Journal of Human Hypertension (1999) 13, (Suppl 1), S75–S80
 1999 Stockton Press. All rights reserved 0950-9240/99 $12.00
Pharmacologic properties of candesartan
cilexetil—possible mechanisms of longacting antihypertensive action
Y Inada, M Ojima, R Kanagawa, Y Misumi, K Nishikawa and T Naka
Pharmaceutical Research Division, Takeda Chemical Industries Ltd, Osaka, Japan
Candesartan cilexetil has shown potent and long-lasting
antihypertensive effects in clinical trials and in several
animal models of hypertension. In spontaneously hypertensive rats, the duration of the antihypertensive effect
of candesartan cilexetil was compared to those of losartan, valsartan, eprosartan, and irbesartan at the same
degree of maximal blood pressure reduction. A single
oral dose of candesartan cilexetil at 0.3 mg/kg reduced
maximal blood pressure by about 25 mm Hg, and the
antihypertensive effect of candesartan cilexetil lasted
the longest, continuing for more than 1 week, without an
effect on circadian rhythm. In a rabbit aortic preparation,
candesartan, active form of candesartan cilexetil,
decreased the maximal contractile response of angiotensin II. This inhibitory mode was different from that of
other angiotensin II-receptor antagonists, and showed a
shift to the right in the angiotensin II-induced contraction curve and/or a small depression of the maximal
response. In kinetic studies using bovine adrenal
cortical membrane and tritiated candesartan, both
receptor association and dissociation were found to be
slow. The dissociation rate of tritiated candesartan binding (t1/2 = 66 min) was five times slower than that of
radiolabelled angiotensin II binding (t1/2 = 12 min). The
insurmountable inhibition of candesartan in vascular
contraction is the result of its tight binding and slow
dissociation from angiotensin II AT1 receptors. These
characteristics are related to the potency and long duration of action in candesartan cilexetil.
Keywords: antihypertensive action; candesartan cilexetil; angiotensin II receptors; kinetic studies; insurmountable inhibition
Introduction
The final purpose of antihypertensive treatment is to
reduce morbidity and mortality from cardiovascular
disease associated with hypertension. To achieve
this aim, well-tolerated antihypertensive agents
with long durations of action are required. The
renin-angiotensin system is a cascade of enzymatic
reactions leading to the formation of its primary
effective molecule, angiotensin II. Angiotensin II is
a potent vasoconstrictor, growth promoter, and
fibrosis promoter. It facilitates vasoconstriction,
increases renal retention volume, and leads to vascular growth that is associated with hypertension.1,2
An inhibitor of this system would be expected to
have an efficacy not only for treatment of hypertension, but also for treatment of various cardiovascular
and renal diseases. The angiotensin II-receptor
antagonists provide a specific blockade of the reninangiotensin system by competing directly with angiotensin II at its receptor. These drugs are therefore
highly specific and effective, as they block the
effects of angiotensin II produced by both the angiotensin-converting enzyme (ACE) and alternative
angiotensin II-generating pathways.3,4 In addition,
because the angiotensin II antagonists do not affect
bradykinin, substance P, or tachykinin metabolism,
Correspondence: Yoshiyuki Inada, Pharmaceutical Research
Division, Takeda Chemical Industries Ltd, 17-85, Juso-honmachi
2-chome, Yodogawa-ku, Osaka 53, Japan
they do not cause the class-specific side effects associated with ACE inhibitors.5 The potential of antihypertensive therapy to reduce morbidity and mortality has been demonstrated in clinical studies
involving large numbers of patients. However, it is
equally clear that the potential of antihypertensive
therapy is not fully realised, and that the complicated results are dependent on the drug profiles.
Recently, many angiotensin II-receptor antagonists
have been used clinically.6,7 Angiotensin II receptor
antagonists vary in their receptor-binding characteristics, and therefore, in their potencies and pharmacologic properties.
