(Hypertension. 1997;30:1260-1266.)
© 1997 American Heart Association, Inc.
Articles |
Analysis of the Effects of Candesartan in the Mesenteric Vascular Bed of the Cat
From the Department of Pharmacology, Tulane University School of Medicine, New Orleans, La.
Correspondence to Philip J. Kadowitz, PhD, Department of Pharmacology SL83, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112. E-mail champion{at}mailhost.tcs.tulane.edu
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Abstract |
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Abstract The effects of the nonpeptide angiotensin II AT1 receptor antagonist candesartan on responses to angiotensin II were investigated in the mesenteric vascular bed of the cat. Under constant-flow conditions, injections of angiotensin II caused dose-related increases in perfusion pressure that were reduced by candesartan in doses of 3, 10, and 30 µg/kg IV. After administration of the AT1 receptor antagonist in a dose of 3 µg/kg IV, the dose-response curve for angiotensin II was shifted to the right in a parallel manner, whereas the administration of higher doses resulted in nonparallel rightward shifts of the angiotensin II dose-response curves. The duration of the inhibitory actions of candesartan were dependent on dose, and the AT1 receptor antagonist did not alter responses to norepinephrine, U46619, vasopressin, neuropeptide Y, BAY K8644, endothelin-1,
,ß-methylene ATP, adenosine,
acetylcholine, and bradykinin. Treatment with the AT2
receptor antagonist PD123,319 or with sodium meclofenamate
did not alter the inhibitory effects of candesartan on
responses to angiotensin II. Candesartan also decreased
pressor responses to angiotensin III and IV with a parallel
shift at the low dose and a nonparallel shift to the right of the
dose-response curve at the high dose. These results indicate that
candesartan is a potent, selective, long-acting AT1
receptor antagonist that, depending on dose, can produce
both competitive and noncompetitive blockade of responses to
angiotensin II, III, and IV.
Key Words: angiotensin peptides • vasoconstriction • angiotensin receptor subtypes
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Introduction |
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Angiotensin II is a potent vasoactive hormone that plays an important role in regulation of vasomotor tone and sodium and water homeostasis.1 2 3 Angiotensin II is formed from angiotensin I by the angiotensin-converting enzyme (ACE) located on the surface of pulmonary capillary endothelial cells,2 and recent studies have suggested that there may be significant ACE activity in upstream resistance vessels near the site of action of angiotensin II within the hindlimb, pulmonary, and mesenteric vascular beds in the cat.4 5 6 7 The development of potent nonpeptide angiotensin II receptor antagonists has led to the identification of at least two angiotensin II receptor subtypes, the AT1 and AT2 receptors.3 8 9 10 AT1 receptors are found in many tissues, including vascular smooth muscle, while AT2 receptor transcripts have been localized in bovine cerebellum and uterus and in rat adrenal medulla.10 11 12 13 14 The function of the AT2 receptor in vivo is uncertain, and it has recently been reported that angiotensin AT2 receptors mediate vasodepressor responses in the rat.15 Other evidence in the literature suggests that AT2 receptors may play a role in fetal growth and development.16 The AT1 receptor, however, is believed to be responsible for most, if not all, cardiovascular responses to angiotensin II.4 5 6 7 17 ACE inhibitors and angiotensin receptor antagonists are the primary therapeutic means of counteracting the hypertensive and hypertrophic effects of angiotensin II.3 18 However, ACE inhibitors have side effects, such as cough, which are believed to be due to the inhibition of bradykinin and substance P degradation.3 18 The synthesis of imidazole analogues, such as losartan, provided the first of a class of nonpeptide angiotensin receptor blocking agents.3 9 17 Losartan is an effective antihypertensive drug that is metabolized to a more active metabolite, and the AT1 receptor–blocking properties of the prodrug and its metabolite, EXP3174, are quite different.3 9 17 19
Candesartan (CV-11974) is a recently synthesized nonpeptide angiotensin II receptor antagonist displaying high affinity for the AT1 receptor.20 21 Candesartan is the metabolite of the orally available compound TCV-116 and, like losartan, is a member of the imidazole class of nonpeptide AT1 receptor antagonists. Candesartan is a noncompetitive AT1 receptor antagonist, whereas losartan is a competitive antagonist at the AT1 receptor. Candesartan has been shown to inhibit angiotensin II–induced aldosterone secretion in rats.21 In addition, candesartan has been shown to produce peripheral vasodilation in rats with renal hypertension.22 This novel AT1 receptor antagonist has been shown to reduce the maximal contractile response to angiotensin II in rabbit aortic strips and to shift the dose-response curve for angiotensin II to the right in a nonparallel manner, providing support for the concept that candesartan is a noncompetitive antagonist for the AT1 receptor.21 23 However, in membrane preparations of adrenal cortical and aortic smooth muscle cells, candesartan increased the Kd without altering the number of receptors for angiotensin II, suggesting that candesartan is a competitive antagonist at the AT1 receptor.20
While the effects of candesartan have been studied in vitro and on pressor responses to angiotensin II in spontaneously hypertensive rats, little or nothing is known about the inhibitory effects of candesartan in the regional vascular bed of the cat. The present study was therefore undertaken to investigate the effects of candesartan on responses to angiotensin II in the mesenteric vascular bed of the cat.
