THE EFFECTS OF SINGLE DOSES OF DEOXYCORTICOSTERONE ACETATE (DOCA) AND CORTISONE ON THE VASCULAR RESPONSE OF FEMALE RATS TO POSTERIOR PITUITARY
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THE EFFECTS OF SINGLE DOSES OF DEOXYCORTICOSTERONE
ACETATE (DOCA) AND CORTISONE ON THE VASCULAR
RESPONSE OF FEMALE RATS TO POSTERIOR PITUITARY
HORMONES. By L. H. HONORE'. From the Department of Physi-
ology, University of Edinburgh.
(Received for publication 18th April 1962)
The effects of single doses of DOCA or cortisone, with or without the adldition
of stilbcQstr ol, on the vascular responses of anesthetized female rats to vasopressin
and oxytocin were studied.
DOCA reduced the sensitivity to the pressor action of vasopressin in all
animals. An initial fall in blood pressure always preceded the rise. After
DOCA the majority of animals responded to oxytocin with a small fall and then
a rise in blood pressure. Cortisone increased the reactivity to vasopressin in
all dioestrous females; during oastrus (natural or stilbcestrol-induced) cortisone
like DOCA reduced the sensitivity to vasopressin. The rise in pressuie was,
except, in the dicstrous females, preceded by a sharp fall. Most of the cortisone-
treated animals responded to oxytocin by a rise usually preceded by a fall in
blood pressure. In three females the blood pressure was unchanged after
oxytocin, and in a few it fell with no subsequent rise. Animals showing a
diphasic response to vasopressin and a pure depressor or a diphasic response to
oxytocin were given dihydroergotamine (DHE) and atropine to see how far the
responses depended on autonomic nervouis activity. With few exceptions after
DHE the depressor phase of the response was abolished and the pressor phase
regularly potentiated. The main exceptions were cortisone-treated aestrous
rats and three of the six females treated with cortisone and stilbcestrol; in these
DHE enhanced the depressor phase of the response to vasopressin and oxytocin,
and atropine given later caused a further enhancement. The results are dis-
cusse(l in ielation to the activity of the autonomic nervouis system.
BYROM [1938] was the first to point out that the vascular responses of the
female rat to vasopressin varied with the cestrogen concentration in the body.
More recently Lloyd [1959 a and b] has studied in the rat the effect of
oophorectomy and treatment with cestrogen and progesterone on the
responses to small doses of the two neurohypophyseal hormones. This paper
describes some of the qualitative and quantitative changes observed in the
responses of female rats to the posterior lobe hormones after a 24-hr. pre-
treatment with single doses of deoxycorticosterone acetate (DOCA) and
cortisone.
METHODS
Animals.-The rats used weighed between 175 and 275 g. The DOCA (deoxy-
corticosterone acetate, Organon) was given subcutaneously in doses from 0 5 to 1 mg.
The cortisone was given intramuscularly as the emulsion of cortisone acetate (Roussel)
in doses from 2-5 to 7-5 mg. (usually 5 mg.). These doses were satisfactory in that
they produced definite changes in the vascular responses studied without causing
any rise in the basal blood pressure. Stilbcestrol propionate (Organon) was given
subcutaneously in doses from 100 ,ug. to 1 mg. in order to produce artificial cestrus,
without regard to the stage of the cycle at which the injection was made. The
334
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vasopressin used was Parke-Davis' Pitressin and the oxvtocin was the synthetic
Sandoz product, Syntocinon. All the animals were kept on stock diets and tap water
without additional salt.
Vaginal smears were stained with Leishman's reagent in order to ascertain the
phase of the female reproductive cycle at the time of each experiment.
The Experimental Technique.-The carotid blood pressure was recorded on a
kymograph while injections with a total volume of 03 ml. of physiological saline
were made into the cannulated femoral vein. All experiments were carried out
approximately 24 hr. after steroid administration under sodium pentobarbitone
anaesthesia given intraperitoneally. The dose required for full aniesthesia was
6-8 mg./100 g. body weight in the steroid-treated animals as compared with
4.5-5.5 mg./100 g. in the normal ones.
