(Hypertension. 2000;35:1215.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Atrial Natriuretic Peptide Is Involved in Renal Actions of Moxonidine
From the Laboratory of Cardiovascular Biochemistry, Centre Hospitalier de L’Universite de Montreal Research Center, Campus Hotel-Dieu, Montreal, Quebec, Canada.
Correspondence to Suhayla Mukaddam-Daher, PhD, Laboratory of Cardiovascular Biochemistry, CHUM Research Center, Campus Hotel-Dieu, Pavilion de Bullion (6-816), 3840 St-Urbain St, Montreal, Quebec, Canada, H2W 1T8. E-mail suhayla.mukaddam-daher{at}umontreal.ca
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Abstract |
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Abstract—Moxonidine, an antihypertensive imidazoline compound, reduces blood pressure by selective activation of central imidazoline I1-receptors and inhibition of sympathetic nerve activity and by direct actions on the kidney, with both mechanisms resulting in diuresis and natriuresis. We hypothesized that the hypotensive and renal actions of moxonidine may be mediated by atrial natriuretic peptide (ANP), a cardiac peptide involved in pressure and volume homeostasis through its vasodilatory, diuretic, and natriuretic actions. Renal parameters were measured on an hourly basis over a period of 4 hours in conscious rats that received bolus intravenous injections of moxonidine (1 to 150 µg/300 µL saline). During the first hour, moxonidine dose-dependently stimulated diuresis, natriuresis, kaliuresis, and urinary cGMP, the index of ANP activity. Moxonidine (50 µg) significantly (P<0.001) stimulated urinary volume (0.35±0.04 versus 1.05±0.09 mL/h per 100 g), sodium (14.3±2.5 versus 51.8±6.5 µmol/h per 100 g), potassium (10.5±2.3 versus 32.3±3.2 µmol/h per 100 g), and cGMP (325±52 versus 744±120 pmol/h per 100 g). Pretreatment with a selective imidazoline receptor antagonist, efaroxan, dose-dependently inhibited moxonidine-stimulated renal parameters. Efaroxan (25 µg per rat) significantly inhibited moxonidine-stimulated diuretic and natriuretic effects and urinary cGMP excretion (744±120 versus 381±137 pmol/h per 100 g, P<0.02). The
2-adrenoceptor
antagonist yohimbine (50 µg per rat) partially yet
significantly inhibited moxonidine-stimulated diuresis and
natriuresis but not cGMP excretion. Plasma ANP was dose-dependently
increased by moxonidine and was inhibited by pretreatment with efaroxan
(220.8±36.9 versus 100.3±31.7 pg/mL, P<0.03) but not
by yohimbine. In conclusion, selective in vivo activation of
imidazoline receptors by moxonidine is associated with dose-dependent
diuresis, natriuresis, and kaliuresis as well as stimulated
plasma ANP and urinary cGMP excretion, thus implicating ANP in the
renal actions of moxonidine.
Key Words: atrial natriuretic factor • receptors, imidazoline • receptors, adrenergic, alpha • natriuresis • cyclic GMP • moxonidine
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Introduction |
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Several important cardiovascular disorders are characterized by increased activity of the sympathetic nervous system (SNS). In essential hypertension, clinical signs of increased SNS tone (eg, higher heart rate) are frequently seen, particularly in younger individuals, as well as several biochemical features such as elevated plasma renin activity or norepinephrine levels. Direct inhibition of peripheral
1-adrenergic and
ß-adrenergic receptors and central activation of
2-adrenergic receptors are routine ways to
reduce high blood pressure by lowering peripheral SNS
activity. In angina and myocardial infarction, excessive SNS activity
is a critical pathophysiological element, and
ß-adrenergic receptor blockers play important curative and preventive
roles. In congestive heart failure, evidences of increased SNS activity
have been found several years ago, and the important clinical benefits
of angiotensin-converting enzyme inhibitors
such as reduced morbidity and mortality rates perhaps could be
explained by their quieting effects on the cardiac sympathetic
activity. Despite their clinical efficacy and the rationale for their
use, drugs activating central 2-adrenergic
receptors (clonidine, -methyldopa) are not first-choice agents in
the therapy of these disorders, particularly because their side effect
profile comprises symptoms such as dry mouth, sedation, and mental
depression. However, the recent discovery of imidazoline receptors
(I-receptors) and a potential role for the activation of I-receptors in
mediating the beneficial effects of central
2-adrenergic agonists has generated a marked
interest in this area and has led to the development of new compounds
