C Basic & Clinical Pharmacology & Toxicology 2004, 94, 291–297.
Printed in Denmark . All rights reserved
Effects of the Calcitonin Gene-Related Peptide (CGRP)
Receptor Antagonist BIBN4096BS on a-CGRP-Induced
Regional Haemodynamic Changes in Anaesthetised Rats
Udayasankar Arulmani,1Martin P. Schuijt,1Jan P. C. Heiligers,1Edwin W . Willems,1Carlos M. Villalo ´n2
and Pramod R. Saxena1
1Department of Pharmacology, Cardiovascular Research Institute ‘‘COEUR’’, Erasmus MC, University Medical Center
Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands and2Department of Pharmacobiology,
CINVESTAV-IPN, Czda. de los Tenorios 235, Col. Granjas-Coapa, 14330 Me ´xico D.F., Me ´xico
(Received October 30, 2003; Accepted March 4, 2004)
Abstract: Several studies suggest that a calcitonin gene-related peptide (CGRP) receptor antagonist may have antimigraine
properties, most probably via the inhibition of CGRP-induced cranial vasodilatation. We recently showed that the novel
selective CGRP receptor antagonist, BIBN4096BS (1-piperidinecarboxamide, -N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-
piperazinyl] carbonyl] pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl) methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-
quinazolinyl)-, [[R-(R,(R*,S*)]), attenuated the CGRP-induced porcine carotid vasodilatation in a model predictive of
antimigraine activity. In order to evaluate the potential safety of BIBN4096BS in migraine therapy, this study was designed
to investigate the effects of intravenous BIBN4096BS on a-CGRP-induced systemic and regional haemodynamic changes
in anaesthetised rats, using radioactive microspheres. In vehicle-pretreated animals, consecutive intravenous infusions of
a-CGRP (0.25, 0.5 and 1 mg kgª1min.ª1) dose-dependently decreased mean arterial blood pressure with an accompanying
increase in heart rate and systemic vascular conductance whereas cardiac output remained unchanged. a-CGRP also
increased the vascular conductance to the heart, brain, gastrointestinal tract, adrenals, skeletal muscles and skin, whilst
that to the kidneys, spleen, mesentery/pancreas and liver remained unaltered. The above systemic and regional haemodyn-
amic responses to a-CGRP were clearly attenuated in BIBN4096BS (3 mg kgª1intravenously)-pretreated animals. These
results indicate that exogenously administered a-CGRP dilates regional vascular beds via CGRP receptors on the basis
of the antagonism produced by BIBN4096BS. Moreover, the fact that BIBN4096BS did not alter baseline haemodynamics
suggests that endogenously produced CGRP does not play an important role in regulating the systemic and regional
haemodynamics under resting conditions.
Migraine is a neurovascular syndrome thought to be associ-
ated with profound dilation of cranial blood vessels and
activation of the trigeminovascular system (Saxena & Tfelt-
Hansen 2000; Goadsby et al. 2002). Several studies have
shown that vasoactive neuropeptides (e.g. neuropeptide Y,
substance P, calcitonin gene-related peptide; CGRP) may be
involved in the aetiology of this disorder (Edvinsson 2001;
Goadsby et al. 2002). Interestingly, circulating plasma levels
of a-CGRP (a 37-amino acid neuropeptide), but not of
other neuropeptides, are significantly elevated during the
headache phase of a migraine attack (Ashina et al. 2000;
Goadsby et al. 2002) and these elevated a-CGRP levels are
normalised by antimigraine agents, such as sumatriptan,
with complete resolution of headache (Goadsby & Edvins-
son 1993). These findings suggest that CGRP may play a
predominant role in migraine pathogenesis, possibly by di-
lating large cranial blood vessels (Williamson & Hargreaves
2001). Therefore, compounds inhibiting either the CGRP
release or its effects, particularly cranial vasodilatation,
Author for correspondence: Pramod R. Saxena, Department of
Pharmacology, Erasmus University, P.O. Box 1738, 3000 DR Rot-
terdam, Holland (fax π31 10 408 94 58, e-mail p.saxena/eras-
may be efficacious in migraine therapy. In this context,
BIBN4096BS (1-piperidinecarboxamide, -N-[2-[[5-amino-1-
[[4-(4-pyridinyl)-1-piperazinyl] carbonyl] pentyl]amino]-1-
dihydro-2-oxo-3(2H)-quinazolinyl)-, [[R-(R,(R*,S*)]), a po-
tent and selective CGRP receptor antagonist (Doods et al.
