in vivo pharmacodynamic interactions between two drugs used in orthostatic hypotension – midodrine...
TRANSCRIPT
doi: 10.1111/j.1472-8206.2006.00450.x
O R I G I N A L
A R T I C L E
In vivo pharmacodynamic interactionsbetween two drugs used in orthostatichypotension – midodrine anddihydroergotamine
Geraldine Jourdana,b,d*, Patrick Verwaerdea,b,d, Atul Pathaka,c,d,Marie-Antoinette Trana,c,d, Jean-Louis Montastrucc,d, Jean-MichelSenarda,c,d
aInserm, U586, Unite de Recherches sur les Obesites, F-31432 Toulouse, FrancebEcole Nationale Veterinaire de Toulouse, UP d’anesthesie-reanimation-urgences, F-31076 Toulouse, FrancecFaculte de Medecine Purpan, Laboratoire de Pharmacologie Medicale et Clinique, F-31000 Toulouse, FrancedInstitut Louis Bugnard IFR31, Universite Paul Sabatier, F-31432 Toulouse, France
I N T R O D U C T I O N
Orthostatic hypotension (OH) is defined as a fall in blood
pressure (BP) of at least 20 mmHg systolic and/or
10 mmHg diastolic during standing [1]. It occurs often
in the elderly (up to 20% of patients aged ‡65 years
[2,3]) probably because of a decrease in baroreflex
sensitivity and concomitant drug use. However, OH is a
more common finding in autonomic nervous system
diseases, which often include alterations of baroreflex
Keywords
dihydroergotamine,
midodrine,
orthostatic hypotension
Received 31 December 2005;
revised 10 February 2006;
accepted 5 October 2006
*Correspondence and reprints:
A B S T R A C T
A combination of midodrine and dihydroergotamine (DHE) is frequently used
clinically in patients suffering from severe orthostatic hypotension (OH). Whereas
midodrine acts as a selective, peripheral alpha1-receptor agonist, DHE displays
complex pharmacology and can behave as an alpha-adrenergic receptor agonist or
antagonist. Surprisingly, the consequences of such a combination on blood pressure
have never been investigated. The present study was performed in order to evaluate
the pressor effects induced by the administration of both midodrine and DHE in old
conscious dogs (n ¼ 6) in experimental condition reproducing autonomic failure-
related baroreflex dysfunction (atropine 0.1 mg/kg). For this purpose, we first studied
the relative potency and intrinsic activity of each agonist and noradrenaline (NA)
for the alpha1-adrenergic receptor. The orders of potency obtained in our study were
0.35, 11 and 400 lg/kg for NA, DHE and midodrine, and intrinsic activity:
NA > midodrine > DHE. These results strongly suggest that DHE really acts in vivo
as an alpha1-adrenoceptor partial agonist. Afterwards, the pressor effects of
coadministration of midodrine (0.4 mg/kg) and DHE (15 lg/kg) were investigated:
in one setting, midodrine was first administered, followed by DHE; in another, DHE
was first administered, followed by midodrine. Our results show that in conscious
dogs, the combination of midodrine and DHE leads to near-complete abolition
of the pressor effect induced by the first administered drug. This in vivo proof of
such antagonistic effects on blood pressure could explain clinical observations
of worsening of OH in humans administered midodrine plus DHE. Although in vivo
results obtained in conscious healthy dogs need to be experimentally and clinically
confirmed in humans suffering from OH, these results strongly suggest that a
midodrine–DHE combined treatment should be avoided in clinical practice.
Journal compilation ª 2006 Blackwell Publishing Ltd. No claims to original French government works Fundamental & Clinical Pharmacology 21 (2007) 45–53 45
pressor responses [4–6]. In addition to the risk of fall and
syncope, OH is also implicated in cognitive decline [7],
cerebrovascular diseases [8] and represents an inde-
pendent predictive factor of mortality [9].