RESULTS
Untreated Females
Experiments on five dicestrous and five cestrous rats gave results in
complete agreement with those of Lloyd [1959 a and b]; she reported that
in the dicestrous female the dose of vasopressin which raised blood pressure
by 10 mm. Hg was of the order of 0.4-0-5 mU/200 g. body weight, whereas
in the cestrous female the same rise in blood pressure followed a smaller dose
(0.3 mU). She also found that oxytocin in doses from 10 to 100 mU had
no effect on the pressure of the dicestrous animal but produced a pure pressor
response of 5-15 mm. Hg in the cestrous or stilbcestrol-treated female.
DOCA-treated Females
DiUestrous.-In all the nine animals studied it was found that doses
of 0.4-0.5 mU of vasopressin failed to produce the 10 mm. Hg rise seen
in the untreated dicestrous female and that doses from 0.7 to 1.6 mU
(mean=1.1 mU/200 g. body weight) were required (fig. 1). In six out of
the nine animals the duration of the pressor response was similar to that
seen in untreated rats (fig. 2); in three out of the nine the response lasted
about four times as long as in the untreated animals. In addition to the
reduced sensitivity to vasopressin, in four animals a sharp depression of
8-20 mm. Hg preceded the elevation in blood pressure (fig. 2 and Table I);
in the remaining five rats only a pressor effect was observed.
Oxytocin was always used in a dose of 100 mU: this had no effect on the
blood pressure of untreated dicestrous females, but in six out of the nine
DOCA-treated rats it provoked a rise in blood pressure of the order of
6-12 mm. Hg, lasting for 3-5 min. (fig. 3), and preceding the rise a sharp fall
in pressure of 4-25 mm. Hg was seen, that is, there was a diphasic response
(fig. 3). In the remaining three rats only the sharp fall in blood pressure
occurred (Table I). In any one rat the presence or degree of the depressor
response to oxytocin was not correlated with the presence or size of the
depression induced by vasopressin.
iEstrous.-Each of the seven cestrous rats treated with DOCA showed a
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reduced sensitivity to vasopressin in that the standard 10 mm. Hg rise in
blood pressure could only be elicited by doses of vasopressin ranging from
0.7 to 1.7 mU (mean = 1-0 mU/200 g. body weight) (fig. 1); this fourfold rise
mu. VP.
0
1.5 L
0 0
0
0 0
00 0 0. 0 00 0 0
1.0
* 0
0 00 0 00
0 0 0 0
0
0.5
o000
* 0d
___ __ _ . __ _ _ _ _- I _ _ _ _ _
N. D. S. D. C. S. C.
FIG. 1.-Changes in sensitivity to vasopressin in steroid-treated female rats.
The intravenous dose of vasopressin required to r aise the blood pressure by
10 mm. Hg.
N =normal; D =treated with DOCA; S +D =treated with stilbcestrol and DOCA;
C = treated with cortisone; S + C = treated with stilbcestrol and cortisone.
0 = cestrous. 0 = dicestrous.
TABLE I.-THE EFFECT OF DOCA ON THE RESPONSE OF THE BLOOD PRESSURE OF FEMALE RATS TO VASOPRESSIN
AND OXYTOCIN
Vasopressin Oxytocin (100 mU)
State No. Pure Pressor Dij Pure Pure
Treatment (vaginal of rats pressor sensitivity res )hasic pressor Diphasic
depressor response
No
smear) used response ponse response response response
DOCA Dicestrus 9 5 decreased 9 4 0 3 6 0
DOCA CEstris 7 5 decreased 7 2 0 1 6 0
(natural)
Stilbcestrol +
DOCA CFstrus 5 5 deereased 5 0 0 0 5 0
in the dose required was not associated with any change in the duration
of the response (fig. 2). The sharp initial fall in pressure seen in the dicestrous
animals occurred in only two of the cestrous ones (fig. 2 and Table I).