(moxonidine and rilminidine) with improved side effect
profiles.1 2 3
One of the important clinical features of increased SNS activity is
sodium and water retention. Many drugs that are beneficial in
cardiovascular disorders are also useful because they
stimulate sodium and water losses by different mechanisms including
altered sodium transport along the tubules. Clonidine tends to
stimulate diuresis and natriuresis by mechanisms that involve
actions on the renal tubule to modulate the actions of
vasopressin4 or by mechanisms independent of vasopressin,
namely through the release of the atrial natriuretic
peptide (ANP), a vasodilator, diuretic, and
natriuretic peptide, which stimulates cGMP
production in different target cells leading to vasodilation
and natriuresis. Previous work from our group and
others5 6 7 8 9 demonstrated that in addition to
sympathoinhibition, 2-adrenergic receptors
play a role in the cardiac release of ANP. We have shown that in vivo
administration of clonidine or its peripherally acting
analogue, ST-91, induces dose-related increases in plasma ANP levels
and results in diuresis and natriuresis5 7 and
that ANP is inhibited by 2-adrenergic receptor
antagonists.6
The actions of clonidine were originally exclusively attributed to
activation of central 2-adrenoceptors and
subsequent decrease of sympathetic nerve activity.10 11
However, several studies have shown that its actions are more related
to its chemical structure as an imidazoline than to its ability to act
as an 2-adrenoceptor agonist.12
These studies led to the identification of a new class of brain
receptors named imidazoline-preferring sites or I-receptors, and
specifically by I1-subtype, whose binding
activity correlates with the hypotensive effect of
clonidine.13
Moxonidine, a newly developed antihypertensive imidazoline compound, is
chemically and pharmacologically similar to clonidine but shows a
100-fold higher affinity to imidazoline I1
receptors over 2-adrenoceptors.14
Moxonidine has been shown to decrease blood pressure by selective
activation of central imidazoline I1-receptors
and subsequent decrease of sympathetic nerve activity14 15
and by direct actions on the kidney resulting in diuresis and
natriuresis.16 17 The aim of the present study was to
show that the hypotensive and renal actions of moxonidine may be
mediated by another mechanism, namely stimulation of the release of
ANP, which plays an integral role in volume and pressure homeostasis in
normal and pathophysiological conditions.
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Methods |
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Female Sprague-Dawley rats (weight 200 to 225 g) were purchased from Charles River. Animals were housed in a temperature- and light-controlled room with food and water ad libitum and maintained for
3 days before experimentation. Experiments were performed with the
approval of the Bioethics Committee of CHUM, according to the
Canadian Guidelines.
Renal Parameters
The renal responses to the various treatments and the possible
involvement of ANP were investigated by assessment of diuresis,
natriuresis, and kaliuresis as well as urinary cGMP (UcGMP), the index
of natriuretic peptide activity, on an hourly basis over a
period of 4 hours (8 AM to noon) in normotensive
conscious rats injected intravenously with imidazoline
compounds, moxonidine (I1 receptor agonist), and
clonidine (mixed 2/I1
agonist) and compared with a nonimidazoline compound, guanabenz
(2-agonist).
On the day of the study, the rats received bolus injections of increasing doses of moxonidine (1, 10, 50, and 150 µg), clonidine (1, 5, and 10 µg), and guanabenz (1, 10, and 25 µg) in 300 µL of 0.9% saline into the tail vein. The control group received an equal volume of saline. The rats were then placed individually in metabolic cages without food and water. Urine was collected every hour over 4 consecutive hours for volume, sodium, potassium, and cGMP measurements.
After the dose-response studies, the receptor types mediating the
effects of treatments were investigated in other groups of rats
pretreated with the I1-receptor
antagonist efaroxan (5, 10, 25, 50, and 100 µg in 300
µL saline) or the 2-adrenoceptor
antagonist yohimbine (10, 25, and 50 µg in 300 µL
saline) injected into the tail vein 10 minutes before the
administration of the agonists moxonidine (50 µg), clonidine (5
µg), and guanabenz (10 µg).
Telemetric Measurement of Blood Pressure
Systolic, diastolic, and mean
arterial pressures and heart rates were measured by
Dataquest IV telemetry system (Data Sciences International).