2000), completely attenuated carotid vasodilatation by
endogenously released (by capsaicin) as well as exogenously
administered CGRP (Kapoor et al. 2003a & b) in an experi-
mental animal model predictive of antimigraine activity
(Saxena 1995; De Vries et al. 1999). Besides its potential
efficacy, the therapeutic effectiveness of BIBN4096BS in
acute migraine treatment will also depend on its pharmaco-
kinetic properties and potential side effects in humans. With
respect to the latter, it has been shown that BIBN4096BS
attenuates CGRP-induced dilatation of human isolated
coronary arteries (Edvinsson et al. 2002), a vascular bed
that is largely affected by the currently used antimigraine
agents (Maassen VanDenBrink et al. 1999).
On the basis of the above, the present study set out to
analyse in anaesthetised rats, the effects produced by intra-
venous administration of BIBN4096BS on: (i) baseline sys-
temic haemodynamics (to investigate its the potential car-
diovascular side effects); and (ii) the systemic and regional
UDAYASANKAR ARULMANI ET AL.
haemodynamic responses to a-CGRP (to ascertain CGRP
Materials and Methods
Experiments were carried out in 13 male Wistar rats (body weight
356∫35 g) obtained from Harlan, Zeist, The Netherlands. The ani-
mals were initially anaesthetised with an intraperitoneal injection of
sodium pentobarbitone (60 mg kgª1), and additional intravenous
bolus injections (5 mg kgª1, intravenous) were provided every 20–
30 min. to maintain the anaesthesia. A catheter was placed in the
trachea for intermittent positive pressure ventilation with a mixture
of oxygen and room air, using a respiratory pump (small animal
ventilator, Harvard Apparatus, Natick, MA, USA). The ventilation
rate was adjusted (40 strokes min.ª1) to keep the arterial blood
gases within the physiological range. The right common carotid ar-
tery was exposed and a catheter connected to a pressure transducer
(Combitrans disposable pressure transducer, Braun, Melsungen,
Germany) was guided via the carotid artery into the left ventricle.
The presence of the catheter tip in the left ventricle was confirmed
by the observation of a sudden switch from an arterial to a ventricu-
lar pressure profile. The right femoral artery was catheterised and
connected to a pressure transducer (Combitrans disposable pressure
transducer, Braun, Melsungen, Germany) for recording blood
pressure, while the left femoral artery was catheterised for the with-
drawal of reference blood samples. The heart rate was measured
with a tachograph (CRW, Erasmus Medical Centre, Rotterdam, The
Netherlands) triggered by electrocardiogram signals. Both arterial
blood pressure and heart rate were recorded on a polygraph (CRW,
Erasmus Medical Center, Rotterdam, The Netherlands). The right
external jugular vein was catheterised for the administration of
compounds (a-CGRP and BIBN4096BS or the corresponding vol-
umes of vehicle).
Distribution of cardiac output. The distribution of cardiac output
was determined with radioactive microspheres (diameter: 15.5∫0.1
mm; S.D.), labelled with141Ce,103Ru,95Nb or46Sc (NEN Dupont,
Boston, USA). For each measurement, about 200,000 microspheres,
suspended in 0.2 ml of physiological saline and labelled with one of
the isotopes, was mixed and injected into the left ventricle over a
period of 15 sec.; the catheter was thoroughly flushed with 0.5 ml
of saline. Starting 10 sec. before each microsphere injection and
lasting 70 sec., an arterial reference blood sample was drawn from
the left femoral artery at a constant rate of 0.5 ml min.ª1, using a
withdrawal pump (Model 55, Harvard apparatus, Natick, USA).