When non-pharmacological therapy fails to prevent
symptoms of OH [10], pharmacological drugs are admin-
istered [11,12] despite the fact that the efficacy of most of
them has not been established in randomized, placebo-
controlled clinical trials [13,14]. Midodrine, a selective
peripheral-acting alpha1-receptor agonist, is a unique
agent in the armamentarium against OH to have shown
successfull efficacy in several recent randomized, con-
trolled studies [15–19]. However, its use is limited to
hospital specialists because of regulatory restrictions. By
contrast, dihydroergotamine (DHE), an ergot derivative
with alpha-adrenergic agonist activity, is widely used by
general practitioners despite the fact that its usefulness
remains to be demonstrated. In fact, it displays a complex
pharmacology because it can behave as an alpha-
adrenergic receptor agonist or antagonist [20]. Mono-
therapy is only effective in a reduced set of patients
needing antihypotensive drugs [21]. The use of a
combination of midodrine and DHE is frequent in severely
disabled patients (J.M. Senard, A. Pathak, unpublished
data) despite the fact that consequences of midodrine and
DHE combination on BP have never been investigated.
The aim of this study was to investigate in conscious
dogs, the pressor effects induced by administration of
both midodrine and DHE in conditions reproducing
baroreflex dysfunction observed in autonomic failure.
M A T E R I A L S A N D M E T H O D S
Animals
Experiments were performed on six Beagle-Harrier male
dogs weighing 10–16 kg, aged 8–9 years. The dogs were
made to fast on the morning of the experiment but had
free access to water ad libitum. All procedures were
conducted in strict compliance with approved French
Agriculture Department for Animal Use for Research and
Education groups.
General procedure
Two days before pharmacological testing
Two days before pharmacological testing, all dogs under-
went a 24-h ambulatory echocardiogram (ECG) record-
ing. Briefly, two bipolar ECG leads were placed in a
diagonal lead placement as described in other studies [22].
The recordings were performed at a 200-Hz sampling rate.
The ELATEC Holter analysis QT software (ELA Medical,
Montrouge, France) was used for analysis. Recordings
were excluded if they only lasted <20 h, if they were of
poor quality, if atrial fibrillation was present or if T-wave
amplitude was <0.15 mV. The 24-h ECG Holter data were
converted into 2880 templates obtained at 30-s intervals.
Only intervals in which >80% of electrocardiographic
complexes were eligible were included. Heart rate (HR)
was analyzed during day, night and 24-h period. Fresh
blood for catecholamine assay was collected from femoral
arterial catheter. Blood samples were obtained from
conscious animals in a supine position and at the end of
the resting period of cardiovascular stabilization, just
before signal acquisition for HR and BP analysis.
On the day of pharmacological testing
Cardiovascular monitoring. Blood pressure and HR were
recorded by means of a catheter introduced into the
abdominal aorta via the femoral artery, connected to
a Baxter Corporation transducer (Baxter Healthcare
Corporation, Irvine, CA, USA) on a Plugsys recorder
(Hugo Sachs Elektronik, Gruenstrasse, Germany) and
stored in a compatible IBM-PC computer. HR was
obtained using a heart period meter triggered by BP.
The BP signal was digitized at 500 Hz. Systolic blood
presure (SBP), diastolic blood presure (DBP) and HR were
computed for each cycle and extracted at regular intervals
of 500 ms. They were then stored in a compatible IBM-PC
computer. Data were the mean of several beats and
corresponded to the average of 1-min recording.
Plasma catecholamine assay. After cannulation of the
saphenous vein, samples were drawn into heparinized
tubes, stored on ice and centrifuged (2000 g, 10 min,
0 �C). Catecholamines were separated by high-pressure
liquid chromatography and quantified by electrochemical
detection. The sensitivity of the method was 10 pg/mL
[23]. Blood samples were obtained from conscious
animals at the end of the resting period of cardiovascular
stabilization before pharmacological testing.