As in untreated cestrous females, oxytocin (100 mU) provoked in six out
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mm-- Hg.
*115
10-I
l3f
Fi(.c. 2. Sensitivity of feinale rats to vasopressin: (1) normal dicvstrous, 0.3- mU;
(2) (di(cstrous treate(d wvith DOCA, 1.1 inU; (3) (dicstrouls treate(i with cortisone,
4-1 i1U; (4) normnal mstrous, 0.4 im1U: (5) mestroiis treate(l vith DOCA, 0-8 1m11UI
(6) (wstrouls treate(1 wvith cortisone, I niU. TiIme marker, 30 sec.
LToflce p)age
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336mnm tq.
I 21
110-
1 00 .
90
115-
105
95
FI(m. 3.- The effect of 100 iimU oxytocin on the blood pressuire of feimiale
rats: (A) (di(ostrolls; (B) wstrous. In both instanves (1) normnal: (2) treate(d
'iti D)OCA; (3) treated( with cortisone. Tiimie imlarker, 30 sec.
jI I 3
tnm FHg. mm Hg .
90
80
3 70
FIG. 4.-The effect of 1.2 mrlU vasopressin on the bloo(d pressure of tlle oestrous femakll
treate(l w iti cortisone: (1) normiial; (2) after DHE; (3) after DHE an(d atropine.
Tiiiie mnarker. 30 sec.
(The pressure scale on the riglit refers to 2 an(d 3.)
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of seven of the present series a transient hypertension of 5-10 mm. Hg (fig. 3).
In one female, in spite of the definite cestrous vaginal smear, the drug in
doses up to 100 mU failed to evoke this expected rise. An initial vaso-
depression of 5-10 mm. Hg was observed in all the animals (Table I).
Stilbcestrol and DOCA-treated Females
Five animals were pretreated with stilbcestrol concurrently with the
DOCA and on the following day all showed vaginal changes typical of cestrus.
These animals showed responses to both oxytocin and vasopressin similar to
those seen in females in natural cestrus pretreated with DOCA, that is, the
sensitivity of the vasculature to vasopressin was reduced to the same extent,
the 10 mm. Hg rise in pressure being produced by 0.8-1.6 mU (fig. 1). No
fall in pressure ever preceded the rise (fig. 2). In all animals, following
oxytocin a depression of 4-9 mm. Hg preceded a rise in pressure of 8-15
mm. Hg (Table I, and fig. 3).
Cortisone-treated Females
Dioestrous.-All the six animals in this group were more than normally
sensitive to the pressor action of vasopressin, a 10 mm. Hg rise in blood
pressure being elicited by doses of 0.025-0-1 mU (mean=0.075 mU/200 g.
body weight) (fig. 1). This increase in sensitivity to the hormone was
accompanied in two animals by an increase in the duration of its effect by
some two to four times. No initial depression was induced by vasopressin,
i.e. the diphasic pattern was never obtained, whether small or relatively large
doses were given (Table II).
The effect of oxytocin was tested in eleven dicestrous females treated with
cortisone. The results showed considerable variation. In three animals
oxytocin caused no change at all in the blood pressure; in two there was a
pure pressor response and in one nothing but a depressor response. The
remaining five animals showed a diphasic blood pressure change (fig. 3 and
Table II), i.e. a sharp fall of 6-14 mm. Hg preceded the longer-lasting rise of
5-15 mm. Hg.