At the end of the experiment, the animal was killed using an over-
dose of sodium pentobarbitone and all tissues were dissected out,
weighed and put in vials. The following tissues were studied: skeletal
muscles, carcass (consisting of bone with skeletal muscle residue,
fat, tail, eyes, and urogenital tract), mesentery/pancreas (for practi-
cal reasons, these two tissues were not studied separately), adrenals,
lungs, kidneys, skin, heart, liver, brain, gastrointestinal tract and
spleen. The lungs were not evaluated further, because a large
amount of radioactivity in the lungs represents the microspheres
that bypass peripheral vascular beds via arteriovenous anastom-
oses, rather than those reaching lungs via the pulmonary artery
(Baile et al. 1982). The radioactivity in the reference blood samples
and the tissues was counted for 5 min. with a g-scintillation counter
(Packard, Minaxi Auto-Gamma 5000 series), using suitable win-
dows for the discrimination of the different isotopes (141Ce: 120–
167 KeV,103Ru: 450–548 KeV,95Nb: 706–829 KeV and46Sc: 830–
965 KeV). All data were processed by a set of specially designed
computer programs (Saxena et al. 1980).
The cardiac output was calculated by multiplying the ratio of
total and arterial blood sample radioactivity by the withdrawal rate
of the arterial reference blood samples (0.5 ml min.ª1). Accordingly,
tissue blood flow was calculated by multiplying the ratio of the
tissue and total radioactivity by cardiac output (Saxena et al. 1980).
Systemic and regional vascular conductances (i.e. cardiac output
and regional blood flow corrected for mean arterial blood pressure)
were calculated, multiplied by hundred and expressed as 10ª2ml
Experimental protocol. The experiments were started after a stabilis-
ation period of about 30 min. after surgery. At this point, the ani-
mals were divided into two groups. The first group (nΩ6) was pre-
treated with the vehicle of BIBN4096BS (0.5 ml of acidified distilled
water; 0.05 ml min.ª1for 10 min.; intravenous; see Compounds
section), while the second group (nΩ7) was pretreated with
BIBN4096BS (3 mg kgª1, intravenous, dissolved in 0.5 ml vehicle
and administered at a rate of 0.05 ml min.ª1over a period of 10
min.). After a 10 min. wait, baseline values of heart rate, mean
arterial blood pressure, cardiac output and its distribution to the
various tissues (see above) were determined and both groups re-
ceived sequential intravenous infusions of a-CGRP (0.25, 0.5 and 1
mg kgª1min.ª1; each dose for 10 min.). After each dose of a-CGRP
infusion, the above-mentioned haemodynamic variables were reas-
Data presentation and statistical analysis. All data are presented as
mean∫S.E.M. The statistical analysis was performed using a SPSS
package for windows (version 10.0; SPSS Inc., Chicago, IL, USA).
The significance of changes within one group (vehicle or
BIBN4096BS) was analysed with repeated-measures ANOVA, fol-
lowed by Greenhouse-Geisser correction for serial autocorrelation
(Ludbrook 1994) and Bonferroni correction for multiple compari-
sons (Overall & Doyle 1996). The significance of the between-group
changes (vehicle versus BIBN4096BS treatments) was first analysed
with repeated-measures ANOVA, including baseline measurements
as a covariate (Overall & Doyle 1994). If the two groups differed
significantly, pairwise comparisons of the corresponding values in
the vehicle- and BIBN4096BS-treated groups were performed using
univariate analysis (Overall & Atlas 1999), followed by Bonferroni
correction. Statistical significance was accepted at P?0.05 (two-
Ethical approval. The Ethics Committee of the Erasmus MC,
Rotterdam, The Netherlands, dealing with the use of animals in
scientific experiments, approved the protocols for the present inves-
Compounds. The following compounds were used: sodium pento-
barbitone (Sanofi Sante b.v., Maasluis, The Netherlands), heparin
sodium (to prevent clotting of blood in the catheters; Leo Pharma-
ceuticalProducts, Weesp, The
BIBN4096BS (both gifts from Dr. H. Doods, Boehringer Ingelheim
Pharma KG, Biberach, Germany).
