(Hypertension. 1999;34:1012-1015.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
From the Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil, and the Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, Faculté de Médecine, ULP, Strasbourg, France.
Correspondence to Maria Cristina O. Salgado, PhD, Department of Pharmacology, School of Medicine-USP, 14049-900 Ribeirão Preto, SP, Brazil. E-mail mcdosalg{at}fmrp.usp.br
| Abstract |
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2-adrenoceptors. In
conclusion, peripheral effects of
2-(2-chlorophenylamino)imidazoline and clonidine involved at least
1- and
2-adrenoceptor activation, whereas
pressor and depressor effects of rilmenidine were mediated by
2-adrenoceptors.
Key Words: adrenergic receptors sympathetic antihypertensive agents
| Introduction |
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Although the hypotensive effect of clonidine-like drugs involves
central imidazoline receptors, many studies suggest the possibility of
a peripheral presynaptic contribution to the depression of
sympathetic tone produced by these drugs.4 5 In this
regard, presynaptic
2-adrenoceptors have been
shown to be involved in the inhibition of norepinephrine
release.6 7 It was recently suggested that
inhibitory presynaptic imidazoline receptors may also be
involved in this response.8 9
The aim of the present work was to investigate and to compare the presynaptic and postsynaptic effects of clonidine, rilmenidine, and an imidazoline derivative, 2-(2-chlorophenylamino)imidazoline, in the peripheral cardiovascular system of pithed rabbits with or without electrically stimulated sympathetic outflow.
| Methods |
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25 cm
down the spinal canal. The rod destroyed the central nervous system and
also served to electrically stimulate the peripheral
sympathetic nerves with a stimulator (20 V, 2 Hz, 0.5 ms). An
indifferent electrode was placed subcutaneously between the
scapulae. In all experiments, a 60-minute period was allowed before any drug injection. Vehicle administration produced no significant effect on hemodynamic parameters. Increasing doses of drugs were injected at 15-minute intervals. When antagonists were used, prazosin (0.1 mg/kg), yohimbine (1 mg/kg), or a combination of the two was injected 10 minutes before the injection of the agonists.
Drugs used were clonidine (RBI), rilmenidine (Servier), 2-(2-chlorophenylamino)imidazoline (synthesized in the Strasbourg laboratory), prazosin hydrochloride (Sigma), yohimbine hydrochloride (Sigma), sodium pentobarbital (Nembutal, Sigma), and pancuronium bromide (Cristalia). Drugs were dissolved in normal saline.
Results were expressed as mean±SEM. Differences between groups were determined by 2-factor ANOVA with repeated measures followed by Student's t test with Bonferroni corrections. Differences within each group were determined by ANOVA for repeated measures followed by Student's t test. A value of P<0.05 was considered statistically significant.
| Results |
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Pithed Rabbits With Electrical Stimulation
Peripheral effects of clonidine, rilmenidine, and
2-(2-chlorophenylamino)imidazoline were also studied in pithed rabbits
with preganglionic electrical stimulation of sympathetic nerves.
Stimulation induced a significant increase in basal mean
arterial pressure (63±3 mm Hg) and heart rate
(266±8 bpm) compared with the nonstimulated group (P<0.05,
n=26). Clonidine (15 to 1000 µg/kg) and rilmenidine (15 to 1000
µg/kg) caused a transient increase in mean arterial
pressure, followed by a dose-dependent depressor effect (Figure 2A and 2B) and reduction in heart rate
(Table). In contrast,
2-(2-chlorophenylamino)imidazoline (15 to 1000 µg/kg) induced only a
dose-dependent pressor effect (Figure 2C), without significant
changes in heart rate (Table).
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To determine the contribution of
2-adrenoceptors to the biphasic effect of
clonidine and rilmenidine, yohimbine (1 mg/kg IV) was administered 10
minutes before the tested drugs. Yohimbine did not change heart rate
but induced a significant decrease in mean arterial
pressure (from 79±4 to 65±4 mm Hg and from 55±2 to 42±3
mm Hg in the rilmenidine- and clonidine-treated groups, respectively).
