < 0.01, as
compared with control or MH rats). 0 controls [n =12]
In four MH rats that exhibited the most severe signs •] benign hypertensives In = lo]
of a cerebral vascular crisis, BP was difficult to measure
(as in other MH rats) at the day prior to blood sampling;
n malignant hypertensives [n =15]

it ranged between 90 and 135 mmHg, while it was 173 t FIG. 3. Plasma osmolality and plasma arginine vasopressin con-
centrations in rats with benign or malignant DOC hypertension.
7 mmHg 3-5 days before. Weight fell by 6.0 t 2.1 g Values are means * SE; *P < 0.05, **P < 0.01, as compared with
during the last 3 days of the study; saline intake was control or with benign hypertensive rats.
35.7 t 8.0 ml/day and food intake 12.3 t 2.2 g/day. In
these four animals, hematocrit values were 47.9, 53.5, 314, 318, 284, and 294 mosmol/kg, and plasma AVP
51.3, and 48.6%, plasma sodium concentrations 143.7, concentrations 4.4, 0.9, 4.4, and 4.1 pg/ml.
140.5, 143.7, and 140.5 meq/liter, plasma urea concen- Experiment ZZ. Plasma renin concentrations were
trations 10.5, 5.5, 8.9, and 10.0 mM, plasma osmolalities markedly reduced in BH and MH rats, the mean values

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F264 MGHRING, MGHRING, PETRI, AND HAACK

being 5.4 t 0.4 pg AI/ml per h for seven BH animals In two DI rats the infusion of angiotensin II at a rate
and 5.8 t 0.3 pg AI/ml per h for seven MH rats, com- of 0.45 and 0.6 pg/h increased BP by 35 and 45 mmHg,
pared with 43.6 * 3.8 pg AI/ml per h for seven control respectively. Within 1 min after the start of the 0.2-ml
rats. Plasma sodium concentrations were 141.6 t 0.5 in injection of angiotensin II antiserum, the BP started to
controls, 142.9 t 0.8 in BH rats, and 145.5 t 0.7 meq/ fall, and it rapidly reached a minimum 25 and 40 mmHg
liter in MH animals (P < 0.01 as compared with BH below the preinjection level. Within 2-4 min the BP
rats); plasma potassium concentrations were 4.30 t returned to preinjection level (Fig. 4). When, in these
0.11, 3.49 t 0.06 and 3.56 t 0.15 meq/liter (P < 0.01 for two animals, 0.2 ml of AVP antiserum was injected, the
BH and MH rats compared with controls). BP remained unaffected (Fig. 4).
Experiment ZZZa. In the two nephrectomized diabetes Experiment ZZZb. In each of the 11 MH rats that were
insipidus rats that were given no infusion, the injection injected with 0.2 or 0.4 ml of the biologically active AVP
of 0.4 ml of AVP antiserum Erwin did not affect BP. In antiserum Erwin, the BP started to decline within l-3
11 other DI rats the infusion of AVP at a rate of 140-260 min after the start of the injection (Fig. 5); within the
rig/kg per h increased mean BP from 92 t 2 mmHg subsequent 2-6 min, the BP reached a minimum and
(range, 85-100 mmHg) to 133 t 14 mmHg (range, 105- started to increase again, reaching the preinjection
150 mmHg), the smallest increase being 15 and the level in 25-100 min (mean, 52 t 8 min in the 11 MH rats
greatest 50 mmHg. In seven of these rats, plasma AVP studied). After the injection of 0.2 ml of AVP antiserum,
was measured when the BP had reached a plateau, and mean BP fell by 62 t 5 mmHg (n, 6; Fig. S), and after
the concentrations varied between 115 and 157 pg/ml the injection of 0.4 ml by 82 t 8 mmHg (n, 5; P < 0.03
(mean, 136 t 6 pg/ml). In the four other rats, the when compared with the mean value after 0.2 ml). After
injection of 0.2 ml of AVP antiserum Erwin induced a injection of 0.4 ml of angiotensin II antiserum (four MH
fall of BP of lo-25 mmHg (mean 16 t 3 mmHg). Within rats), 0.4 ml of angiotensin I antiserum (two MH rats),
2 min after the injection BP started to decline and and 0.4 ml of serum obtained from a normal rabbit
reached a minimum within the next 2-6 min. Then BP (three MH rats), the BP remained virtually unchanged.
started to rise again, and it reached the preinjection In each of two other MH rats, the injection of 0.4 ml of
level lo-15 min after the injection of the antiserum. (A the two biologically inactive AVP antiserums Kaspar
typical experiment is presented in Fig. 4.) In two other and Oskar did not affect BP.
DI rats the injection of 0.4 ml of AVP antiserums Kas- The injection of 0.2 ml of AVP antiserum Erwin to two
par and Oskar did not affect BP. Similarly, after the BH rats did not affect the BP. But the injection of 0.4 ml
injection of 0.4 ml of serum obtained from a normal of this antiserum to seven BH rats induced a transient
rabbit in two of the above DI rats BP remained un- fall of mean BP, which ranged from 15 to 35 mmHg
changed (Fig. 4).
cant rol AVP
0.2 ml AVP 0.4 ml control serum antiserum
. 0.4 ml 0.4 ml
antiserum serum
1 1
150