(Estrous.-In sharp contrast to the dicestrous females, all the nine animals
in this group showed a decrease in sensitivity to vasopressin: the 10 mm. Hg
rise was evoked only by doses from 0.6 to 1.4 mU (mean=1.0 mU/200 g.
body weight) instead of the usual 0.2-0.3 mU required in untreated cestrous
animals (fig. 1). Apart from this decrease in sensitivity, no change in the
pattern of the pressor response to vasopressin was observed (fig. 2). However,
in contra-distinction to the cortisone-treated dicestrous animals in none of
which vasopressin caused a preliminary fall in blood pressure, six out of the
nine cestrous females showed a marked initial depressor response of 5-16
mm. Hg before the rise appeared (fig. 2 and Table II).
In eight out of the nine animals treated with cortisone there was no
VOL. XLVII, NO. 4.-1962 23
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alteration in the extent or duration of the pressor response to oxytocin as
compared with that seen in normal cestrous females (fig. 3). A preliminary
fall in pressure was seen only in five of the nine cestrous females (fig. 3 and
Table II).
Stilbcestrol and Cortisone-treated Females
Six females were injected with stilbcestrol to induce artificial cestrus and
it was surprising to note 24 hr. later that in two of these animals the vaginal
smear suggested dicestrous, although the vascular responses of these animals
were of the cestrous type. All these rats showed a response to vasopressin
which resembled that in natural cestrus after cortisone, i.e. the sensitivity
to vasopressin was reduced, a dose of 0-7-1.6 mU (mean= 1-1 mU/200 g.
body weight) being required to produce a 10 mm. Hg rise in pressure (fig. 1).
The duration of the rise in pressure was normal (fig. 2). In five out of the
six animals a marked initial fall in blood pressure of 3-11 mm. Hg preceded
the rise (Table II).
The transient hypertension provoked in these females by 100 mU of
oxytocin was in every way similar to that seen in untreated cestrous females.
There was, however, one difference between the cortisone-treated animals
in natural cestrus and those cortisone-treated rats in which aestrus was
induced, namely that the latter without exception displayed a preliminary
fall in pressure which varied from 5 to 17 mm. Hg (Table II and fig. 3).
EFFECT OF DIHYDROERGOTAMINE (DHE) AND ATROPINE ON THE DEPRESSION
OF BLOOD PRESSURE INDUCED BY VASOPRESSIN AND OXYTOCIN
The depressor component of the response to the neurohypophyseal
hormones in castrate male rats was found by Honore and Lloyd [1961] to be
dependent upon the integrity of the sympathetic system, and they suggested
that it was centrally determined. It was possible that the preliminary
depression observed in the present experiments following the two posterior
pituitary hormones depended on the same factor. The experiments described
below were made on some of the rats previously mentioned which showed a
diphasic or a purely depressor response. The drugs used to block the
autonomic outflow were the adrenergic blocking agent dihydroergotamine
(DHE) (0.2-0.5 mg. per animal) and the cholinergic blocking drug atropine
(0.1-0.5 mg.).
DOCA -treated Females
DHE was administered intravenously to three dicestrous and two cestrous
females treated with DOCA, and to two females given DOCA together with
stilbcestrol; in every case the initial depression following vasopressin was
abolished and the pressor response to these same hormones was potentiated.
Atropine given before DHE to two of the dioestrous and two of the cestrous
females had no effect on the depressor response (Table III).
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Cortisone-treated Females
The situation was more complex with this group of animals. DHE was
given to the six dicestrous rats treated with cortisone which showed a
depression following oxytocin; in every case the depressor response was
suppressed and in five the pressor effect potentiated. Atropine given to
two of these animals before the DHE did not affect the depressor phase of
the response to oxytocin. The pressor response to vasopressin also was
enhanced after DHE in those six dicestrous females which exhibited only a
monophasic pressor response to vasopressin (Table IV). On the other hand,
in all the six cestrous females treated with cortisone in which DHE was
used to produce sympathetic blockade, the depressor phase of the response
to vasopressin and oxytocin was unaffected or even increased after DHE
(Table IV). The effectiveness of the sympathetic blockade achieved by
DHE was always tested by the administration of 0.1 ,ug. noradrenaline and
in every instance the block was found to be complete. Atropine administered
to five of these animals after DHE brought about a potentiation of this
DHE-resistant depression (fig. 4).
