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(Hypertension. 1997;30:83-87.)
© 1997 American Heart Association, Inc.
Articles |
Clonidine and ST-91 May Activate Imidazoline Binding Sites in the Heart to Release Atrial Natriuretic Peptide
From the Laboratory of Cardiovascular Biochemistry, Research Center, Hotel-Dieu Hospital, Montreal, and Pharmacology Department, Faculty of Medicine, University of Montreal (C.L.) (Quebec, Canada).
Correspondence to Dr Jolanta Gutkowska, Laboratory of Cardiovascular Biochemistry, Centre de Recherche Hotel-Dieu de Montréal, 3850 St-Urbain St, Marie-de-la-Ferre Pavilion, Montreal, Quebec H2W 1T8, Canada. E-mail gutkowsj{at}ere.umontreal.ca
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Abstract |
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Abstract It is well established that the antihypertensive drug clonidine acts through specific imidazoline receptors in the brain and kidney to increase diuresis, natriuresis, and kaliuresis. We have previously shown that the effects of clonidine are associated with elevated plasma atrial natriuretic peptide (ANP). Similar to clonidine, ST-91, a clonidine analogue that does not cross the blood-brain barrier, evokes renal responses that are also associated with elevated plasma ANP. The mechanisms of ANP increase elicited by these imidazoline drugs are unclear. Since ANP is primarily released from the cardiac atria, we investigated the direct effect of the imidazoline drugs on ANP release by incubating left and right atrial sections with 10-6 mol/L ST-91 in the presence and absence of efaroxan, a selective imidazoline I1 receptor antagonist, for 30 minutes at 37°C. ST-91 significantly stimulated ANP release, and the effect was inhibited by 10-6 mol/L efaroxan. Further studies using heart perfusion with the imidazoline drugs with and without antagonists over 30 minutes revealed that both clonidine and ST-91 gradually stimulated ANP release. Also, perfusion with these compounds resulted in a gradual decrease in heart rate, but bradycardia was significant only with clonidine. The effects of ST-91 were inhibited by 10-6 mol/L efaroxan and to a lesser extent by 10-6 mol/L yohimbine, implying that the actions of ST-91 were mainly mediated by I1 receptors. On the other hand, the actions of clonidine were inhibited by 10-5 mol/L efaroxan and by 10-6 mol/L yohimbine, an
2-adrenoceptor antagonist, which may suggest
that the actions of clonidine were preferentially mediated by
2-adrenoceptors in the heart. These results indicate
that the peripheral actions of clonidine are probably
mediated by 2 and imidazoline receptors and may involve
direct stimulation of ANP release by the cardiac atria—an effect that
may account for the increase in plasma ANP levels and diuresis
and natriuresis observed in vivo after administration of clonidine and
its analogues.
Key Words: imidazoles • clonidine • yohimbine • atrial natriuretic factor • receptors, adrenergic, alpha
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Clonidine is a centrally acting antihypertensive agent that belongs to the class of imidazoline
-receptor agonists. Administration of clonidine to
hypertensive patients lowers blood pressure, an effect that has been
attributed to activation of 2-adrenergic receptors and
subsequent decrease of sympathetic nerve activity in the central
nervous system.1 However, other 2 agonists
that show higher affinity to the receptors do not lower blood pressure
but share with clonidine its side effects, such as daytime sedation and
dry mouth. Further studies on the mechanisms of action of imidazoline
drugs have shown that the hypotensive effect is mediated by a new class
of receptors named imidazoline-preferring sites or imidazoline
receptors.2 3 Radioligand binding studies
demonstrated the presence of imidazoline sites in many tissues, most
often in cells containing the 2-adrenergic receptors
such as in the ventrolateral medulla in the central nervous system,
kidney, adrenal gland, and pancreas.4 Recently, two
imidazoline receptors with molecular masses of 70 and 60 kD have been
purified from bovine adrenal medulla and rabbit
kidney.5 6 The nature and physiological role of imidazoline receptors are yet unclear; however, these receptors are distinct from adrenergic and histaminergic receptors. Imidazoline receptor subtypes have been defined according to their ligand affinity. Binding sites named I1 are present in human brain stem, rat brain, and kidney and show higher affinity for [3H]clonidine or clonidine analogues; whereas I2 sites, which are present in rabbit forebrain, smooth muscle urethra, and rat and human kidney, show a 100-fold-lower affinity for clonidine but high affinity for [3H]idazoxan. I2 sites are further subdivided according to their affinity for the chlorothiazide diuretic amiloride.4
Clonidine administration in vivo increases plasma atrial natriuretic peptide (ANP) levels and results in diuresis and natriuresis7 that may not be only centrally mediated. We have recently shown8 that ST-91, a structural clonidine analogue that does not cross the blood-brain barrier,9 evokes renal responses similar to those observed with clonidine, which may suggest a peripheral action.8 Moreover, these responses are associated with elevated plasma ANP and enhanced urinary excretion of cGMP, the second messenger of ANP. The effects are inhibited by ANP antibody and by efaroxan, a selective I1 antagonist. These findings suggest that the actions of ST-91 are mediated by peripheral imidazoline receptors and may involve ANP release.8
The mechanisms of elevated plasma ANP by clonidine and ST-91 are not clear. Since the cardiac atria are the primary site of ANP release, the aim of the present studies was to determine whether these imidazoline drugs can directly act on the cardiac atria to release ANP and whether this effect is specifically mediated by imidazoline receptors.