Candesartan cilexetil, developed by Takeda
Chemical Industries Ltd, Japan, is the prodrug of
candesartan, a novel, specific, and competitive
antagonist of the angiotensin II type 1 (AT1) receptors.8–11 Candesartan cilexetil showed antihypertensive action in clinical trials and in animal models of
hypertension.6,7,12,13 In this report, we compare the
duration of the antihypertensive effect of candesartan cilexetil with that of other AT1-receptor antagonists. We also review the relationship between duration of action and mode of inhibition of angiotensin
II-induced effects.
Antihypertensive effects in spontaneously
hypertensive rats
This study compared the duration of the antihypertensive action in spontaneously hypertensive rats
(20 to 32 weeks of age). Blood pressure was meas-
Pharmacologic properties of candesartan cilexetil
Y Inada et al
S76
til produced a maximal blood pressure reduction
similar to those of losartan 30 mg/kg and irbesartan
100 mg/kg (Figure 2a). The antihypertensive action
of candesartan cilexetil at 0.3 mg/kg and 1 mg/kg
persisted for over 20 h, and for nearly 60 h, respectively, and was more prolonged than for the other
angiotensin II-receptor antagonists (Figure 2b).
Inhibitory effects on the contractile response
induced by angiotensin II in rabbit aortic strips
Figure 1 Antihypertensive effects of candesartan cilexetil in
spontaneously hypertensive rats. Blood pressure was measured
in every 5 min by telemetry method. The values of blood pressure
were expressed by the average for each 30 min (n = 5–8).
ured every 5 min by the telemetry method. The
values of blood pressure were expressed by the average for each 30 min (mean of six measurements). As
shown in Figure 1, candesartan cilexetil, 0.3 to
10 mg/kg p.o., dose dependently lowered blood
pressure, with a prolonged duration at doses of
1 mg/kg and greater.
The maximal reduction of blood pressure was calculated from the mean blood pressure of each 30min period minus the average of the mean blood
pressure on the previous day of administration. The
duration of action was calculated as the area over
the curve for 1 week after the administration, divided by the maximal reduction of blood pressure.
The maximal reductions of blood pressure with candesartan cilexetil at 0.1, 0.3, 1, and 10 mg/kg p.o.
were as follows: −23.3 ± 1.9, −28.5 ± 1.4, −31.5 ± 1.8,
and −40.4 ± 2.2 (mean ± s.e.m.), respectively. At a
dose of 0.3 mg/kg, candesartan cilexetil produced a
maximal blood pressure reduction similar to those
of losartan 10 mg/kg, eprosartan 100 mg/kg, irbesartan 30 mg/kg, and valsartan 10 mg/kg on day 1
(Figure 2a). At a dose of 1 mg/kg, candesartan cilexe-
The contractile responses in helical strips of rabbit
thorathic aorta induced by angiotensin II were measured using a force-displacement transducer. The
mean force development in responses to increasing
concentrations of angiotensin II was recorded with
and without AT1-receptor antagonist. The response
to angiotensin II in the presence of AT1-receptor
antagonist was expressed as percentage of the maximal response (100%) to angiotensin II that was
obtained prior to the AT1-receptor antagonist incubation period.
As shown in Figure 3, candesartan inhibited the
angiotensin II-induced contractile response of rabbit
aorta at very low concentrations (0.1 nmol/L).11 Candesartan at 1 nmol/L almost completely inhibited
the angiotensin II-induced contractile response of
the strip, indicating non-competitive antagonism
(insurmountable inhibition). Irbesartan at 1 to
100 nmol/L, and losartan at 10 to 100 nmol/L,
shifted the angiotensin II-induced contractile curve
to the right in a parallel fashion, with no decrease
of
the
maximal
response
(surmountable
inhibition).11,14 These compounds showed competitive antagonism. EXP3174, an active metabolite of
losartan, at a concentration of 0.01 to 1 nmol/L,
caused a shift to the right in the angiotensin II concentration-contractile response curve, but with a
small depression of the maximal response, which
showed a mixed antagonism with both competitive
and
non-competitive
types
(insurmountable
inhibition).11,14
The inhibition of the angiotensin II (3 nmol/L)induced contraction by the pretreatment with candesartan at 0.1 to 1 nmol/L for 60 min was not reco-
Figure 2 Comparison of antihypertensive effect and its duration of angiotensin II receptor antagonists in spontaneously hypertensive
rats, means ± s.e.m. (n = 4 –9).