Five of the females treated with cortisone together with stilboestrol were
given DHE, and four of the five were given atropine before DHE, and in
every instance the atropine alone in no way modified the response to vaso-
pressin, whereas in all five rats DHE administration abolished the depressor
component of the response to vasopressin. Similarly with oxytocin, atropine
given alone did not alter the existing pattern of response. When DHE was
given after the atropine in three of the four rats the depressor response was
suppressed and in one it persisted. The fifth rat received DHE first, the
depressor response to oxytocin was not abolished, and when atropine was
subsequently given the depressor phase was enhanced (Table IV).
DISCUSSION
The results described above indicate that DOCA and cortisone modify
the vascular responses of female rats to the posterior lobe hormone. In all
the females studied, whether in dicestrus or in natural or stilbcestrol-induced
cestrus, DOCA reduced the vascular sensitivity to the pressor action of
vasopressin. On the other hand, DOCA brought out the pressor effect of
oxytocin in the majority of the females investigated (Table I). Lloyd [1959 a],
Lloyd and Pickford [1961] and Honore and Lloyd [1961] have shown that
in the dicestrous female and in the male rat oxytocin, though visibly dilator
to the mesoappendix vessels, had no effect on the blood pressure in doses
up to 100 mU, but provoked a transient hypertension in these same animals
after surgical or pharmacological interference with the sympathetic nervous
system. After pretreatment with DOCA, however, even before interference
with the sympathetic nervous system a pressor response to oxytocin was
observed in six of the nine dicestrous females; sympathetic blockade enhanced
this pressor effect of oxytocin. Lloyd [1959 a] has shown in normal cestrous
Downloaded from Exp Physiol (ep.physoc.org) by guest on February 4, 2015342 Honore'
female rats with sympathetic system intact that oxytocin has a pressor
action in doses of 25-100 mU, and in the females here investigated during
natural or artificial oestrus DOCA did not qualitatively or quantitatively
alter the existing pressor response to oxytocin.
In sharp contrast to DOCA, cortisone potentiated the pressor activity of
vasopressin in all the dicestrous females; however, like DOCA, it reduced
the sensitivity to vasopressin in all the females in natural or artificial cestrus
and in four of the fifteen males tested. Cortisone was also similar to DOCA
in bringing out the pressor action of oxytocin in most of the dicestrous females
and in having no significant observed effect on the pressor response to
oxytocin in females in normal or induced cestrus (Table II).
It appears from these observations that in dicestrous female rats DOCA
and cortisone exert opposite effects, the former desensitizing and the latter
sensitizing to the pressor action of vasopressin, but that in the presence of a
high concentration of cestrogens and in relation to the pressor action of
oxytocin they exert similar effects. An explanation why the pressor
potentiality of oxytocin is brought out by agents which have opposite effects
on the reactivity to vasopressin must await further information.
The desensitization to vasopressin by DOCA is unexpected, since
Friedman, Nakashima and Friedman [1960] have shown that vasopressin
and DOCA exert similar extrarenal effects on the distribution of Na+, K+
and water in relation to the vascular smooth muscle membrane; both
hormones tend to raise the Na+ and water content of the vascular muscle
and lower its K+ content. They also demonstrated that vasopressin in
small doses acted synergistically with DOCA in precipitating the advent of
DOCA-induced hypertension in rats [Friedman, Friedman and Nakashima,
1959]. On the other hand, they found that large doses of vasopressin would
antagonize the hypertensive effect of DOCA in rats-an antagonism which
appeared 3 hr. after the subcutaneous injection of massive doses of Pitressin
tannate [Friedman, Nakashima and Friedman, 1954 and 1955; Friedman,
Friedman and Nakashima, 1955]. It remains to be determined whether there
is any relationship between this last observation and the results of the acute
experiments described in this paper.