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Methods |
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Experiments were performed on normally hydrated female Sprague-Dawley rats weighing 200 to 250 g. The animals were housed at 22°C under a 12-hour light/dark cycle. Laboratory chow (Ralston-Purina) and water were available ad libitum before the experiment.
In Vitro Incubation of the Atria
The animals were euthanized in the morning between 8 and 9
AM. The hearts were quickly excised and rinsed with cold
saline, and then the left and right atria were cut in six sections
each. Atrial sections of each heart were incubated at random in 24-well
plates containing 1 mL sterile Joklik medium (MEM) with protease
inhibitors added (1 mg EDTA, 10 µL of 1 mmol/L
phenylmethylsulfonyl fluoride, and 10 µL of 0.5 mmol/L
pepstatin A; Sigma Chemical Co) per 1 mL of medium at 37°C in a 5%
CO2 incubator. Stimulation of ANP release by ST-91 and
specificity of the receptor type mediating the release were determined
by incubating the atria in MEM containing 10-6
mol/L ST-91 alone or with 10-6 mol/L efaroxan,
a selective antagonist of the I1 receptor, or
with yohimbine, the 2-adrenergic receptor
antagonist.
Samples (50 µL) were collected from each well before and at 15 and 30 minutes after incubation and placed in a corresponding set of prechilled tubes at 4°C for the determination of ANP content. The volume taken was replaced by the appropriate medium. The atrial tissues were retrieved at the end of incubation, homogenized, and centrifuged. Protein concentration in the supernatant was measured spectrophotometrically with bovine serum albumin as a standard.
ST-91 hydrochloride (kindly provided by Boehringer Ingelheim Laboratories), clonidine, yohimbine, and efaroxan (Sigma) were dissolved in sterile MEM immediately before use.
Heart Perfusion Studies
Heart perfusion was performed as previously described by Lambert
et al.10 On the day of the study, the animals were
heparinized (1000 U IP) and anesthetized with pentobarbital (40
mg/kg IP). The hearts were rapidly excised and immediately placed in an
ice-cold Krebs-Henseleit solution saturated with oxygen. The heart was
then rapidly mounted on a perfusion system and perfused retrogradely
via the aorta at 37°C and a pressure of 80 cm H2O
(59 mm Hg) according to the method of Langendorff. The
Krebs-Henseleit perfusion solution (mmol/L: NaCl 117, KCl 4.7,
CaCl2 2.5, KH2PO4 1.2,
MgSO4 1.2, NaHCO3 25, Na2EDTA 0.5,
and dextrose 11) had a pH 7.4 when gassed with 95% O2 and
5% CO2. The base of the pulmonary artery was
incised to allow efficient drainage of the right ventricle. Heart rate
was continuously monitored via electrodes placed at the apex of the
heart and aorta and connected to an AC current amplifier and was
recorded at a paper speed of 10 mm/s (model 50-9927, Ealing
Scientific Ltd). Coronary flow was measured every minute by
timed collections of the effluent. At the end of a 15-minute
equilibration period, agonists (clonidine and ST-91) and
antagonists (efaroxan and yohimbine) were added to the
buffer and perfusion was maintained for an additional 30 minutes.
Effluent samples were collected in polystyrene tubes containing 150
µL phenylmethylsulfonyl fluoride, 150 µL EDTA, and 100 µL
of 1% bovine serum albumin. Samples were stored at -20°C
until analysis.