.
s 130
If
E 110
E
;J
fr AVP infusion 260 ng/ kg/ h
3
en
cn
W
e 0.2 ml AZI 0.2 ml AVP AVP AlI
antiserum antiserum
II antiserum ant iserum 0.4 ml 0.4 ml
0
0 1 1

'3 150 .
m
130,

110 I t I
5 rnin

angiotensin II infusion 2 pg / kg /h 10 min


FIG. 4. Evaluation of biological activity of antisera. Effect of va-
sopressin (AVP) or angiotensin II (AID antiserum on blood pressure FIG. 5. E :t of vasopressin (AVP) or angiotensin II (AID antise-
of 2 individual rats with diabetes insipidus, which were infused rum on bloo ressure of a conscious unrestrained rat exhibiting a
either with arginine-vasopressin (upper panel) or with angiotensin benign COW of DOC hypertension (rat 40) and of a rat with
II (Lower pane& For further details see text. malignant I J hypertension (rat 48).

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VASOPRESSIN IN MALIGNANT DOC HYPERTENSION F265
--
In recent balance studies, the onset of malignant
benign
hypertensives malignant hypertensives hypertension in rats with unilateral renal artery steno-
I sis and an untouched contralateral kidney has been
a fwrther analyzed (27, 30, 32). Based on this analysis and
- 200 on similar clinical observations we have extended the
II vicious circle concept of Wilson and Byrom. When blood
z pressure increases to a critically high range, renal salt
and water loss ensues, resulting in hypovolemia; subse-
quently, the renin-angiotensin system is markedly acti-
150 vated, whereby high blood pressure levels are main-
tained and a vicious circle situation develops. Due to
progressive vasoconstriction and hemoconcentration in
the presence of high blood pressure, microcirculation
and vascular permeability are altered to an extent that
finally induces the chain of events that result in vascu-
100 lar damage. Consistent with this concept was the cru-
cial observation that under a self-selection regimen rats
with malignant renal hypertension took large amounts
of saline whereby they compensated for renal salt and
water loss; subsequently, all signs of malignant hyper-
0.4 ml AVP-AB 0.4 ml AVP-AB 0.2 ml AVP-AB
tension either did not develop or they nearly or com-
pletely disappeared, although blood pressure levels
FIG. 6. Effect of vasopressin
sure of rats with benign
antibody
or malignant
(AVP-AB)
DOC hypertension.
on blood pres-
First
were finally as high as before (32). In addition to these
values give mean blood pressures of conscious unrestrained animals obervations, which clearly indicated that a sudden salt
before injection of antibody, second values give minimum blood and water loss triggered the onset of malignant hyper-
pressures after injection of the antibody. tension, it could be demonstrated that by activation of
the renin-angiotensin system subsequent to salt and
(Figs. 5 and 6). As in the MH rats, BP similarly started water depletion high blood pressure levels were main-
to fall in 2-4 min afier the injection and reached its tained. In rats with unilateral renal artery stenosis, the
minimum during the next 2-8 min; within 25-50 min competitive angiotensin II antagonist saralasin lowered
after the injection (mean 36 t 4 min; P < 0.05 compared blood pressure more effectively the higher the plasma