Pharmacological testing
All experimental protocols were performed after a
15-min resting period of cardiovascular stabilization
(i.e. 20 min after placement of femoral catheter). In the
first part of the study, we assessed the cardiovascular
dose–response effects of three intravenous doses of
noradrenaline (NA) (0.5, 1 and 2 lg/kg) with or without
atropine pretreatment (0.1 mg/kg). Atropine pretreat-
ment was performed to antagonize the baroreflex-
induced changes in HR in order to reproduce in dogs,
46 G. Jourdan et al.
Journal compilation ª 2006 Blackwell Publishing Ltd. No claims to original French government works Fundamental & Clinical Pharmacology 21 (2007) 45–53
the usual decrease in parasympathetic nervous system
activity observed in humans associated with autonomic
failure. The 0.1 mg/kg atropine dose was defined after
preliminary experiments indicating a rather complete
suppression of HR changes induced by NA (data not
shown) and duration of blockade longer enough to allow
experiments lasting for 1 h.
The effects of midodrine alone, DHE alone or midodrine
plus DHE combination on SBP, DBP and HR were analyzed
at differents times after intravenous administration. First,
preliminary studies were carried out to establish the
kinetic of pressor effects induced by 0.4 mg/kg midodrine
(Figure 1a) and 15 lg/kg DHE (Figure 1b) administered
alone. These doses were chosen in accordance to data
from literature [24–27], and from two preliminary studies
(not shown).
A dose–response experiment was thereafter performed
using six i.v. cumulative doses of midodrine (0.15, 0.3,
0.4, 0.45, 0.8 and 1.0 mg/kg; n ¼ 6) administered at
10-min intervals. Another dose–pressor response curve
with four i.v. cumulative doses of DHE (5, 10, 15 and
20 lg/kg; n ¼ 6), administered at 6 minutes intervals
was also carried out. Cardiovascular parameters were
analyzed before any drug administration, 4 min after
atropine (0.1 mg/kg) and 9 min after each midodrine
dose or 5 min after each DHE dose (i.e. at the time of
maximal BP increase as determined in the experiments
investigating the kinetic of the pressor effect).
Finally, we assessed the pressor effects of midodrine
plus DHE combination in two other experimental settings.
In the first setting (A), DHE (15 lg/kg) was administered
first and 5 min later, two cumulative doses of midodrine
(0.4 and 0.8 mg/kg) were injected at 10-min intervals
(experimental group A; n ¼ 6). Another group (control
group A; n ¼ 6) just received two cumulative doses of
midodrine (0.4 and 0.8 mg/kg). In the second setting (B),
midodrine (0.4 mg/kg) was administered first and
10 min later, a single dose of DHE (15 lg/kg) was
injected (experimental group B; n ¼ 6). Another group
(control group B; n ¼ 6) received a single dose of DHE
(15 lg/kg). Cardiovascular parameters were analyzed as
indicated above. In the last part of this study, we assessed
in two dogs the pressor effects of DHE (15 lg/kg) after
alpha1-adrenoceptor blockade by pretreatment with
prazosin (0.1 mg/kg) (without atropine pretreatment).
Statistical methods and data analysis
All results are presented as mean ± standard error of the
mean (SEM). Dose–response curves were fitted by a
nonlinear regression to a sigmoidal using the program
Sigmaplot (Sigmaplot 2002 for Windows version 8.02
SPSS Inc. 1986–2001). All statistical comparisons were
performed after examination of homoscedasticity. Intra-
group comparisons were performed using one-way
ANOVA followed when required by a Dunnett’s post hoc
0
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(b)
0 5 10 15 20 25 30
Time after midodrine injection (min)
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Time after DHE injection (min)
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Figure 1 (a) Effects of a single i.v. injection of midodrine (0.4 mg/kg)
on systolic (j) and diastolic (d) BP changes. Maximal effect
was reached after 9–12 min (SBP, +53 ± 7 mmHg and DBP,
+43 ± 4 mmHg) and remained stable for at least 30 min. (b) Effects
of a single i.v. injection of DHE (15 lg/kg) on systolic (j) and
diastolic (d) BP changes. Maximal effect was reached after 4–6 min
(SBP, +84 ± 8 mmHg and DBP, +70 ± 5 mmHg). Changes in
BP represented the difference between BP value at any time and
BP value after atropine pretreatment. Values are expressed as
mean ± SEM (n ¼ 6).
Midodrine and DHE in vivo interactions 47
Journal compilation ª 2006 Blackwell Publishing Ltd. No claims to original French government works Fundamental & Clinical Pharmacology 21 (2007) 45–53
test and between-group comparisons, using Student’s
t-test or Aspin–Welsh test. A P-value <0.05 was
considered significant.