a-CGRP was dissolved in distilled water, while BIBN4096BS was
initially dissolved in 0.5 ml of 1N HCl, then diluted with 4 ml of
distilled water, and then adjusted to pH 6.5 by 1N NaOH.
Baseline values of systemic and regional haemodynamic vari-
Baseline values of systemic haemodynamic variables in the
13 anaesthetised rats used in this investigation were: heart
rate, 266∫10 beats min.ª1; mean arterial blood pressure,
108∫3 mmHg; cardiac output, 68∫4 ml min.ª1and sys-
mmHgª1. Baseline values of regional vascular conductances
(10ª2ml minª1mmHgª1/100 g tissue) were: brain, 32∫4;
heart, 409∫58; liver, 35∫3; gastrointestinal tract, 124∫24;
mesentery/pancreas, 32∫4; adrenals, 257∫52; kidneys,
BIBN4096BS ON a-CGRP-INDUCED REGIONAL HAEMODYNAMICS
417∫38; spleen, 92∫24; skeletal muscle, 5∫0.4; and skin,
5∫1. These values were similar to those reported earlier
from our laboratories (Schuijt et al. 1999).
The baseline values in the animals pretreated with vehicle
(nΩ6) and BIBN4096BS (nΩ7) did not differ significantly:
heart rate (275∫19 versus 259∫8 beats min.ª1); mean ar-
terial blood pressure (108∫3 versus 108∫5 mmHg); cardiac
output (68∫6 versus 69∫6 ml min.ª1); systemic vascular
conductance (63∫6 versus 65∫7 10ª2ml min.ª1mmHgª1)
and regional vascular conductances (10ª2ml min.ª1
mmHgª1/100 g tissue) in brain (32∫5 versus 33∫6), heart
(393∫101 versus 423∫72), liver (33∫6 versus 36∫2), gas-
trointestinal tract (103∫16 versus 141∫43), mesentery/pan-
creas (33∫7 versus 32∫4), adrenals (282∫96 versus
235∫58), kidneys (445∫56 versus 394∫54), spleen (100∫50
versus 85∫16), skeletal muscle (5∫0.5 versus 4∫0.5) and
skin (6∫1 versus 4∫0.7).
Fig. 1. Absolute values of heart rate (HR), mean arterial blood pressure (MAP), cardiac output (CO) and systemic vascular conductance
(SVC) before (a-CGRP, 0 mg kgª1min.ª1; baseline) and following intravenous infusions of a-CGRP (0.25, 0.5 and 1 mg kgª1min.ª1) in
anaesthetised rats pretreated intravenously with BIBN4096BS (3 mg kgª1, nΩ7) or the corresponding volume of the vehicle (0.5 ml, nΩ6).
All values are expressed as mean∫s.e.mean. *P? .05 compared to baseline values;
.P?0.05 compared to the corresponding dose in vehicle-
Systemic haemodynamic responses to a-CGRP.