Measurement of ANP
In preliminary experiments, the heart effluent was extracted by
Sep-Pak C18 cartridges (Millipore Corp) and purified by
high-performance liquid
chromatography.11 The elution profile was
identical to that of circulating rat ANP(1-28), confirming the identity
of ANP in the effluent. ANP in the samples (effluent or incubation
medium) was measured in at least three dilutions by radioimmunoassay
using an antibody that recognizes the carboxy terminal of the molecule,
as previously described by Gutkowska.11 The effect of
variation in atrial size was avoided by normalizing ANP release to the
protein concentration of each section. ANP content in the perfusion
effluent was corrected for the flow per minute.
Statistical Analysis
Data storage, graphical output, and statistical analysis
assessed by one-way ANOVA were accomplished with RS1
data-analysis software (BBN). Statistical significance was
taken at a value of P<.05. All data are reported as
mean±SE.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Fig 1
shows the results obtained from five experiments in which
left and right atrial sections were incubated over 30 minutes with
ST-91. The addition of ST-91
(10-6 mol/L) to the incubation medium evoked
significant release of ANP measured at 15 and 30 minutes (Fig 1). ANP
levels obtained by incubating the atria with ST-91 in the presence of
10-6 mol/L efaroxan were similar to control
values at corresponding time points.
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Perfusion of the heart with Krebs-Henseleit buffer resulted in a
gradual mild decrease in heart rate and flow. ANP concentration in the
effluent gradually increased over the perfusion time to reach a maximum
of 1.4-fold at 30 minutes, which was not significantly different from
basal levels. Addition of ST-91 to the perfusion buffer stimulated the
release of ANP, from basal values of 4.4±1.2 to 29.5±5.9 ng/min at 30
minutes (P<.002). The effect was only partially (30%,
P=NS) inhibited by the addition of
10-6 mol/L yohimbine to the buffer (Fig 2). However, the ST-91–stimulated release of ANP was
significantly inhibited (P<.005) by the addition of
10-6 mol/L efaroxan, and the values obtained
were also lower (P<.05) than those obtained by yohimbine
(Fig 2).
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P<.05 vs ST-91 plus yohimbine.
Perfusion with 10-6 mol/L clonidine resulted
in stimulation of ANP release in the effluent that was not inhibited by
10-6 mol/L efaroxan. However, the stimulated
ANP release was significantly inhibited by efaroxan at
10-5 mol/L (P<.0001). Blockade of
the 2-adrenergic receptors with
10-6 mol/L yohimbine also inhibited
(P<.0001) ANP release to control levels (Fig 3).
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Fig 4 shows that ST-91 gradually decreased heart rate
from basal levels of 350±7 to 286±26 beats per minute at 30 minutes,
but the effect was not different from control values at corresponding
time points. The addition of yohimbine (10-6
mol/L) but not efaroxan (10-6 mol/L) reversed
the bradycardic effect. On the other hand, perfusion with clonidine
resulted in a greater decrease in heart rate, from an average of
345±17 to 245±10 beats per minute (P<.05). This decrease
was not inhibited by 10-6 mol/L efaroxan but
was completely inhibited by 10-5 mol/L
efaroxan. Yohimbine at 10-6 mol/L also
inhibited the effect of clonidine on heart rate (Fig 4).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The results of the present study show that the imidazoline compounds clonidine and its structural analogue ST-91 in relatively high concentrations have a direct effect on the release of ANP from the cardiac atria. The mechanisms involved in ANP release may include activation of imidazoline binding sites and/or
2-adrenoceptors present in the heart.
The imidazoline receptors are a new class of receptors that are
distinct from 2-adrenergic receptors because they show
low affinity for the catecholamines epinephrine and
norepinephrine.12 Imidazoline receptors have
been shown in brain, kidneys, urethra, liver, and platelets, where
in many cases the distribution of these receptors parallels that of
2-adrenergic receptors.4 13
Little information is available about the localization and function of
imidazoline receptors. However, these receptors have been implicated in
important physiological effects, such as the
regulation of blood pressure.14 The hypotensive effects of
some 2-adrenergic receptor drugs in some species are
mediated by imidazoline receptors. In the rat, imidazolines decrease
blood pressure by activation of imidazoline receptors present in
the rostral ventrolateral medulla oblongata.15 Other
studies have showed that imidazoline receptors may also be present
prejunctionally on postganglionic sympathetic nerve terminals.