Drugs
Atropine sulfate was obtained from Aguettant (Lyon,
France). Noradrenaline bitartrate and prazosin were from
Sigma Chemical Co. (Lyon, France). Midodrine hydrochlo-
ride was a generous gift from Nycomed (Linz, Austria) and
DHE from Novartis Pharma (Rueil-Malmaison, France).
R E S U L T S
Holter monitoring
Data from 24-h Holter ECG recording indicate that dogs
had 24-h HR (98 ± 4.6 bpm) similar to that observed at
the beginning of any midodrine–DHE experiment and
obtained through BP recording post-processing. How-
ever, the expected reduction in HR at night was not
observed in our old dogs (HR day vs. night: 100.4 ± 5.2
vs. 95 ± 4.7 bpm, ns).
Plasma catecholamines
In the resting period, in our old conscious dogs,
noradrenaline and adrenaline levels were 626.5 ±
56.9 and 345.5 ± 45.6 pg/mL, respectively.
Effects of atropine on BP and HR
Atropine alone (0.1 mg/kg i.v.) drastically increased HR
(+139 ± 11 bpm) and decreased SBP by 35 ± 8 mmHg.
When administered after atropine, at the moment of the
midodrine- or DHE-induced maximal BP increase, a non-
significant decrease in HR by 5 ± 5 and 7 ± 8 bpm for
midodrine and DHE, respectively, was observed. More-
over, a non-significant decrease in HR was also observed
between the beginning and the end of each experiment
(data not shown).
Agonist dose–response experiments
A 140-mmHg increase in SBP was considered as the
maximal increase acceptable in our conscious dogs
(Figure 2). Dose–response curve graphic analysis showed
that the dose required to produce a 50-mmHg increase in
SBP was 0.35 lg/kg for NA, 11 lg/kg for DHE and
400 lg/kg for midodrine.
Pressor effects of midodrine plus DHE combination
Midodrine pressor effects after DHE
During baseline periods (i.e. before and after atropine
pretreatment), mean values of SBP and DBP were not
significantly different in control versus experimental
group A (P > 0.05) (Table I). In controls, i.v. injections
of midodrine (0.4 or 0.8 mg/kg) induced a significant
increase in both SBP and DBP. In experimental group A
(midodrine administered after DHE), midodrine induced
Log dose (µg/kg)–2
0
20
40
60
80
100
120
140
160
–1 0 1 2 3 4
Sys
tolic
blo
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pre
ssu
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(m
mH
g)
Figure 2 Cumulative dose–response curves for NA (–––), DHE (- - -)
and midodrine (...) injected by i.v. route on systolic BP changes in
conscious dogs after atropine pretreatment (0.1 mg/kg). Systolic BP
changes represented the difference between maximal systolic BP
after any dose of agonist and baseline systolic BP after atropine
pretreatment. Values (d) are expressed as mean ± SEM (n ¼ 6).
The dose of agonist required to produce a 50-mmHg systolic BP
increase was obtained by graphic analysis (…).
Table I baseline values of HR, systolic and diastolic BP in control
and experimental groups in the setting midodrine after DHE
combination (A).
Control
group A
Experimental
group A
Student’s
t-test
Systolic BP (mmHg)
Before any drug administration 216 ± 5 227 ± 3 NS
After atropine pretreatment 190 ± 7 191 ± 5 NS
After DHE pretreatment (15 lg/kg) – 259 ± 9 –
Diastolic BP (mmHg)
Before any drug administration 90 ± 3 98 ± 2 NS
After atropine pretreatment 98 ± 4 102 ± 4 NS
After DHE pretreatment (15 lg/kg) – 155 ± 8 –
HR (bpm)
Before any drug administration 111 ± 2 102 ± 6 NS
After atropine pretreatment 228 ± 10 228 ± 9 NS
After DHE pretreatment (15 lg/kg) – 231 ± 11 –
Values are expressed as mean ± SEM.
Differences between control and experimental groups were tested for
statistical significance by Student’s t-test (P < 0.05 was considered
significant).