Pharmacologic properties of candesartan cilexetil
Y Inada et al
S77
Figure 3 Comparison of inhibitory effects of angiotensin II receptor antagonists on angiotensin-induced contraction in rabbit aorta. The
response to angiotensin II in the presence of AT1 receptor blockade was expressed as percent of the maximal response (100%) to
angiotensin II, obtained prior to the 30-min AT1-receptor blockage incubation period (reproduced from Shibouta et al11). Results are
expressed as means ± s.e.m (n = 3–5).
vered 2 h after washing in the rat portal vein.15 In
contrast, after 2 h of washing, the inhibition of the
angiotensin II-induced contraction by pretreatment
with irbesartan, losartan, and EXP3174 was almost
reversed. Thus, the duration of the inhibitory effect
of candesartan on contractile response induced by
angiotensin II is longer than that of irbesartan, losartan, or EXP3174.15
Table 1 Inhibitory effects of various angiotensin II-receptor
antagonists on the specific binding of [125I]angiotensin II to the
human AT1 receptor
Compound
Candesartan
EXP3175
Eprosartan
Irbesartan
Valsartan
Inhibition IC50: mol/L
3.0
9.2
5.3
8.0
6.0
×
×
×
×
×
10−9
10−9
10−8
10−9
10−8
Inhibitory effects on the binding of
[125I]angiotensin II to the human angiotensin AT1
receptor prepared from COS-7 cells
Human AT1 receptors were isolated from a human
heart cDNA library and transfected into COS-7
cells.16 Crude membrane fractions from the cells
were used for the assay of binding inhibition of AT1receptor antagonists. Inhibitory effects of AT1-receptor antagonists on [125I]angiotensin II binding were
examined. As shown in Table 1, inhibitory activities
were expressed as IC50 values (the effective concentrations for half-inhibition). Candesartan inhibited
the binding of [125]angiotensin II in human AT1
receptors at an IC50 value of 3.0 × 10−9 mol/L. Candesartan was the most potent of the angiotensin II
receptor antagonists tested. The inhibitory potencies
of these agents were in the following order: candesartan ⭓ irbesartan, EXP3174 ⬎ eprosartan and valsartan.
Kinetics studies of [3H]candesartan or
[125I]angiotensin II in bovine adrenal angiotensin
II receptor
In association experiments,17 the specific binding of
[3H]candesartan and [125I]angiotensin II at AT1
receptor sites prepared from bovine adrenal cortex
was determined at various time intervals. In these
experiments, the specific binding of [3H]candesartan
increased slowly and reached equilibrium after 90
min. This equilibrium was maintained for as long as
180 min of incubation. Figure 4a shows pseudo firstorder kinetics plots of initial binding of [3H]candesartan and [125I]angiotensin II to membranes. The specific binding of [125I]angiotensin II (0.2 nmol/L)
increased more rapidly than that of [3H]candesartan
and reached equilibrium after 60 min. The associ-
Pharmacologic properties of candesartan cilexetil
Y Inada et al
S78
Figure 4 The specific binding of [3H]candesartan and [125I]angiotensin II at AT1-receptors prepared from bovine adrenal cortex, determined at various time intervals. Beq is the amount of specific binding at equilibrium, and Bt is the specific binding at time t. (앩) angiotensin
II, (쐌) candesartan (reproduced from Ojima et al17).
ation rate constants of [3H]candesartan and [125I]angiotensin II were calculated from these studies to be
0.0059 and 0.0660 min/nmol/L, respectively.
In the dissociation experiments,17 [3H]candesartan
and [125I]angiotensin II were incubated to steady
state, excess unlabelled ligands were added, and
specific AT1 binding was examined at various time
intervals. The dissociation rate constants were calculated from Figure 4b, and are 0.0104, and 0.0571
min/nmol/L, respectively, for candesartan and angiotensin II. Dissociation of the [3H]candesartan from
AT1 receptor had an initial half-life (t1/2) of 66 min.