Rats were anesthetized with enflurane gas, and through a midline abdominal incision, the flexible catheter of the transmitter was inserted into the descending aorta just below the renal arteries. The transmitter was inserted into the peritoneal cavity and sutured to the abdominal wall. After surgery, the rats were housed unrestrained in individual cages in a quiet room with a 12:12-hour lighting schedule. The rats were allowed 10 days of recovery. Then, each cage was placed over a receiver panel that monitored output from the transmitter, that is, frequency in Hz. The signals from the receiver were consolidated by multiplex (BCM 100) and were stored and analyzed by a personal computer. The absolute pressure was corrected automatically for changes in atmospheric pressure.
Data were collected every minute, before, and over a period of 4 hours after injection into the tail vein of either saline vehicle (300 µL), 50 µg moxonidine, or 5 µg clonidine.
Drugs
Moxonidine (kindly provided by Solvay Pharmaceuticals GMBH) was
dissolved in 0.001 mol/L acetic acid in normal saline. Clonidine
hydrochloride, yohimbine hydrochloride, and efaroxan hydrochloride
(Sigma Chemical Co) and guanabenz acetate (RBI) were dissolved in
normal saline. All solutions were freshly prepared before the
injection.
Plasma and Tissue ANP Determination
Rats were killed by decapitation 10 to 15 minutes after
moxonidine treatment or saline vehicle. Blood (1 mL) was collected in
prechilled tubes containing protease inhibitors in a final
concentration: 1 mmol/L EDTA, 5 µmol/L Pepstatin A, and
10 µmol/L phenylmethylsulfonyl fluoride (Sigma Chemical
Co). Blood was centrifuged at 4°C and plasma was stored at
-80°C until assayed. The hearts were immediately excised, and left
and right atria and ventricles were separated. The tissues were
homogenized in 0.1 mmol/L acetic acid containing
protease inhibitors (as above) at 4°C. After 20 minutes
of centrifugation at 30 000g, supernatants
were collected, aliquoted, and stored at
-80°C.18
Immunoreactive ANP was determined by specific radioimmunoassay18 in serial dilution of tissue homogenates and in plasma after extraction by Sep-Pak C18 cartridges (Millipore) as previously described.18 Protein content of tissue homogenates was measured spectrophotometrically with BSA used as a standard.
UcGMP was measured by radioimmunoassay established in our laboratory according to a previously described method.19 Urinary sodium and potassium concentrations were measured with a flame photometer, and excretions per hour were calculated. Renal parameters were normalized to percent body weight.
Statistical Analysis
Data storage, graphical output, and statistical analysis
assessed by 1-way ANOVA were accomplished with the use of RS1 data
analysis software (BBN). The pressures and heart rate data were
averaged at 15-minute intervals. Statistical analysis was
accomplished with 2-way ANOVA (time and treatment) with repeated
measures followed by Fisher’s least-squares difference multiple
comparison with saline-injected controls, with the use of an SAS
statistical analysis package (SAS Institute). Statistical
significance was taken as P<0.05. All data are reported as
mean±SE.
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Results |
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Renal parameters measured over a period of 4 hours after moxonidine in conscious normotensive rats revealed that the effects were more pronounced during the first hour of treatment. During the first hour, moxonidine stimulated urinary excretion of volume, sodium, potassium, and cGMP in a dose-dependent manner. Clonidine and guanabenz also dose-dependently stimulated the renal responses (Figure 1). Urine volume was 0.35±0.04 mL/h per 100 g body wt in control saline-treated rats and was equally increased by 50 µg moxonidine (1.05±0.09 mL/h per 100 g, n=8, P<0.001), 5 µg clonidine (1.19±0.18 mL/h per 100 g, n=5, P<0.001), and 10 µg guanabenz (1.12±0.10 mL/h per 100 g, n=5, P<0.001). Thus, further studies were performed with the use of these doses.
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The receptor types involved in the renal actions were determined by injecting the rats with agonist doses that increased urinary output to similar levels and inhibition of the responses by selective antagonists. Figure 2 shows that pretreatment with efaroxan and yohimbine dose-dependently reversed the renal responses evoked by 50 µg moxonidine. Significant inhibitory effect of efaroxan on urine output (P<0.001) and sodium excretion (P<0.03) occurred at a low dose of 10 µg per rat. Efaroxan at 25 µg per rat significantly inhibited moxonidine-stimulated urine volume (1.17±0.08 vs 0.21±0.06 mL/h per 100 g body wt, n=20, P<0.001) and excretion of sodium (51.8±6.5 to 19.3±6.5 µmol/h per 100 g, P<0.001), potassium (32.3±3.2 vs 19.6±7.3 µmol/h per 100 g, P<0.04), and UcGMP (744±120 vs 381±137 pmol/h per 100 g, P<0.02). Efaroxan at 50 µg per rat totally inhibited all renal parameters measured (Figure 2).