The absolute changes in systemic haemodynamics following
consecutive intravenous infusions of a-CGRP (0.25, 0.5 and
1 mg kgª1min.ª1) in the animals pretreated intravenously
with BIBN4096BS (3 mg kgª1) or the corresponding vol-
ume (0.5 ml) of the vehicle are shown in fig. 1. a-CGRP
dose-dependently decreased mean arterial blood pressure
(maximum percent change from baseline: 55∫5), but in-
creased systemic vascular conductance (maximum percent
change from baseline: 56∫21) and heart rate (maximum
percent change from baseline: 17∫3). BIBN4096BS pre-
treatment produced an attenuation of the systemic haemo-
dynamic responses produced by a-CGRP. Under these con-
ditions, the highest dose of a-CGRP elicited small, though
significant, decreases (maximum percent changes from base-
line) in: (i) mean arterial blood pressure (28∫4 versus 51∫7
UDAYASANKAR ARULMANI ET AL.
Fig. 2. Absolute values of regional vascular conductances before (a-CGRP, 0 mg kgª1min.ª1; baseline) and following intravenous infusions
of a-CGRP (0.25, 0.5 and 1 mg kgª1min.ª1) in anaesthetised rats pretreated intravenously with BIBN4096BS (3 mg kgª1, nΩ7) or the
corresponding volume of the vehicle (0.5 ml, nΩ6). All values are expressed as mean∫s.e.mean. *P?0.05 compared to baseline values;
.P?0.05 compared to the corresponding dose in vehicle-pretreated animals.
BIBN4096BS ON a-CGRP-INDUCED REGIONAL HAEMODYNAMICS
in vehicle pretreated animals); and (ii) systemic vascular
conductance (16∫6 versus 27∫8 in vehicle pretreated ani-
Regional haemodynamic responses to a-CGRP.
Fig. 2 depicts absolute changes in regional vascular conduc-
tance following consecutive intravenous infusions of a-
CGRP (0.25, 0.5 and 1 mg kgª1min.ª1) in the animals pre-
treated intravenously with BIBN4096BS (3 mg kgª1) or the
corresponding volume of the vehicle. a-CGRP increased
vascular conductance (maximal percent change from base-
line) to the brain (124∫45), gastrointestinal tract (80∫35),
heart (74∫31), adrenals (87∫37), muscle (79∫27) and skin
(154∫37), whilst that to the mesentery/pancreas, liver,
spleen and kidneys remained unchanged. BIBN4096BS at-
tenuated the above regional haemodynamic changes in-
duced by a-CGRP. The vascular conductance to the kidneys
decreased significantly in vehicle-pretreated animals follow-
ing the highest dose of a-CGRP (1 mg kgª1min.ª1), but
this was not the case in the animals pretreated with
CGRP receptors are widely distributed throughout the
body and are predominantly expressed in the nervous sys-
tem including perivascular nerves (Okimura et al. 1987;
Sternini et al. 1992). Therefore, CGRP may play an import-
ant role in regulating peripheral vascular tone and in con-
trolling blood flow to various organs (Poyner et al. 2002).
Several lines of evidence suggest that an increase in the re-
lease of CGRP is a potential causative factor in some path-
ological conditions including migraine (Wimalawansa
1996). Hence, the advent of BIBN4096BS may represent an
important headway in treating migraine.
Apart from the implications discussed below, our study
in anaesthetised rats shows that BIBN4096BS: (i) had no
effect on baseline systemic and regional haemodynamics,
suggesting cardiovascular safety, and (ii) antagonised a-
CGRP-induced changes in systemic and regional haemo-
dynamics, demonstrating a wide distribution of CGRP re-
Systemic haemodynamic changes to a-CGRP.
The potential role of CGRP in regulating the systemic
haemodynamics has been studied extensively in several spe-
cies, including man (Franco-Cereceda et al. 1987; Ventura
et al. 2000; Rasmussen et al. 2001). Accordingly, CGRP
decreases systemic blood pressure through its potent vaso-
dilator effect on the peripheral arteries (van Rossum et al.