Activation of imidazoline receptors inhibits norepinephrine
release in rabbit pulmonary artery and aorta3 16
as well as in the rabbit heart.17
The endogenous ligand for the imidazoline receptors is named CDS, for clonidine-displacing substance. This substance, isolated from bovine brain and shown to displace [3H]clonidine and [3H]p-aminoclonidine from both adrenergic and nonadrenergic sites,18 19 was later identified by mass spectroscopy as agmatine, a bacterial amine that was not shown in mammals.20 CDS also has been identified in other tissues, including lungs, kidneys, and heart, and in higher concentrations, in stomach and aorta.21
It was difficult in the present study to dissociate
pharmacologically and functionally between activation of heart
2 and imidazoline receptors. In many cases, stimulation
of I1 receptors and 2-adrenoceptors produces
identical physiological responses. All
I1 receptor agonists, including agmatine, have comparable
affinity for the 2-adrenoceptors, and no
antagonist is available that selectively blocks the
I1 receptor without an effect on
2-adrenoceptors. Idazoxan is the only compound that has
demonstrated functional I1 receptor antagonist
activity. This compound has affinity for I1,
I2, and 2 receptors.4 Minor
structural changes have been shown to dramatically influence the
I2 receptor versus 2-adrenoceptor
selectivity of idazoxan analogues. We used an idazoxan analogue,
efaroxan, which is a good tool for discriminating between the
imidazoline receptor types because it shows high affinity for the
I1 and low affinity for the I2 receptor.
However, efaroxan retains affinity for
2-adrenoceptors.22
Stimulation of ANP release by ST-91 was mainly inhibited by
10-6 mol/L efaroxan and only partially by
10-6 mol/L yohimbine. However,
clonidine-stimulated ANP release was inhibited by
10-6 mol/L yohimbine and
10-5 mol/L but not
10-6 mol/L efaroxan, although this
concentration was enough to antagonize the effects of ST-91. The
discrepancy of different effects elicited by two imidazoline drugs may
reflect either different receptor type or receptor affinity, especially
given that structural substitutions result in different affinities. The
possibility of multiple I1 receptor subtypes cannot be
ruled out, but the inhibition of clonidine actions by
10-6 mol/L yohimbine as well as by
10-5 mol/L efaroxan, which shows high affinity
for 2 receptors, suggests that clonidine may
preferentially activate heart 2 receptors.
Therefore, heart imidazoline receptors are probably activated
by ST-91, whereas clonidine preferentially activates heart
2 receptors. This finding is in line with the previous
report that the vasoconstrictor action of 4-aminotolazoline in the rat
aorta is mediated by 2 activation, whereas the
constrictor action of 4-isothiocyanatotolazine in this tissue may be
mediated by an imidazoline receptor.22 23
The decrease in heart rate by imidazoline drugs has been previously
shown but attributed to their action on the central nervous system
through facilitated vagal baroreceptor reflex.24 Perfusion
with ST-91 did not significantly affect heart rate. However, clonidine
resulted in bradycardia, which was equally reversed by yohimbine and
higher doses of efaroxan, and these effects paralleled the changes
in ANP. Therefore, it is reasonable to assume that the mechanisms
leading to bradycardia in the isolated heart preparation in the absence
of reflex mechanisms are most likely mediated by activation of
2 receptors in the heart through the release of ANP. The
bradycardic effect of ANP has been previously shown.25
In conclusion, the imidazoline compounds are thought to act on central
imidazoline receptors to reduce vascular tone. However, this study
indirectly demonstrates the presence of imidazoline binding sites and
2-adrenoceptors in the heart and shows that these
receptors are functional because their activation stimulates ANP
release. Clonidine and ST-91, two partial 2-receptor
agonists, potentially stimulate the release of ANP by activation of
heart 2-adrenoceptors, imidazoline receptors, or both,
an effect that may account for the elevated plasma ANP and the renal
responses observed in vivo after administration of clonidine and its
analogues.7 Moreover, the presence of CDS in heart and
aorta and identification of imidazoline receptors in the same tissues
suggest a local regulatory function that may involve ANP. Further
studies are required to localize and characterize cardiac imidazoline
receptors and to elucidate the role of imidazoline receptors in the
control of ANP secretion under physiological and
pathophysiological conditions.
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Acknowledgments |
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This work was supported by grants from The Medical Research Council of Canada (MT-10337 and MT-11674) and the Heart and Stroke Foundation of Canada (J.G.). The authors gratefully acknowledge the technical assistance of Céline Coderre, Nathalie Charron, and Marie-France Legault. The authors also wish to thank Dr Than-Vinh Dam for his expert assistance in the preparation of manuscript figures.
Received September 19, 1996; first decision October 16, 1996; accepted December 2, 1996.
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