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Methods |
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Seventy-five adult cats of either sex weighing 2.2 to 4.3 kg were sedated with ketamine hydrochloride (10 to 15 mg/kg IM) and anesthetized with pentobarbital sodium (30 mg/kg IV). Supplemental doses of pentobarbital were given as needed to maintain a uniform level of anesthesia. At the end of an experiment, the animals were killed by injection of pentobarbital (30 mg/kg IV) followed by intravenous injection of 2 mL of a saturated KCl solution.
For experiments, the trachea was cannulated, and the animals either spontaneously breathed room air or were ventilated with a Harvard model 607 ventilator at a volume of 40 to 60 mL at 15 to 22 breaths per minute. An external jugular vein was catheterized for the intravenous administration of drugs, and a carotid artery was catheterized for the measurement of systemic arterial (aortic) pressure. For constant-flow perfusion of the mesenteric vascular bed, the superior mesenteric artery was approached through a midline abdominal incision and cleared of surrounding connective tissue. The mesenteric vascular bed was denervated by ligating and cutting the perivascular nerves to the small intestine as they course along the superior mesenteric artery. After the administration of heparin sodium (1000 U/kg), the femoral artery was cannulated and connected to the inlet side of a perfusion circuit. The outlet side of the perfusion circuit was connected to a catheter inserted into the superior mesenteric artery. Blood flow to the small intestine was maintained constant with a Sigmamotor model T-8 perfusion pump.
Superior mesenteric arterial perfusion pressure was measured by way of a lateral tap in the perfusion circuit located between the pump and the outlet side of the perfusion circuit. Superior mesenteric arterial perfusion pressure and systemic arterial pressure were measured with Statham P23 pressure transducers and were recorded on a Grass model 7 polygraph. Mean pressures were derived by electronic averaging, and the perfusion rate was set so that superior mesenteric arterial perfusion pressure approximated systemic arterial pressure and was not changed during the experiment. The flow rate was determined by timed collection and ranged from 26 to 36 mL/min. The agonists used in these experiments were injected directly into the superior mesenteric artery perfusion circuit distal to the pump in small volumes (30 and 100 µL). These procedures have been described previously.7 It is estimated that with supplemental doses of anesthesia and administration of agonists and antagonists, the animals received approximately 10 mL of 0.9% NaCl solution per hour during the course of an experiment.
Candesartan astra Hässle (2-ethoxy-1-[(2'-[1H-tetraxol-5-yl]biphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylic acid) was dissolved in a 1N Na2CO3/0.9% NaCl solution (1:20). Acetylcholine chloride, angiotensin II, angiotensin III, angiotensin IV, bradykinin, neuropeptide Y, [Arg8]-vasopressin, adenosine, and norepinephrine hydrochloride (Sigma Chemical Co) and endothelin-1 (Peptide Laboratory, Tulane University, New Orleans, La) were dissolved in 0.9% NaCl. U46619 (Upjohn) was dissolved in 100% ethanol at a concentration of 10 mg/mL and was diluted in 0.9% NaCl. BAY K8644 (Miles Inc) was dissolved in a 1:4 solution of cremophor EL and Tris-HCl (50 mmol/L, pH 7.4). The resulting suspension was warmed, and polyethylene glycol and Tris (pH 7.4) were added to make a stock solution that was stored in a brown bottle in a freezer. PD123,319 and sodium meclofenamate (Parke Davis) were dissolved in 0.9% NaCl solution. Working solutions of all agonists were prepared on a frequent basis, stored in brown stoppered bottles, and kept on crushed ice during the course of an experiment. Vehicles for the drugs used in these studies had no significant effect on mesenteric perfusion pressure or on responses to the vasoactive agents. All agonists were injected directly into the mesenteric perfusion circuit in small volumes in a random sequence, and sufficient time was permitted between agonist injections for pressure to return to baseline values.