1997). The blockade of CGRP-induced hypotension by
BIBN4096BS (fig. 1) confirms that this response was me-
diated by a CGRP receptor. Interestingly, the hypotensive
response to the highest dose of a-CGRP (1 mg kgª1min.ª1,
intravenous) was only partly blocked by BIBN4096BS; this
may be attributed, at least in part, to the lower affinity of
BIBN4096BS for the rat CGRP receptor (spleen; KiΩ3.4
nM) compared to the human recombinant CGRP receptor
expressed in SK-N-MC cells (KiΩ14.4 pM) (Doods et al.
2000). Consistent with our findings, it has been reported
that BIBN4096BS is more potent than CGRP8–37at the rat
CGRP receptor (Poyner et al. 2002). However, a non-speci-
fic vasodilatation to CGRP via the production of nitric ox-
ide cannot be categorically excluded in our experiments
(Akerman et al. 2002; de Hoon et al. 2003).
On the other hand, with respect to the tachycardic re-
sponses to a-CGRP observed in the present study, it is
worthy of note that cardiac CGRP receptors are more
abundant in the sinoatrial node and atria than in the ven-
tricles (Du et al. 1994; Bell & McDermott 1996; Wimala-
wansa 1996; Opgaard et al. 2000). Most importantly, this
response is resistant to b-adrenoceptor antagonists, sug-
gesting a direct chronotropic action of a-CGRP in the rat
heart (Marshall et al. 1986). However, putative involvement
of a baroreceptor reflex mechanism cannot be entirely ruled
out in our experimental set-up.
It is worthy of note that CGRP is a potent inotropic
agent in rabbits, pigs as well as humans (Van Gelderen et
al. 1995; Bell & McDermott 1996), but not in rats (Ishikawa
et al. 1987; Bratveit et al. 1991). This may explain the lack
of effect of a-CGRP on cardiac output in our study (fig. 1).
Regional haemodynamic changes by a-CGRP.
The regional haemodynamic responses to a-CGRP ob-
served in our study clearly demonstrate the vasodilator
properties of CGRP in different vascular beds. Further-
more, the CGRP-induced increases in vascular conduc-
tances in the heart, brain, gastrointestinal tract, adrenals,
skin and skeletal muscle were attenuated by BIBN4096BS
(fig. 2), indicating that these responses are mediated via
CGRP receptors. However, tissues such as liver, spleen,
mesentery/pancreas and kidneys did not apparently show
any changes following CGRP infusions. Several possible ex-
planations for this lack of effect of CGRP, amongst others,
may include: (i) tissue-dependent factors such as the density
of CGRP receptors and coupling efficiency, and/or (ii) a
blunting effect via the activation of compensatory pressor
mechanisms triggered by a reduction in systemic blood
pressure (DiPette et al. 1989; Gardiner et al. 1990).
Clinical implications of CGRP antagonism by BIBN4096BS.
Lastly, we would like to consider the possible clinical impli-
cations of BIBN4096BS safety in antimigraine therapy.
BIBN4096BS, which is effective in antagonising CGRP-in-
duced responses in both in vivo and in vitro studies (Edvins-
son et al. 2002; Moreno et al. 2002; Verheggen et al. 2002;
Kapoor et al. 2003a & b), has been shown effective in a
phase II clinical trial for acute antimigraine therapy (Ed-
vinsson 2003; Olesen et al. 2004). In this context, our study
shows that BIBN4096BS did not compromise the blood
flow in a number of tissues, even in a dose that may be
considered relatively higher than that used in the clinic.
Thus, BIBN4096BS does not show any unwanted cardio-
vascular effects in our experiments.
UDAYASANKAR ARULMANI ET AL.
In conclusion, the present investigation demonstrates
that: (i) exogenously administered a-CGRP dilates several
regional vascular beds in a dose-dependent manner; and (ii)
endogenous CGRP does not play an important role in regu-
lating systemic and regional haemodynamics.
This study was partly supported from funds obtained
from Boehringer Ingelheim Pharma KG (Biberach, Ger-
many) for a contract research project with Erasmus Pharma
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