48 G. Jourdan et al.
Journal compilation ª 2006 Blackwell Publishing Ltd. No claims to original French government works Fundamental & Clinical Pharmacology 21 (2007) 45–53
an increase in SBP and DBP reaching only a statistically
significant level for the 0.8 mg/kg dose (one-way ANOVA,
Dunnett’s post hoc test: P < 0.05). The changes in SBP
and DBP were significantly different for any dose of
midodrine between control and experimental groups A
(P < 0.05) (Figure 3).
DHE pressor effects after midodrine
During baseline periods (i.e. before and after atropine
pretreatment), mean values of SBP and DBP were not
significantly different in controls and in experimental
group B (P > 0.05) (Table II). In control group B (DHE
alone) as in experimental group B (DHE administered
after midodrine), a single i.v. injection of DHE (15 lg/kg)
induced a significant increase in SBP and DBP at any
time of evaluation (one-way ANOVA, Dunnett’s post hoc
test: P < 0.05). Between-group analysis showed that the
increases in DBP were significantly (P < 0.05) different
5, 10 and 15 min after DHE administration and
increases in SBP only 5 and 10 min after (Figure 4).
Pressor effects of DHE after alpha1-adrenoceptor
blockade
Prazosin (0.1 mg/kg) pretreatment only partially blocked
the pressor response induced by DHE (Figure 5).
D I S C U S S I O N
In the present study, the pressor effects of a coadminis-
tration of two antihypotensive drugs, midodrine and DHE,
were investigated in vivo in old conscious dogs. Our
results show that DHE acts in vivo as an alpha1-
adrenoceptor partial agonist in contrast to midodrine
which acts as a full agonist. Consequently, the combina-
tion of these two agonists in old conscious dogs (>8 years
old) do not potentiate each other’s pressor effect but lead
to a drastic reduction of blood pressure level.
First and foremost, the choice of our canine model
needs comments. In fact, we deliberately decided to study
old animals (age >8 years old) with high resting BP
010
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0 0.4 0.8
Cumulative doses of midodrine (mg/kg)
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loo
d p
ress
ure
chan
ges
(m
mh
g)
#
#
#*
*
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100
0 0.4 0.8
Cumulative doses of midodrine (mg/kg)
Sys
tolic
blo
od
pre
ssu
rech
ang
es (
mm
Hg
)
#
#
#*
*
Figure 3 Effects of two cumulative doses of midodrine (0.4 and
0.8 mg/kg) administered alone (–––) and after DHE pretreatment
(15 lg/kg) (- - -) on systolic (j) and diastolic (d) BP changes.
Values are expressed as mean ± SEM (n ¼ 6). Differences between
control and experimental groups were tested for statistical signifi-
cance by Student’s t-test (*P < 0.05 was considered significant).
Differences in control and experimental groups were tested for
statistical significance by one way ANOVA followed by Dunnett’s
post hoc test (#P < 0.05) was considered significant versus baseline
values. Atropine pretreatment and DHE pretreatment values
(maximal values obtained) were considered as baseline value for
control and experimental group, respectively.
Table II baseline values of HR, systolic and diastolic BP in control
and experimental groups in the setting DHE after midodrine
combination (B).
Control
group B
Experimental
group B
Student’s
t-test
Systolic BP (mmHg)
Before any drug administration 216 ± 8 221 ± 8 NS
After atropine pretreatment 183 ± 9 186 ± 9 NS
After midodrine pretreatment
(0.4 mg/kg)
– 231 ± 5 –
Diastolic BP (mmHg)
Before any drug administration 95 ± 5 103 ± 9 NS
After atropine pretreatment 106 ± 8 105 ± 7 NS
After midodrine pretreatment
(0.4 mg/kg)
– 144 ± 4 –
HR (bpm)
Before any drug administration 99 ± 4 109 ± 2 NS
After atropine pretreatment 237 ± 11 239 ± 9 NS
After midodrine pretreatment
(0.4 mg/kg)
– 233 ± 8 –
Values are expressed as mean ± SEM.
Differences between control and experimental groups were tested for
statistical significance by Student’s t-test (P < 0.05 was considered
significant).