In the first series of experiments, the effects of candesartan in doses
of 3 to 30 µg/kg IV on responses to angiotensin II
were investigated. The slope of the dose-response curves for responses
of angiotensin II were compared before and after
administration of candesartan to determine whether the curves were
shifted to the right in a parallel or a nonparallel fashion. The
response to the 0.3-µg dose of angiotensin II was
compared over intervals up to 4 hours after administration of
candesartan (3 to 30 µg/kg IV) to estimate the duration of the
AT1 receptor blockade, and the response to
norepinephrine was investigated over the 4-hour period to
assess the responsiveness of the vascular bed over time. In other
experiments to assess the role of interaction with the AT1
receptor, responses to the angiotensin peptides were
compared before and after administration of PD123,319 and the
subsequent administration of candesartan in doses of 3 µg/kg
IV or 30 µg/kg IV. The effects of candesartan on responses to
angiotensin III and IV and the effects of treatment with
the cyclooxygenase inhibitor sodium
meclofenamate (2.5 mg/kg IV) on the inhibitory
effects of candesartan on responses to angiotensin II were
investigated. The effects of candesartan on responses to agonists that
act by a variety of mechanisms were investigated to assess the
selectivity of the AT1 receptor blockade. In these
experiments, responses to BAY K8644, U46619, ,ß-methylene ATP,
endothelin-1, vasopressin, and neuropeptide Y were investigated to
determine whether candesartan interfered with responses mediated by
calcium entry through L-type channels or responses mediated by the
activation of thromboxane or ATP receptors or
non-AT1 peptide receptors. In addition, the effects of
candesartan on responses to endothelium-dependent and
independent vasodilator agents were investigated.
Responses were measured in absolute units (mm Hg) as maximal change in perfusion pressure from baseline and are expressed as mean±SE. The data were analyzed using a one-way analysis of variance and Scheffé's F test or a paired t test.24 The slopes for each dose-response curve for angiotensin II, III, and IV were determined by a best-fit analysis and were compared statistically with a paired t test. A value of P<.05 was used as the criterion for statistical significance.
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Results |
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Effects of Candesartan on Responses to Angiotensin II
The effects of candesartan on responses to angiotensin II in the mesenteric vascular bed were investigated, and these data are summarized in Fig 1
. After administration
of candesartan in a dose of 3 µg/kg IV, increases in perfusion
pressure in response to angiotensin II were reduced
significantly, and the dose-response curve for the peptide was shifted
to the right in a parallel manner (Fig 1, Table 1). When the dose of candesartan was
increased to 10 µg/kg IV in another set of experiments,
vasoconstrictor responses to angiotensin II were decreased
significantly, and the shift to the right of the dose-response curve
was not parallel (Fig 1, Table 1). The administration of candesartan in
a dose of 30 µg/kg IV resulted in a marked decrease in the
response to angiotensin II, and the dose-response curve for
the peptide exhibited little if any positive slope after treatment with
the AT1 receptor antagonist (Fig 1, Table 1).
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The duration of the inhibitory effect of candesartan on
responses to angiotensin II was evaluated by comparing
responses to the peptide in the control period to responses obtained at
periods up to 240 minutes after administration of the AT1
receptor antagonist. In control experiments, responses to
the 0.3-µg dose of angiotensin II were not changed at
intervals up to 240 minutes after administration of the vehicle for
candesartan (data not shown). After administration of candesartan (3
µg/kg IV), increases in mesenteric perfusion pressure in
response to the 0.3-µg injection of angiotensin II were
reduced significantly at periods up to 120 minutes, and responses to
the peptide were not significantly different from control 180 minutes
after administration of the AT1 receptor
antagonist (Fig 2). After
administration of candesartan in a dose of 10 µg/kg IV,
responses to angiotensin II (0.3 µg) were reduced
significantly at all time periods studied, and the response to the
peptide was decreased by approximately 50% 240 minutes after
administration of the AT1 receptor antagonist
(Fig 2).