with MH rats), the BP had returned to the preinjection renin concentrations were (15, 23); and similar results
level, and in four of the seven BH rats it leveled off at have been obtained with pepstatin, an inhibitor of the
BP values 20-40 mmHg higher than before the injection renin-angiotensinogen reaction (unpublished observa-
of the AVP antiserum. The injection of 0.4 ml of control tions).
serum, which was given to four of these BH rats either Obviously, the concept outlined above cannot be as-
before or after the injection of the AVP antiserum, did cribed to the pathogenesis of those forms of malignant
not affect the BP. hypertension in which the renin-angiotensin system is
In the five control rats, the injection of 0.4 ml of either not activated (3, 13, 24). This is particularly the case in
AVP antiserum Erwin (five tests in five rats), or angi- malignant DOC hypertension of rats. Here, in fact, the
otensin II antiserum (two tests), or the control serum renin-angiotensin system remains markedly sup-
(three tests) did not affect BP. In these animals mean pressed, as Gavras et al. have recently shown (14) and
BP was 116 t 3 mmHg. as has been confirmed in the present studies. Further-
more, the angiotensin II antagonist saralasin (14) as
When mean BP values, measured directly in the con-
well as a biologically active angiotensin II antiserum
scious animal, were plotted against systolic BP values,
recorded in the same rats by-tail plethysmography in (present studies) did not lower BP in this pathophysio-
light ether anesthesia 1 or 2 days before, a very close logical situation. Since BP levels remained high in spite
relationship was found (r. = 0.95, P < 0.001, n, 29) and of decreasing blood volume, vasopressor systems other
the regression line was not different from that which than renin-angiotensin should have become activated.
equaled a 1:l relationship (y = 0.9% + 3.07). Based on the findings of an unchanged renal norepi-
nephrine content and on the absence of an activation of
the suppressed renin-angiotensin system in rats with
DISCUSSION
malignant DOC hypertension, Gavras et al. (14) con-
Wilson and Byrom (42) were the first to recognize the cluded “absence of positive evidence for a role of vaso-
“vicious circle” in the pathogenesis of the malignant constrictor substances in the pathogenesis of vascular
course of renal hypertension in rats. Their notion has damage.” The findings made in the present studies ren-
been that blood pressure per se should cause vascular der it unnecessary to draw such a “conclusio per exclusi-
damage in the so far unaffected kidney; this kidney onem”.
should, in turn, maintain or aggravate hypertension, The experiments presented in this communication
whereby further vascular damage would be induced; followed the experimental protocol and findings of Gav-
and, finally the organism would die in renal failure or
9 ras et al. (14). In balance studies, these authors had
subsequent to heart attack or stroke shown that, similarily to malignant renal hypertension

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F266 MOHRING, MijHRING, PETRI, AND HAACK