In contrast, dissociation of the [125I]angiotensin IIAT1 receptor complex caused by the addition of
excess angiotensin II was rapid, with a t1/2 of 12 min.
The dissociation rate of [3H]candesartan was five
times slower than that of [125I]angiotensin II.
Discussion
Candesartan provides a highly potent, long-acting,
and selective angiotensin II type 1 (AT1) receptor
blockade.10,11,17,18 It is administered orally as the
inactive prodrug, candesartan cilexetil, which is
rapidly and completely converted to candesartan
during gastrointestinal absorption.19 Candesartan
cilexetil has been shown to possess potent and longlasting antihypertensive effects in several animal
models and clinical trials of patients with hypertension.6,7,12,13,20 In spontaneously hypertensive rats,
single oral doses of candesartan cilexetil (0.1–
10 mg/kg) reduced blood pressure by 25 to 40
mm Hg for more than 10 h, and the effect at 1 mg/kg
was pronounced even after 48 h (−30 mm Hg).
Other angiotensin II receptor antagonists require
a much higher dose to induce a similar antihypertensive effect as that of candesartan cilexetil
0.3 mg/kg (losartan, 1 mg/kg; irbesartan, 30 mg/kg;
eprosartan, 100 mg/kg; and valsartan, 10 mg/kg)
(Figure 2). These differences of the doses required
to produce similar antihypertensive effects in spontaneously hypertensive rats are larger than the differences found in IC50 values for inhibitory effects
on the binding of [125I]angiotensin II at human AT1
receptors. Although several factors, including
bioavailability and protein binding (except the binding potency in vitro), affect the antihypertensive
effect,19,21 it is thought that a more important factor
than the difference in IC50 values exists to explain
these differences in antihypertensive efficacy.
In spontaneously hypertensive rats, oral administration of candesartan cilexetil at 1 mg/kg for 2
weeks reduced blood pressure by 30 to 50 mm Hg
for more than 24 h. The antihypertensive effects of
candesartan cilexetil correlated well with the ex
vivo inhibition of the drug on angiotensin II-induced
contractile responses in aortic strips prepared from
the treated rats.12 Specifically, candesartan cilexetil
inhibited the angiotensin II-induced contractile
responses in the aorta isolated 5 and 24 h after oral
administration, when the blood pressure was significantly reduced in vivo. This ex vivo inhibitory
effect, however, was not evident when the blood
pressure-lowering effects had disappeared. These
findings suggest that inhibition of the action of angiotensin II at its receptor site on the vascular wall
determines the degree and time course of the antihypertensive effects of candesartan.
In aortic strip preparations from the rabbit (Figure
3a), candesartan has been shown to produce a clear,
dose-dependent reduction in the maximum contraction of vascular strips exposed to angiotensin II. In
contrast, losartan and irbesartan shifted the contractile response curve to the right, without affecting the
maximal response.14 This indicates a competitiveinhibiting profile, in which angiotensin II is able to
displace losartan and irbesartan at the AT1 receptor.