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After administration of candesartan in a dose of 30 µg/kg IV,
responses to angiotensin II (0.3 µg) were markedly
reduced or abolished when evaluated at time intervals up to 240 minutes
(Fig 2
). Increases in mesenteric arterial perfusion
pressure in response to injection of norepinephrine (0.3
µg) were not different from control when evaluated 120 and 240
minutes after administration of candesartan in doses of 3, 10, and 30
µg/kg IV (Fig 2).
Influence of PD 123,319
The effects of PD 123,319 on responses to angiotensin
II and on the inhibitory effects of candesartan on
responses to angiotensin II were investigated, and these
data are summarized in Fig 3. After
administration of PD 123,319 in a dose of 10 mg/kg IV, increases
in perfusion pressure in response to angiotensin II were
not changed (Fig 3). In animals treated with PD 123,319 (10
mg/kg IV), the administration of candesartan in a dose of 3
µg/kg IV shifted the dose-response curve for
angiotensin II to the right in a parallel manner (Fig 3).
In animals pretreated with PD 123,319 (10 mg/kg IV), the
administration of candesartan in a dose of 30 µg/kg IV shifted
the dose-response curve for angiotensin II to the right in
a nonparallel manner (Fig 3). The effect of treatment with the
cyclooxygenase inhibitor sodium
meclofenamate on the inhibitory effects of candesartan on
responses to angiotensin II were investigated, and after
treatment with meclofenamate in a dose of 2.5 mg/kg IV, the
administration of candesartan in a dose of 3 µg/kg IV resulted
in a parallel shift to the right of the dose-response curve for
angiotensin II (data not shown). After treatment with
sodium meclofenamate (2.5 mg/kg IV), the administration of
candesartan in a dose of 30 µg/kg IV caused a nonparallel
shift to the right of the angiotensin II dose-response
curve (data not shown).
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Effects of Candesartan on Responses to Angiotensin III
and IV
The effects of the 3- and 30-µg/kg IV doses of
candesartan on responses to angiotensin III and IV were
investigated, and these data are summarized in Fig 4. After administration of candesartan in
a dose of 3 µg/kg IV, increases in mesenteric perfusion
pressure in response to angiotensin III and
angiotensin IV were decreased significantly, and the
dose-response curves for both peptides were shifted to the right in a
parallel manner (Fig 4, Table 1). The administration of candesartan in
a dose of 30 µg/kg IV produced a marked decrease in the
response to angiotensin III and IV, and the dose-response
curves for both peptides displayed little or no positive slope after
administration of the AT1 receptor antagonist
in a dose of 30 µg/kg IV (Fig 3, Table 1). The effects of
pretreatment with PD123,319 on the inhibitory effects of
candesartan on responses to angiotensin III and IV were
investigated, and after treatment with PD123,319 (10 mg/kg IV),
the administration of candesartan in a dose of 3 µg/kg IV
shifted the dose-response curves for both peptides to the right in a
parallel manner (data not shown). After treatment with PD123,319, the
administration of candesartan in a dose of 30 µg/kg IV shifted
the dose-response curves for angiotensin III and IV to the
right in a nonparallel fashion (data not shown).
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Selectivity of the AT1 Receptor Blockade
The selectivity of the AT1 receptor–blocking effects
of candesartan was determined by investigating the effects of the
antagonist on responses to agents that change mesenteric
vascular resistance by a variety of mechanisms, and these data are
summarized in Figs 5 and 6. After
administration of candesartan in doses of 10 and 30 µg/kg IV,
vasoconstrictor responses to the thromboxane A2
mimic U46619, BAY K8644, vasopressin, and neuropeptide Y were not
changed (Fig 5). Biphasic responses to ,ß-methylene ATP and
endothelin-1 and vasodilator responses to adenosine,
bradykinin, and acetylcholine were not altered (Figs 5 and 6).
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Influence of Candesartan on Baseline Pressures
The influence of candesartan in doses of 3 to 30
µg/kg IV on baseline systemic arterial and
mesenteric perfusion pressures are summarized in Table 2. The AT1 receptor
antagonist was without significant effect on mean systemic
arterial or mesenteric perfusion pressure when values were
compared before and 20 to 30 minutes after administration of the
AT1 receptor antagonist (Table 2).