(30>, salt and water balance becomes negative during drinking solution containing 171.1 meq sodium/liter.
the onset of the malignant course of DOC hypertension. However, this explanation would only be valid if DOC
Furthermore, salt and water loss were quantitatively hypertensive rats augment their saline intake during
reflected in weight loss. Thus, changes in daily weight the onset of malignant hypertension, when they start to
gain could be taken as the parameter to detect the onset lose sodium and water. But this has not been observed
of the malignant course in DOC hypertensive rats (14). in most of the animals; and some of the rats even had a
The findings reported in this communication confirm reduced saline intake, when blood sampling was per-
that experimenta .I. approach. formed and elevated plasma sodium concentrations
In most of the animals in which BP increased to a were measured. Therefore, animals with malignant
range of 170-190 mmHg, weight loss occurred during DOC hypertension seem to lose more water than so-
the period of observation, i.e., during the 4th-7th wk dium. Provided that extrarenal water loss did not
after the start of DOC treatment. It was only in these change substantially, this implies that in comparison
animals that signs of a vascular crisis were observed, with benign hypertensive rats the urine should have
such as malignant nephrosclerosis or stroke, and some become less concentrated. Such a possible impairment
of these animals died. The fact that such signs of a in the concentrating capability of the kidney has been
vascular crisis were not found in all of the weight-losing related to the increasing BP per se in rats with renal
rats (and in none of the borderline cases) indicates that and spontaneous hypertension (37).
the chain of events resulting in vascular damage was The increase in plasma sodium concentration was the
most likely triggered subsequent to the onset of sodium main factor for increasing plasma osmolality during the
and water loss. onset of malignant DOC hypertension. Together with
The course of malignant DOC hypertension appeared hypovolemia the hyperosmolality should have stimu-
to be phasic (14). After a period of weight loss, during lated vasopressin release (11)) thereby increasing
which signs of a vascular crisis became apparent, the plasma vasopressin concentration in rats with malig-
animals could recover with respect to daily weight gain, nant DOC hypertension. The rise of plasma vasopressin
food intake, and general condition. But after some days concentration, as well as the concomitant increase of
elapsed, a further malignant phase developed (see Fig. plasma sodium concentration ‘7 might have counterbal-
2). This is exactly the same feature which has been anced the stimulating effect of hypovolemia on renal
described for rats with malignant renal hypertension renin release (40). Thus, the activity of the renin-angi-
(27). In addition, in both pathophysiologic situations otensin system remained m .arkedly suppressed. Fur-
renal function is impaired, as indicated by an increase thermore, the increased plasma concentration of vaso-
of plasma urea concentration (13, 32, 41). Furthermore, pressin might have increased renal vascular resistance,
volume depletion was reflected in an increase of hema- and thereby reduced the GFR (36>, and, thus, induced a
tocrit in both malignant renal and malignant DOC hy- rise of plasma urea concentration. Arteriolar and glo-
pertension (14,30). But in DOC hypertensive rats it was merular damage might have contributed to the rise of
only during the onset of the malignant course that plasma urea in those mali gnant hypertensive rats
hematocrit was found to be elevated. When hematocrit where it was present.
was measured during the later course of malignant In rats exhibiting a benign course of DOC hyperten-
DOC hypertension, it was always found reduced. Such a sion, plasma vasopressin concentration was also in-
reduction in hematocrit of the rats with malignant DOC creased in comparison with normotensive control rats,
hypertension has been demonstrated to be due to mi- but by far 1.ess than in malignant hypertensive animals.
croangiopathic hemolytic anemia (13, 41), and it is That increase could have been the consequence of a
found in spite of volume depletion (14). Since in the moderate rise of plasma sodium concentration as well as
present studies hematocrits were always determined of plasma osmolality, which have been observed in the
during an apparent malignant phase, i.e., during a present studies. Since vasopressin release seems al-
phase-of sodium and water loss, the reduced hematocrits ready to be stimulated on the first day of DOC adminis-
of the animals exhibiting a second malignant phase tration (28), this finding indicates that plasma vasopres-
most likely did not reflect hypervolemia. In contrast to sin concentration could be elevated throughout the
malignant DOC hypertension, we have only occasion- course of DOC hypertension. Thus, the pattern of
ally observed such a reduction of packed cell volume in change in plasma vasopressin concentration closely re-
malignant renal hypertension of rats (unpublished ob- sembled the change of plasma renin and angiotensin II
servation). concentration observed during the development of renal
Negative sodium balance of rats exhibiting a malig- hypertension in rats (30-32). This increase of plasma
nant course of DOC hypertension (14) was not reflected vasopressin concentration could be of great pathoge-
in a reduction of plasma sodium concentration, as is the netic significance, not only during the malignant course
case in malignant renal hypertension (30, 32). In fact, but also during the development of DOC hypertension
plasma sodium concentration increased. This difference in rats, since Friedman et al. (12) noticed either no or a
could be explained to a certain extent by the difference markedly attenuated BP increase in lesion-induced dia-
between the experimental protocols. While malignant betes insipidus rats treated with DOC for 3 wk.
renal hypertensive rats could drink water only in order Based on the findings of an increase in plasma vaso-
to compensate for volume depletion and, thereby, could pressin concentration in rats exhibiting a benign course
“dilute” their extracellular sodium, rats with malignant of DOC hypertension and of a further increase in rats
DOC hypertension could drink only 1% saline, i.e., a with malignant DOC hypertension, an attempt has