In the presence of yohimbine (Figure 3),
clonidine (n=5) or rilmenidine (n=6) elicited only long-lasting
dose-dependent pressor effects. Although the magnitude of the pressor
responses to clonidine was not significantly affected after yohimbine,
those elicited by rilmenidine were attenuated. Surprisingly, the
bradycardic effects of clonidine were not prevented by yohimbine. In
contrast, those elicited by rilmenidine were prevented by yohimbine
(Table).
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| Discussion |
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The potent vasopressor effects of clonidine and
2-(2-chlorophenylamino)imidazoline in nonstimulated rabbits were
significantly inhibited by yohimbine and prazosin, indicating that
these compounds produced vasoconstriction by stimulation of
postsynaptic vascular
1- and
2-adrenoceptors. The pressor effects of low
doses of clonidine were mainly due to stimulation of
2-adrenoceptors, whereas additional
stimulation of
1-adrenoceptors occurred at
higher doses. This observation confirmed previous observations in
pithed rats.11 12 The weak pressor effects of rilmenidine
were significantly inhibited by yohimbine and were unaffected by
prazosin, suggesting that rilmenidine exhibited some selectivity for
postsynaptic vascular
2-adrenoceptors.
The presynaptic
2-adrenergic activity of
clonidine and rilmenidine was confirmed in stimulated pithed rabbits;
in these conditions, these compounds produced a hypertensive effect,
followed by depressor and bradycardic effects. Yohimbine prevented the
depressor effects of both drugs, suggesting that these effects were
probably mediated by presynaptic
2-adrenoceptor. The pressor effects of
clonidine were not affected by yohimbine, whereas those induced by
rilmenidine were significantly reduced. These results confirmed the
selectivity for
2-adrenoceptors of rilmenidine
observed in the nonstimulated animals. The fact that the maximal
depressor effect of rilmenidine, observed in stimulated animals, was
much weaker than that of clonidine strongly suggests that rilmenidine
acted on presynaptic
2-adrenoceptors as a
partial agonist.13 Such an effect might also explain that
rilmenidine caused
2-adrenoceptormediated
vasoconstriction that was also weaker than that of clonidine.
Surprisingly, bradycardia induced by clonidine was insensitive to
yohimbine. In contrast, studies performed in pithed rats have shown
that clonidine inhibited electrically induced tachycardia
and that this effect was sensitive to
2-adrenoceptor
antagonists.12 14 Recently, the presence of a
presynaptic imidazoline receptor has been suggested in the human
heart,15 as well as in rabbit aorta and pulmonary
arteries16 and rat vena cava.9 Our results do
not exclude the possibility that rilmenidine and clonidine elicit
effects through a putative presynaptic imidazoline receptor in
sympathetic stimulated pithed rabbits. Experiments with selective
antagonists are needed to further clarify our observations
in pithed rabbits.
In nonstimulated rabbits, the vasoconstrictive effect of 2-(2-chlorophenylamino)imidazoline was more sensitive to prazosin than to yohimbine. Consistent with this observation is the fact that this derivative, like phenylephrine (data not shown), produced neither depressor nor bradycardic effects in stimulated pithed rabbits. Our results show that a very weak chemical change, the absence of a chloride atom in position 6 on the aromatic ring, largely altered the pharmacological profile of the drug.
In conclusion, peripheral effects of clonidine and
2-(2-chlorophenylamino)imidazoline involve
1-
and
2-adrenoceptor activation. The weak
pressor and depressor effects of rilmenidine in pithed rabbits with or
without stimulation suggest that this drug acts as a partial agonist on
peripheral
2-adrenoceptors.
| Acknowledgments |
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Received May 8, 1999; first decision June 15, 1999; accepted July 13, 1999.
| References |
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