Midodrine and DHE in vivo interactions 49
Journal compilation ª 2006 Blackwell Publishing Ltd. No claims to original French government works Fundamental & Clinical Pharmacology 21 (2007) 45–53
levels in order to compare with findings in humans
which that during autonomic failure, supine arterial
hypertension is found in around 70% of patients and is
frequently associated with neurogenic OH [28]. Cate-
cholamine plasma levels were obtained in these condi-
tions of high BP measurement, i.e. in conscious animals
and at the end of the resting period. These levels are
indeed slightly greater than those obtained in similar
conditions by our team; however, the subjects were
younger (<2 years old) [29]. These findings exclude
abnormal sympathetic activation as well as any rela-
tionship between high BP, stress and sympathetic
activation. To the best of our knowledge, modification
of age-related catecholamine plasma levels are not well
defined in dogs but a slight increase is a common finding
in elderly humans [30]. Taken together, these data
suggest that high BP levels in our dogs can be related
to age-impaired baroreflex activity. Moreover, additional
data coming from 24-h Holter ECG recording indicate
that animals had 24-h HR similar to those observed in
midodrine-DHE experiments (98 ± 4.6 bpm) but that
the normal reduction in HR at night is no longer
observed [31]. This lower HR variability (night/day) is
also a common finding in old patients suffering from
severe OH [32, 33]. Finally, in order to reproduce the
decreased parasympathetic nervous system regulation of
HR frequently reported in autonomic nervous system
diseases, dogs were also pretreated with atropine. As
reported in the literature and in accordance with our
experimental observations (no significant decrease in HR
between the beginning and the end of experiment),
atropine remained effective for 1–112
h, i.e. the maximal
duration of our experiments and allowed us to be sure of
complete blockade of parasympathetic nervous system
during all the procedures. Taken together, these data
suggest that our canine model closely reproduces chan-
ges observed in old human patients suffering from
autonomic failure, especially supine high BP.
The first part of this study was designed to determine
potency and intrinsic activity of both midodrine and
DHE. The potency of an agonist is usually defined as the
drug concentration or dose required to produce a half-
maximal response (ED50). However, defining ED50 would
require using very large doses of drugs with potential
deleterious adverse reactions linked to excessive increase
in BP. This is the reason why we decided to define the
dose necessary to produce a reasonable increase in BP,
50 mmHg. The potency order obtained in our study was
0.35, 11 and 400 lg/kg for NA, DHE and midodrine,
respectively. Efficacy or intrinsic activity of a drug is
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Time (min)
#*
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#
# #
##
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0 5 10 15 20 25
Time (min)
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es (
mm
Hg
)#
#*
#
#*
#
##
#
#
#
Dia
sto
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loo
d p
ress
ure
chan
ges
(m
mh
g)
Figure 4 Effects of a single dose of DHE (15 lg/kg) administered
alone (–––) and after midodrine pretreatment (0.4 mg/kg) (- - -) on
systolic (j) and diastolic (m) BP changes. Values are expressed as
mean ± SEM (n ¼ 6). Differences between control and experimen-
tal groups were tested for statistical significance by Student’s t-test
(*P < 0.05 was considered significant). Differences in control and
experimental groups were tested for statistical significance by one
way ANOVA followed by Dunnett’s post hoc test (#P < 0.05 was
considered significant versus baseline values. Atropine pretreatment
and midodrine pretreatment values (maximal values obtained) were
considered as baseline value for control and experimental group,
respectively.)
Prazosin DHE
Blood pressure
Heart rate
Systolic
MeanDiastolic
32392879251921591800144010807203600
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0
0
40
80
120
160
200
70
140
210
280
350
Time (s)
Time (s)
Figure 5 Typical record of pressor effects of DHE (15 lg/kg) after
prazosin pretreatment on BP and HR on one dog.
50 G. Jourdan et al.
Journal compilation ª 2006 Blackwell Publishing Ltd. No claims to original French government works Fundamental & Clinical Pharmacology 21 (2007) 45–53
characterized by the magnitude of the maximal response.
It is reflected as a plateau in the log dose–response curve.