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VASOPRESSIN IN MALIGNANT DOC HYPERTENSION F267

been undertaken in the present studies to clarify the malignant hypertensive animals). Thus, arginine
whether vasopressin exerted vasoconstriction in both of vasopressin appears to act as a vasopressor hormone in
these situations. For this purpose a vasopressin antise- this pathophysiologic situation. Consistent with this
rum was used, which proved to be biologically active. conclusion are observations made in some of the MH
“Biological activity” has been defined as the capability animals, in which BP had fallen to rather low levels
of a vasopressin antiserum to lower BP in rats with during the days prior to blood sampling. In these rats,
hypothalamic diabetes insipidus in which BP was raised plasma vasopressin concentrations were si .mi lar to those
by vasopressin infusion. Such a blood pressure-lowering of BH rats. Furthermore, in those rats that represented
effect was not seen when BP was raised by the infusion a group of borderline cases and in which hypovolemia
of angiotensin II. Furthermore, BP was not affected by was not present despite day-to-day variations of body
the vasopressin antiserum when no infusion of vaso- weight (see RESULTS), plasma vasopressin as well as BP
pressin was given. levels were higher than in BH animals.
Only one of the three vasopressin antiserums tested In rats with benign DOC hypertension, the vasopres-
proved to be biologically active, although the in vitro sin antiserum also lowered BP transiently. But the
characteristics, which had been evaluated at 4°C under decrease of BP was less by far than in malignant hyper-
equilibrium conditions, and in Tris buffer (26), appeared tensive rats. This suggests that plasma vasopressin par-
to be similar. Thus, the similarity of these in vitro ticipates in the maintenance of high BP in rats with
characteristics did not necessarily imply similarity to in benign DOC hypertension, but its quantitative contri-
vivo activities. A possible explanation for this discrep- bution seems to be of minor importance in malignant
ancy could be that, despite similar affinity constants of hypertensive animals. In control rats, the injection of
various antibodies, their initial rate constants of equili- 0.4 ml of the vasopressin antiserum never induced a fall
bration, which would determine their acute effects in of BP. This finding would be consistent with the notion
vivo, might vary considerably, especially at different that vasopressin is not involved as a vasoconstrictor
temperatures (E. Hackenthal, personal commun ica- hormone in normal blood pressure regulation. However,
tion). But, unfortunately, very little is known about the as outlined above, lack of an inhibitory effect of an
in vivo kinetics of antibody-antigen associations, i.e., antibody should be interpreted with caution.
about how antibodies inhibit the effects of hormones in It could be argued that the injection of the AVP
vivo. Recently, it has been shown that, in vivo, angi- antiserum induced a fall of BP by blocking AVP-me-
otensin II antibodies equilibrate within minutes with diated antidiuresis and thus causing rapid volume de-
their antigen and that fractional antibody occupation pletion. However, from studies in DI rats (39) it is
seems to be remarkably small, when the antigen apparent that such a diuresis might only amount to 0.2
plasma concentration falls into the range of the affinity ml per min in animals weighing 300 g, which would
constant of the antibody (33). There the degree of anti- equal a reduction of extracellular fluid volume of about
body occupation would be determined by the antigen 3%/10 min. This figure cannot account for the marked
concentration in the medi urn; on the other hand, the fall of BP observed in the present studies.
biological effect of an antibody would depend critically Besides the use of antibodies or competitive antago-
on its plasma concentration, because this determines nists, another approach often is used to demonstrate
the amount of antigen bound and, hence, the inhibitory that the measured increase in plasma concentration of a
effect of the antibody. Thus, at low antigen concentra- vasopressor hormone caused the given increase of BP:
tions an inhibitory effect of the antiserum would become infusing the vasopressor hormone and relating the in-
apparent with the increasing volume of antiserum in- duced plasma concentrations to the increase of BP (2,7).
jected. Furthermore, for a given plasma concentration Such an approach has been successful in elucidating the
of the antibody its inhibitory effect would be enhanced role of the renin-angiotensin system in the pathogenesis
with i ncreasing pl .asma antigen co ncentrations; but if of renal hypertension (2, 5, 9, 19). Furthermore, such
antigen concentrations are raised to “supramaximal” studies have also demonstrated that a marked enhance-
levels (as has possibly been done in the experiments in ment of the BP-elevating effect of the given plasma
which vasopressin had been infused), the inhibitory renin or angiotensin II concentrations may occur in
effect of the antibody would, for a given antibody various hypertensive states.
plasma concentrat ion, progressively decline. Finally, From the present studies it becomes apparent that a
since the antibody interferes with the steady-state sys- vasoconstrictor effect of vasopressin in DOC hyperten-
tem of secretion rate and metabolic clearance rate of the sion of rats should also be markedly enhanced. In the
antigen, these two variables will determine the dura- diabetes insipidus rats that were infused with vasopres-
tion of the inhibitory effect of the antibody, i.e., the time sin, BP increased only to levels found in the benign
until the original plasma antigen concentrations are hypertensive animals, although the induced plasma va-
reestablished. sopressin concentrations were eventually about 40 times
The injection of the biologically active vasopressin higher. The mechanism underlying such a change in
antiserum in rats with malignant DOC hypertension sensitivity has not been elucidated in the present stud-
induced a transient fall of BP to normal or even subnor- ies, but recent experiments performed by Cowley et al.
mal levels. (The injection of the two inactive vasopres- (8) could provide some explanation. These authors have
sin antiserums, of a biologically active angiotensin II evaluated the BP-increasing effect of exogenous vaso-
antiserum, of an angiotensin I antiserum with low titer, pressin in dogs under varying experimental conditions.
and of a serum from a normal rabbit did not affect BP in When the baroreceptor reflex was interrupted by dener-