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Discussion |
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Results of the present investigation demonstrate that the nonpeptide angiotensin II AT1 receptor antagonist candesartan reduces pressor responses to angiotensin II in the mesenteric vascular bed of the cat. Inasmuch as blood flow was maintained constant, the increases in perfusion pressure in response to the peptide reflect increases in mesenteric vascular resistance. The inhibitory effects of low doses of candesartan were overcome when larger doses of angiotensin II were administered, and the shift to the right of the dose-response curve was parallel, suggesting that at the low dose, the AT1 receptor blockade was competitive in nature. However, at higher doses of candesartan (10 to 30 µg/kg IV), responses to angiotensin II were reduced markedly, and the blockade was not surmounted when higher doses of angiotensin II were administered. Moreover, at higher doses of candesartan, the dose-response curves for angiotensin II were shifted to the right in a nonparallel manner, suggesting that the blockade was noncompetitive in nature. Although responses to angiotensin II were reduced significantly by candesartan, responses to agonists that change mesenteric perfusion pressure by a variety of mechanisms were not altered, indicating that candesartan is a selective angiotensin AT1 receptor antagonist in the mesenteric vascular bed of the cat. Candesartan in doses of 3 to 30 µg/kg IV had no significant effect on systemic arterial or mesenteric perfusion pressure in the cat, indicating that the AT1 receptor antagonist had no agonist activity in the systemic or mesenteric vascular bed of the cat, and the results with candesartan on baseline pressures are similar to data with losartan, DuP 532, and EXP3174 on baseline pressures in the cat.4 5 6 19
Novel non-AT1/AT2 binding sites for angiotensin IV have been reported to be present in a number of tissues.25 Angiotensin IV has been shown to have modest pressor activity in normal human subjects and to possess vasoconstrictor activity in the mesenteric and hindlimb vascular beds of the cat and rat.5 6 7 26 27 Previous studies in the mesenteric vascular bed of the cat have demonstrated that vasoconstrictor responses to angiotensin III and IV are mediated by AT1 receptor activation and suggest that angiotensin IV has 100-fold less affinity for the AT1 receptor.7 Data from the present study are consistent with previous studies showing that pressor responses to angiotensin III and IV in the mesenteric vascular bed of the cat are mediated by AT1 receptor activation7 and show that responses to angiotensin III and IV are inhibited in a competitive manner by the low dose of candesartan and that at a high dose, the antagonism is noncompetitive in nature. It has been reported that AT2 receptor activation by angiotensin II and III mediates a vasodepressor response in the rat and that vasodepressor responses are enhanced after AT1 receptor blockade with DuP 753.15 This vasodepressor activity was not observed in the mesenteric vascular bed of the cat before or after administration of candesartan. The reason for the differences with regard to the character of responses to angiotensin II and III in the present study and in the rat are uncertain but may reflect differences in species, vascular bed studied, or experimental procedure followed. In addition to the presence of AT1 and AT2 receptor subtypes, the AT1 receptor has been subdivided into AT1A and AT1B receptor subtypes in the rat.3 It would be of interest to determine whether AT1A and AT1B receptor subtypes are expressed in the cat and, if they are, to ascertain their relative distribution on resistance vessel elements in the mesenteric vascular bed.
The duration of the inhibitory effects of candesartan on
responses to angiotensin II was related to the dose of the
antagonist studied. The half-life of the
inhibitory effect of candesartan in a dose of 3
µg/kg IV on responses to angiotensin II was less
than 180 minutes, whereas the half-life of the inhibitory
effects of the 30 µg/kg IV dose was far more than 4 hours. The
reactivity of the mesenteric vascular bed to vasoconstrictor agents was
unchanged in that responses to norepinephrine were not
altered during this 4-hour period. The inhibitory effects
of candesartan on responses to the angiotensin peptides
were selective in that vasoconstrictor responses to U46619,
vasopressin, neuropeptide Y, and BAY K8644; biphasic responses to
endothelin-1 and ,ß-methylene ATP; and vasodilator responses to
acetylcholine, adenosine, and bradykinin were not altered after
administration of candesartan in doses up to 30 µg/kg IV.