EXP3174, the active metabolite of losartan, showed
a mixed-inhibiting profile. It has been reported eprosartan produced surmountable (competitive) inhibition,22 but valsartan,23 and irbesartan24 produced
insurmountable inhibitions. In these reports, irbesartan and valsartan showed insurmountable inhibition, but they had a mixed type of competitive and
non-competitive inhibition, and were not totally
non-competitive. Furthermore, following washings,
irbesartan was shown to have a competitive manner
Pharmacologic properties of candesartan cilexetil
Y Inada et al
of inhibition after 22 h of equilibrium had been
reached.14
The antihypertensive effect of candesartan cilexetil in spontaneously hypertensive rats was more prolonged than that of other agents. The duration of
antihypertensive action is thought to be related to
the inhibitory manner of the non-competitive inhibition; such inhibition is thought to produce a
longer effect on the contractile response induced by
angiotensin II in vascular preparations in vitro.15
In in vitro kinetic studies,17 [125I]angiotensin II dissociated rapidly, with an initial half-time of dissociation (t1/2) of 12 min in adrenal cortical membranes, which is similar to the result of Grossman et
al25 using the membrane fraction of bovine adrenal
cortex (t1/2 of [125I]angiotensin II = 13–23 min. It has
been shown that [3H]losartan dissociated rapidly
from angiotensin II-binding sites in rate adrenal
microsomes (t1/2 of [3H]losartan = 2.5 min).26 In contrast, the dissociation rate of [3H]candesartan was
five times slower than that of [125I]angiotensin II (t1/2
of [3H]candesartan = 66 min). Kinetic receptor-binding studies have demonstrated that the dissociation
half-life of candesartan from AT1 receptor is
approximately five times longer (66.3 min) than that
of angiotensin II (12.2 min) and 33 times longer than
that of losartan (2.5 min).26 Furthermore,
[125I]EXP985, a close structural analog of losartan,
which, like candesartan, showed insurmountable
antagonism in vascular contraction studies, also dissociates slowly from angiotensin II-binding sites (t1/2
of [125I]EXP985 = 58 min).27 Aiyar et al28 showed
that the dissociation rate of SB203220, which exhibits a partial insurmountable antagonism of angiotensin II-induced contraction in rabbit aorta, is slower
than that of SK&F108566, a surmountable antagonist. These findings suggest that the insurmountable
antagonism caused by candesartan is attributable to
its slow dissociation from angiotensin AT1 receptors.
Recent attention has focused on the relationship
between the duration of antihypertensive action and
the prevention of end-organ damage. Candesartan
cilexetil (1–10 mg/kg) completely prevented the
incidence of stroke, and reduced left ventricular
mass and nephrosclerosis in stroke-prone spontaneously hypertensive rats.29 These doses of candesartan cilexetil also markedly reduced blood pressure. However, even at a lower dose of 0.1 mg/kg,
which had no effect on blood pressure, candesartan
cilexetil reduced the incidence of stroke, and significantly reduced urinary albumin excretion. Furthermore, candesartan cilexetil prevented cerebral
and renal injury in a renin-angiotensin-independent
model, the DOCA/salt hypertensive rat.30
The expression of various genes is up-regulated in
cardiovascular tissues of stroke-prone spontaneously hypertensive rats and DOCA/salt hypertensive rats. Candesartan cilexetil suppressed
expression of the genes for transforming growth factor-␤1 and the extracellular matrix proteins in the
kidney, heart, and blood vessels.31–33 These inhibitory effects on gene expression may contribute to the
prevention of hypertension-induced cerebral and
renal injury, cardiac hypertrophy, and vascular
thickening conferred by candesartan cilexetil, irrespective of any action of the drug on systemic haemodynamics.
The tight and long-lasting binding of candesartan
at the AT1 receptor found during in vitro studies has
been confirmed in human subjects. For example, in
a study of 27 healthy, male volunteers, Delacretaz
and colleagues concluded that candesartan cilexetil
is a well tolerated, potent, and long-lasting antagonist of angiotensin II.34 In this study, candesartan
cilexetil (1, 2, 4, or 8 mg once daily) produced a
dose-dependent reduction in the rise of systolic
blood pressure in response to an intravenous
infusion of angiotensin II. Importantly, the
reduction in blood pressure produced by candesartan cilexetil was found to be maintained throughout
the 24-h dosing period, despite a fall in the plasma
concentration of candesartan. This phenomenon
reflects the tight binding of candesartan at the AT1
receptor and slow dissociation from it.
In conclusion, the present studies have indicated
that candesartan binds tightly and dissociates
slowly for the binding sites in AT1 receptors. The
insurmountable inhibition of candesartan in contractions induced by angiotensin II may be attributed to their tight binding and slow dissociation
properties for AT1 receptor, and these characteristics
may be related to the long-lasting antihypertensive
effect of candesartan cilexetil in vivo. These longlasting properties of candesartan cilexetil might be
beneficial for the treatment of hypertension and
related diseases.
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