In our experimental conditions, the maximal pressor
effect (Emax) was obtained only for DHE but it appeared
to be the lowest of the three values. According to these
data and to the graphic analysis (Figure 2), the order of
intrinsic activity between each agonist on the pressor
response was: NA > midodrine > DHE. Consequently,
our study strongly suggests that DHE acts as an alpha1-
adrenoceptor partial agonist. It binds to the alpha1-
adrenergic receptor with higher affinity than midodrine
but its efficacy is lower than that of midodrine. To the
best of our knowledge, there is no other in vivo study
assessing this alpha1-adrenoceptor partial agonist beha-
vior of DHE. This result is in good agreement with in
vitro studies and other data from literature [27].
Our results also show that combination of two alpha1-
adrenoceptor agonists, midodrine (a full agonist) with
DHE (a partial agonist) leads to near-complete abolition
of the pressor effect of the first administered drug. In
order to demonstrate a possible pharmacological antag-
onism between these two agonists, we tried to find the
best experimental conditions: (i) doses of agonists indu-
cing maximal systolic and diastolic pressor increases
were used (DHE 15 lg/kg and midodrine 0.8 mg/kg)
and (ii) in experiments with both drugs, the second
agonist was always administered at the moment of the
maximal pressor effects of the first one supposing that a
maximal percentage of the total number of alpha1-
adrenoceptors was then occupied.
In these experimental conditions, our results showed a
significant decrease in midodrine pressor responses when
administered after DHE (Figure 3). These results could be
interpreted as follows. DHE interacts with alpha1-
adrenoceptors and then reduces the total number of
available sites for midodrine. Despite higher affinity, DHE
possesses a lower degree of efficacy than midodrine, a full
agonist. As a consequence, the maximal pressor effect of
midodrine after DHE pretreatment is reduced. These first
experimental results demonstrated that a partial agonist
could antagonize in vivo action of a full agonist [34].
The results of the second combined treatment show
that, after midodrine pretreatment, DHE hypertensive
response was just partially decreased 5 and 10 min after
administration. We have no satisfactory explanation for
this result. Considering our experimental doses, it is
possible that DHE, despite higher affinity does not
completely succeed in removing midodrine from its
receptor sites. Some pharmacokinetic interactions be-
tween midodrine and DHE can also be hypothesized
(unexplored in our experimental work). Our results
showing that prazosin, an alpha1-adrenoceptor blocker,
only partially prevented the pressor effects of DHE
strongly suggest that, similar to other ergot derivatives,
DHE interacts with other receptors than alpha1-adreno-
ceptors, especially 5-hydroxytryptamine (5-HT) recep-
tors [35,36]. The affinity of DHE for several receptors
(a1-HT, 5-HT receptors, etc.) explains that prevision of
its interactions with another drug, as midodrine, remains
speculative. Further studies could then be necessary inclu-
ding midodrine and DHE dose–response curves under
blockade of the different subtypes of 5-HT receptors.
Limitations of the study
This canine model did not reflect all changes in the
autonomic nervous system activity encountered during
human autonomic failure. Hence, modification of postsy-
naptic alpha-adrenoceptors and altered responses to
vasopressor drugs response have also been described
[37]. As a consequence, the clinical relevance of our
experimental results obtained in old dogs remained
unpredictable concerning coadministration of midodrine
and DHE for the treatment of OH in humans. Further
studies of experimental models of autonomic failure and
OH [38] on the one hand and relevant clinical trials
including both healthy volunteers and autonomic failure
patients on the other hand, should then be performed to
confirm these promising initial in vivo outcomes.
C O N C L U S I O N
Our study demonstrated in vivo in dogs a potential
antagonism between midodrine and DHE, suggesting a
risk for a combined treatment with midodrine plus
DHE. Indeed, some clinical observations (J.M. Senard,
A. Pathak, unpublished data) have shown that OH
worsening is an adverse reaction of such combined
treatment in humans. Although in vivo results obtained
in conscious old dogs need to be clinically confirmed in
humans suffering from OH, these results strongly
suggest that a combined treatment of midodrine-DHE
has to be avoided in practice.
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