These data suggest that candesartan is a selective, potent
antagonist at the AT1 receptor, and an
interaction of candesartan with other pressor and depressor systems was
not observed in the mesenteric vascular bed of the cat. Candesartan had
no significant effect on baseline systemic arterial or
mesenteric perfusion pressures, suggesting that angiotensin
II has little or no role in maintaining baseline tone in the mesenteric
or systemic vascular bed of the cat under the conditions of the
present experiments. This observation is in agreement with results
in the conscious rat.21
In the present study, the administration of candesartan in doses of 10 and 30 µg/kg IV shifted the dose-response curve for angiotensin II to the right in a nonparallel manner. These results are consistent with results in the rabbit aortic strip and suggest that candesartan is a noncompetitive AT1 receptor antagonist.21 However, when the dose of candesartan was reduced to 3 µg/kg IV, a different pattern of angiotensin AT1 receptor blockade was observed in the mesenteric vascular bed. At a dose of 3 µg/kg IV, candesartan shifted the dose-response curve of angiotensin II to the right in a parallel manner, with a slope that was not different from control, suggesting that at this lower dose, the AT1 receptor blockade induced by candesartan is competitive. Thus, the properties of the blockade of responses to angiotensin II induced by candesartan are dependent on the dose of the AT1 receptor antagonist studied. The inhibitory effects of candesartan on vasoconstrictor responses to angiotensin III and IV were similar in that at the 3-µg/kg IV dose, a parallel shift of the dose-response curves was observed, whereas at 30 µg/kg IV, the rightward shift of the dose-response curves was nonparallel. The explanation for the difference in the inhibitory effects of the high and low dose of candesartan is uncertain.
Although candesartan antagonized contractile responses to angiotensin II in rabbit aortic strips in a noncompetitive manner, binding studies with angiotensin II in bovine adrenal cortical and rabbit aortic smooth muscle membranes show that candesartan increased the Kd of the radioligand for the AT1 receptor without a change in the maximal number of receptors.20 21 These data suggest that candesartan interacts in a reversible and competitive manner with AT1 receptors and are different from the results of contractile studies in rabbit aortic strips.20 The explanation for the difference in results in ligand-binding studies and in contractile studies is uncertain but may involve the complex molecular mechanisms involved in the mediation of angiotensin-induced vasoconstriction.21
It is possible that at low doses of candesartan, the AT1 receptor class is antagonized in a competitive manner, whereas the effects at high doses are open to several interpretations, one being an interaction with AT2 receptors. However, the observation that the inhibitory effects of the low and high doses of candesartan are not altered by pretreatment with the AT2 receptor ligand PD123,319 suggests that an interaction with the AT2 receptor does not account for the nonparallel rightward shift of the angiotensin II dose-response curve. The finding that pretreatment with the cyclooxygenase inhibitor sodium meclofenamate does not alter the inhibitory effects of candesartan suggests that an interaction with cyclooxygenase products does not account for differences observed with low and high doses of the AT1 receptor antagonist. It is also possible that the difference in effect of the low and high dose of candesartan may be related to a complex interaction of the AT1 receptor antagonist with its receptor or may be explained by the presence of spare angiotensin II AT1 receptors in the mesenteric vascular bed of the cat. Moreover, there may exist in the mesenteric vascular bed a population of spare angiotensin AT1 receptors that can be blocked irreversibly without a reduction in the slope of the dose-response curve for angiotensin II. When the dose of antagonist is increased to the point at which the spare receptors are inactivated, then a nonparallel shift of the dose-response curve for angiotensin II would be observed, and the maximal response would be reduced.28 29 Such a mechanism may possibly explain the differences observed with low and higher doses of candesartan in the mesenteric vascular bed of the cat; these results, suggesting the presence of spare AT1 receptor, are in agreement with results with EXP3174 in the hindlimb vascular bed and of ligand-binding studies in the rat portal vein.19 30 31 However, the hypothesis about spare AT1 receptors is highly speculative, and additional experiments with other noncompetitive AT1 receptor antagonists are needed to determine whether the receptor reserve theory is adequate to explain the present results with candesartan in the mesenteric vascular bed of the cat.
In conclusion, the results of the present study show that candesartan is a potent, selective, long-acting AT1 receptor antagonist in the mesenteric vascular bed of the cat. These data also indicate that the type of blockade induced by candesartan is dependent on dose, with competitive antagonism observed at the low dose and noncompetitive blockade of angiotensin II responses observed at higher doses. These data may suggest a complex interaction between candesartan and the AT1 receptor or may be interpreted to suggest the presence of spare angiotensin II AT1 receptors in the mesenteric vascular bed of the cat.
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Acknowledgments |
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The studies were supported in part by NIH grant HL15580 and a grant from the American Heart Association–Louisiana, Inc. H.C. Champion was supported by NIH grant HL09474.
Received March 17, 1997; first decision April 29, 1997; accepted April 29, 1997.
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