A comparison of the size of the pressor response to vasopressin brought
out a further antagonism, namely that between endogenous or synthetic
oestrogen and cortisone. Stilbeestrol alone increases vascular reactivity to
vasopressin [Lloyd, 1959 a] and, as shown here in dicestrous females, the
sensitivity to vasopressin was enhanced by cortisone, yet a combination of
stilbcestrol with cortisone reduced the response to vasopressin. No similar
antagonism between these steroid substances was noticed when oxytocin
was used. This may depend on the dose of oxytocin given or on the
stereochemistry of the posterior pituitary hormones.
In all but two groups of rats the administration of vasopressin and
oxytocin following treatment with DOCA and cortisone led, in the majority
of animals, to a fleeting initial depression of the blood pressure. The
exceptional groups were the dicestrous females pretreated with cortisone and
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the females treated with stilbcestrol and DOCA concurrently-both groups
of animals showing no initial fall in pressure following vasopressin. Further
analysis of the depressor phase of the response to vasopressin and oxytocin
showed that where it occurred, it could be divided into two types: one in
which it was a$olished by DHE and one in which it was not abolished. In
the former group are included all the rats which received DOCA and the
cortisone-treated dicestrous females; in the latter group are included all the
cortisone-treated cestrous females. Surprisingly the cortisone-treated females
rendered cestrous by stilbcestrol pretreatment differed from those in natural
cestrus; they showed a depressor response to the posterior lobe hormones
which disappeared after DHE. In the second group DHE far from sup-
pressing the initial fall in pressure following vasopressin and oxytocin tended
to enhance it. Where the depressor phase was abolished by DHE, the
pressor component of the response to both neurohypophysial hormones was
increased and DHE could also potentiate the pressor response to vasopressin
in animals where no depressor phase was present as in the cortisone-treated
dicestrous females. The potentiation therefore was not always or necessarily
due to the mere elimination of the initial depression. In fact in the animals
which exhibited a DHE-resistant initial depression, the pressor response to
both hormones was regularly enhanced after DHE administration.
In a number of animals atropine was used in an attempt to assess the
importance of cholinergic mechanisms in the appearance of the depressor
fraction of the response to vasopressin and oxytocin. In all instances in
which atropine was given before DHE, it had of itself no effect on the response
to vasopressin and oxytocin and DHE given later led to the result which
might be expected had it been given alone.
No firm explanation of these facts is available, but it may be suggested
that where DHE, with or without atropine, abolished the depressor phase
of the response to both test hormones, this must have been due to removal of
sympathetic influence, that cholinergic and sympathetic dilator mechanisms
were unimportant in this context and that the remaining pressor effect was
peripherally determined. In cortisone-treated cestrous females the early
fall in blood pressure was enhanced by both DHE and atropine, that is, in
this instance the removal of autonomic influence had the opposite effect to
that already mentioned. Again the depressor response must be peripherally
determined and depend on the vasculature or on the heart.
ACKNOWLEDGMENTS
I would like to thank Dr. Mary Pickford sincerely for her interest and support.
This work was financed by a grant made to Dr. Pickford under the United States
Air Force Contract AF61 (052-272).
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REFERENCES
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of the rat to vasopressin", Lancet 234, 129-13 1.
FRIEDMAN, S. H., FRIEDMAN, C. L. and NAKASHIMA, M. (1955). "Independence of
pressor and depressor effects of small doses of Pitressin in the rat ", Amer. J. Physiol.
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FRIEDMAN, S. H., FRIEDMAN, C. L. and NAKASHIMA, M. (1959). "Accelerated appearance
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FRIEDMAN, S. H., NAKASHIMA, M. and FRIEDMAN, C. L. (1955). "Specificity of depressor
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HONORE, L. H. and LLOYD, S. M. (1961). "The effects of castration on the vascular
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