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F268 MOHRING, MijHRING, PETRI, AND HAACK

vation, the dose-response curve was shifted to the left by DOC hypertension vasopressin might play a role similar
a factor of 60-100. When such studies were performed to that ascribed to the renin-angiotensin system in ma-
under angiotensin II or noradrenaline infusion (8), the lignant renal hypertension. This conclusion is based on
effect was less by far. Thus, the baroreceptor reflex the demonstration of increased plasma vasopressin con-
seems to be sensitized, i.e., its feedback gain increased, centrations in malignant DOC hypertension of rats, on
under vasopressin infusion as compared with angioten- the BP-lowering effect of a specific vasopressin antise-
sin II or noradrenaline infusion. Finally, Cowley et al. rum, and on the earlier demonstration of vasopressin-
showed that in decapitated dogs that were given an induced vascular damage by Byrom (4). Preliminary
infusion of noradrenaline in order to maintain normal reports from our laboratory suggest that the neurohy-
BP levels, the dose-response curve for vasopressin was pophyseal vasopressor principle might also induce sys-
further shifted to the left, the sensitivity being in- temic vasoconstriction during the development of malig-
creased now by a factor of 8,000. Such an increase in the nant renal hypertension (29) and of acute renal failure
sensitivity to the vasoconstrictor effect of neurohy- in rats (18). Finally, other studies have reported that in
pophyseal hormones by catecholamines (and vice versa) man urinary excretion rates of vasopressin are in-
has been repeatedly demonstrated (1, 6) since the early creased in essential hypertension (21) and that plasma
work of Kepinow (20) in 1912. vasopressin levels are elevated during malignant hyper-
These observations could be most significant for un- tension (34).
derstanding the vasoconstrictor effect of vasopressin in
DOC hypertension of rats. It has been shown that the We are grateful to Dr. E. Hackenthal for the gift of the angioten-
sin II antiserum and for the measurement of plasma renin concen-
metabolism of catecholamines is altered in DOC hyper-
trations. We thank Dr. D. Ganten for giving us the angiotensin I
tension, the result being a moderate increase in circu- antiserum, and we thank CIB,A, Wehr/Baden, for supplying us with
lating noradrenaline concentration (10, 35). Further- DOC (Percorten m). We acknowledge the preparation of the histolog-
more, hyperresponsiveness to exogenous vasopressin as ical specimen by Mrs. Gerda Jost and the critical review of the
well as to noradrenaline has been demonstrated in DOC manuscript by Dr. K. G. Hofbauer.
These studies were supported by the German Research Founda-
hypertension of rats (17). Thus, a noradrenaline-me- tion.
diated increase in the sensitivity of vascular smooth Preliminary reports of parts of these studies have been presented
muscles as well as a damped sensitivity of the barore- in The Lancet I: 170-173, 1976, at the Fourth Meeting of the Interna-
ceptor .reflex could underlie the greatly enhanced vaso- tional Society of Hypertension in Sydney, February 1976 (Proceed-
constrictor effect of vasopressin in DOC hypertension of ings to be published in CZin. Sci. IMoLecuLar Med.), and at the Tenth
Annual Meeting of the European Society for Clinical Investigation
rats. This suggestion implies an interrelated role of in Rotterdam, April 1976 (ref. 29).
vasopressin and the sympathetic nervous system in the Send requests for reprints to Dr. Jan Mohring, Centre de Re-
pathogenesis of DOC hypertension as well as of its cherche Merrell International, 16, rue d’Ankara, 67000 Strasbourg,
malignant course. France.
In summary, the findings made in the present studies
strongly suggest that in the pathogenesis of malignant Received for publication 21 June 1976.

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