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Clonidine and guanabenz injections with and without prior inhibition by efaroxan revealed that in contrast to moxonidine, the stimulated renal effects were not altered by 10 µg efaroxan, whereas 25-µg concentrations significantly decreased urinary output and sodium and potassium but not cGMP excretion (Table).
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Moxonidine-stimulated renal actions were also inhibited by 50 µg
yohimbine but not to control levels (Figure 2). Yohimbine
partially yet significantly inhibited moxonidine-stimulated
diuresis (1.17±0.09 vs 0.73±0.08 mL/h per 100 g,
P<0.02) and natriuresis (51.8±6.5 vs 21.5±6.9
µmol/h per 100 g, P<0.02), which implies that the
renal actions of moxonidine may also be mediated by
2-adrenoceptors. However, the dose of
yohimbine (50 µg) that significantly inhibited the renal responses to
clonidine and guanabenz (Table) did not significantly inhibit
UcGMP excretion evoked by moxonidine. Taken together, these results may
imply that the renal actions of moxonidine are selectively mediated by
I1 receptors and that ANP, through its marker
UcGMP, is dose-dependently involved in these actions.
Plasma ANP levels measured 15 minutes after intravenous injection with increasing doses of moxonidine (10, 50, 100, and 150 µg) were significantly (P<0.01) stimulated from 67.9±10.1 pg/mL in control saline-treated rats to 143.3±12.0, 231.4±38.3, 314.5±55.7, and 349.7±15.4 pg/mL, respectively (Figure 3). However, administration of 50 µg moxonidine did not significantly alter ANP content in cardiac right and left atria or ventricles (data not shown). Plasma ANP was also increased by 5 µg clonidine (125.7±15.3 pg/mL; P<0.04) and 10 µg guanabenz (138.8±23.6 pg/mL, P<0.02).
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Moxonidine-stimulated circulating ANP was inhibited by pretreatment with 25 µg efaroxan (220.8±36.9 vs 100.3±31.7 pg/mL, P<0.03). Pretreatment with 50 µg yohimbine tended to but did not significantly inhibit moxonidine-stimulated ANP (147.5±43.0 pg/mL) (Figure 3).
Telemetric measurement of blood pressure (Figure 4) revealed that there was no significant difference between the effects of clonidine (5 µg) and moxonidine (50 µg) as compared with saline vehicle. Mere handling of the animals and injection of either drug or saline increased blood pressure parameters, but the increase in systolic pressure by moxonidine and clonidine was less than that caused by saline, implying a mild hypotensive effect. Both treatments significantly (P<0.002) reduced heart rate at 15, 30, and 45 minutes after treatment but not at 60 minutes or thereafter. However, no difference was observed between the bradycardic effects of moxonidine and clonidine.
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Discussion |
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The results of the present study show that selective in vivo activation of imidazoline receptors by moxonidine, in doses that do not reduce blood pressure, is associated with dose-dependent diuresis, natriuresis, and kaliuresis as well as stimulated plasma ANP and UcGMP excretion, thus implicating ANP in the renal responses to moxonidine. In addition to imidazoline receptors, the mechanisms involved in the renal actions of moxonidine may partially include activation of
2-adrenoceptors and
subsequent increase in plasma ANP.
The renal responses to intravenous administration of
moxonidine may be both centrally and peripherally mediated.
Studies by Penner and Smyth16 20 demonstrated that central
administration of moxonidine increases sodium excretion without
changing blood pressure and that the renal responses to
intracerebroventricular moxonidine are attenuated by renal denervation,
implying that an intact sympathetic nervous system is important in the
renal responses to intracerebroventricular moxonidine, whereby
moxonidine may act through the renal nerves to inhibit renal nerve
activity, which leads to increased sodium excretion. In support, Kline
and Cechetto21 showed in anesthetized rats that
intravenous infusion of rilminidine, an imidazoline
compound that also shows higher selectivity to imidazoline receptors
than 2-adrenoceptors as compared with
clonidine, decreased mean arterial pressure, heart rate,
and renal nerve activity and evoked significant renal responses and
that these renal effects were markedly inhibited in the chronically
denervated kidneys.21 On the other hand, moxonidine may
act peripherally on imidazoline receptors identified in the
kidney proximal tubules and inner medulla,22 23 24 where
their action has been associated with inhibition of Na/H
exchanger.25 Intrarenal infusion of moxonidine markedly
increases urine flow rate, sodium excretion, and osmolar
clearance26 and modulates noradrenaline
release in isolated rat kidneys.27
The present study shows that in addition to the reported mechanisms by which moxonidine increases sodium and water excretion, moxonidine may also increase plasma ANP, which in turn would act on the kidney to cause diuresis and natriuresis through the release of cGMP.28 Acute intravenous administration of moxonidine to normotensive rats dose-dependently and significantly increased plasma ANP and enhanced diuresis, natriuresis, and kaliuresis as well as UcGMP, the index of ANP activity, thus implicating ANP in the renal actions of moxonidine. These effects were inhibited by efaroxan at doses 10 to 50 times lower than those required to inhibit the renal actions of ST-91, a peripherally acting clonidine analogue,7 confirming the selective involvement of I1 receptors in the renal responses.
The contribution of 2-adrenoceptors to the
actions of moxonidine was investigated with the use of yohimbine, a
selective 2-antagonist, and
comparing its inhibitory effects on the renal
parameters evoked by moxonidine with those of clonidine
(mixed I1/2-agonist) and guanabenz
(2-agonist). Although the 3 agonists used
evoked similar renal responses, yohimbine significantly inhibited all
the renal parameters stimulated by clonidine and guanabenz
and moxonidine-stimulated diuresis and natriuresis but not
kaliuresis and UcGMP excretion. In addition, efaroxan inhibited the
diuretic and natriuretic effects of guanabenz and
clonidine almost to control levels but failed to inhibit UcGMP. These
findings imply that different mechanisms may be involved in the renal
effects of the 3 compounds and suggest a dissociation between the
actions of imidazoline receptors and those of
2-adrenoceptors. In the kidney, activation of
2-adrenoceptors stimulates free water
clearance, whereas activation of imidazoline receptors stimulates
osmolar clearance.26 Diuresis after in vivo
activation of 2-adrenoceptors results from
inhibition of cAMP and subsequent antagonism of vasopressin in the
renal cortical and medullary collecting tubules,4 whereas
the natriuretic response to moxonidine occurs independent
of the renal actions of vasopressin, through stimulation of
prostaglandins29 and, as the present study
shows, ANP.
ANP may be implicated in the actions of moxonidine. Both ANP and moxonidine enhance glomerular filtration rate and/or reduce tubular reabsorption of sodium and water as well as suppress renal nerve activity, effects markedly attenuated by sympathetic blockade by prazosin in humans and animals.30 Furthermore, the lower heart rate observed with moxonidine treatment may also be explained as a consequence to the marked elevation of ANP in plasma, as ANP has been reported to have negative chronotropic actions31 32 through increased cGMP, stimulation of Ca- and voltage-activated potassium channel (BK) activity through activation of cGMP-dependent protein kinase (PKG),33 or inhibition of cardiac sympathetic nerve activity by inhibiting ganglionic transmission.34 The sites of imidazoline receptors involved in ANP release have not been determined in this study. However, intravenous moxonidine may activate imidazoline receptors in the ventral medulla to cause sympathoinhibition in various organs including the heart. Hansson et al35 reported that chemical and surgical cardiac sympathectomy leads to an increased level of ANP in the Purkinje fibers of bundle branches.35 In addition, imidazoline receptors may be present in the heart and may directly or indirectly affect ANP release from cardiac myocytes and/or ANP granules identified in the conduction system.36 Further studies are required to identify the presence of imidazoline receptors in the heart.
In summary, this study presents new evidence that moxonidine, by selective activation of imidazoline receptors, increases sodium and water excretion and that these renal actions are associated with elevated plasma ANP and its marker, UcGMP. These results may suggest the presence of imidazoline receptors in the heart, the primary site of ANP release.
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Acknowledgments |
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The authors gratefully acknowledge the excellent technical assistance of Céline Coderre and Nathalie Charron and the statistical assistance of Marie-Claude Guertin. This work was supported by grants from The Medical Research Council of Canada (MO-15417) and the Heart and Stroke Foundation of Canada.
Received September 24, 1999; first decision November 3, 1999; accepted January 5, 2000.
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