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2-adrenoceptors in caudal
ventrolateral medulla to cardiovascular regulation in rat
Third Department of Internal Medicine, University of The Ryukyus School of Medicine, Nishihara, Okinawa 903-01, Japan
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The inhibitory action of
2-agonists on the
cardiovascular neurons has been elucidated in the rostral ventrolateral
medulla (RVLM) but not in the caudal ventrolateral medulla (CVLM). Our study aimed to clarify whether microinjection of clonidine into the
CVLM elicits any cardiovascular effect and whether endogenous 2-adrenoceptor-mediated
mechanisms contribute to the tonic activity of the CVLM neurons. In
male Sprague-Dawley rats (7-9 wk old, 270-320 g) anesthetized
with urethan, unilateral microinjection of 8 nmol of clonidine into the
CVLM (n = 10) increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) by 12.1 ± 1.8 mmHg (mean ± SE, P < 0.01) and
25.8 ± 4.8% (P < 0.01), while
heart rate (HR) remained unaltered. Unilateral microinjection of 2 nmol
of SKF-86466, a selective blocker of the
2-adrenoceptors, into the CVLM
(n = 10) decreased MAP, HR, and RSNA
(
11.6 ± 2.6 mmHg, 26 ± 7 beats/min, and 15.3 ± 1.7%, respectively, P < 0.01 for each). Artificial cerebrospinal fluid caused neither a
cardiovascular effect nor a sympathetic response. Prior injection of
SKF-86466 into the ipsilateral CVLM attenuated the effects of
clonidine. Bilateral microinjection of muscimol into the RVLM abolished
the effects of both clonidine and SKF-86466 injected into the CVLM. The
pressor and sympathoexcitatory effects of clonidine injected into the
CVLM suggest a neuroinhibitory action of the drug on the CVLM neurons.
In addition,the depressor and sympathoinhibitory effects of SKF-86466
injected into the CVLM indicated that activation of
2-adrenoceptors by endogenous
ligand inhibits CVLM neurons. The effects of clonidine and the
2-adrenoceptor antagonist in the CVLM require the integrity of the RVLM.
imidazole receptor; clonidine; blood pressure; renal sympathetic nerve activity
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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CLONIDINE ELICITS A hypotensive effect through actions
in the central nervous system. Intravenous administration of clonidine reduces pre- and postganglionic discharge in sympathetic nerves (11,
24). The pressor area in the ventrolateral medulla (VLM), the rostral
VLM (RVLM), has been nominated as a site of the hypotensive action of
clonidine (2, 20). Microinjection of clonidine into the RVLM produced a
long-lasting hypotensive effect in normotensive and hypertensive
animals (2, 5, 7, 20). In addition, intracisternally injected
-methyldopa, an
2-adrenoceptor agonist, reduced
baroreflex gain and resting tone of renal sympathetic nerve activity
(RSNA) (6). Although imidazole receptors are thought to contribute to
the hypotensive effect of clonidine or these analogs in the RVLM (3, 7,
8, 10), there is also evidence suggesting that
2-adrenoceptors mediate the
action of clonidine in the RVLM (1, 5). The hypotensive effect of systemically administrated clonidine was attenuated after
2-adrenoceptor blockade (12,
21).
In the VLM, there is another important cardiovascular center, the
caudal VLM (CVLM). Neurons in the CVLM send tonically inhibitory inputs
to the RVLM (4). A number of neuroexcitatory or neuroinhibitory substances, including glutamate, glycine, GABA, angiotensin II, or
opioids, act on both the RVLM and the CVLM neurons to modulate peripheral sympathetic activity (4). It is demonstrated that 2-adrenoceptors or imidazole
receptors exist in the CVLM (22, 25). However, action of clonidine and
role of 2-adrenoceptors in CVLM
have not been extensively studied. We therefore examined whether
clonidine delivered to the CVLM locally exerted any cardiovascular or
sympathetic effects through acting on the
2-adrenoceptors and whether
endogenous
2-adrenoceptor-mediated
mechanisms contributed to the tonic activity of the CVLM neurons.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Animal preparation. Male Sprague-Dawley rats (7-8 wk of age, 270-320 g), purchased from Charles River, were anesthetized with urethan (1.0 g/kg ip). The right femoral artery and vein were cannulated for measurement of arterial pressure and administration of drugs. Body temperature was maintained within 37 ± 1°C with the use of a heat pad. Arterial blood gases and pH measured at the end of the experiments were within normal limits (mean PO2 = 103 ± 13.4 mmHg, mean PCO2 = 33.9 ± 1.3 mmHg, mean pH = 7.44 ± 0.02).
Anesthetized rats were fixed on a stereotaxic frame (Narishige Scientific Instruments, Tokyo, Japan) in a supine position. The trachea and esophagus were transected in the lower neck and reflected rostrally. The distal trachea was cannulated for artificial ventilation (Rodent Ventilator model 683; Harvard, South Natick, MA). After retraction of the bilateral longus capitis muscles, the inferior occipital bone was removed and the dura was incised and retracted to expose the ventral surface of the medulla, which was kept moist by endogenous cerebrospinal fluid. Particular care was taken not to damage the aortic depressor and the carotid sinus nerves.
The left kidney was exposed via transperitoneal approach. A branch of renal nerves was identified around the renal artery and vein distal to the left adrenal vein; it was then separated from surrounding tissues and placed on a bipolar silver wire electrode (no. 7855, A-M Systems). When an optimal neurogram was obtained, the nerve and the electrode were embedded in silicone gel (Siligel 604; Wacker, Munich, Germany) and allowed to harden. For measurement of RSNA, original renal nerve signals were amplified and filtered between 30 and 1,000 Hz (DPA-100E; Dia Medical System, Tokyo, Japan). The amplified nerve pulses were counted using a spike counter (DSE-325A, Dia Medical System).
Microinjection procedure. Four-barrel micropipettes with tip diameters of 20-50 µm, made from calibrated microbore capillary glass tubing (Accu-Fill 90; Clay Adams, Parsippany, NJ), were used for the microinjections. Tips were drawn on a glass micropipette puller (type PE-2, Narishige Scientific Instruments). The injections were made over a 30-s period with a handheld syringe. The injected volume was measured by observing the movement of the fluid meniscus along a reticule by microscope.
The CVLM and RVLM were identified by injection of 2 nmol of L-glutamate based on the criteria of our previous studies (16, 17, 23). The CVLM corresponded to the injection sites located between the second and third rootlet of the hypoglossal nerve, 1.9-2.1 mm lateral to the midline and 0.7-0.9 mm below the ventral surface, and the RVLM was located 0.6-1.0 mm rostral to the most rostral rootlet of the hypoglossal nerve, 1.7-1.9 mm lateral to the midline, and 0.5-0.8 mm below the surface (17, 23).
Experimental
protocols. To determine cardiovascular
and sympathetic effects of clonidine or endogenous
2-adrenoceptor-mediated mechanisms in the CVLM, clonidine (8 nmol/50 nl) or SKF-86466 (2 nmol/50 nl), a selective
2-adrenoceptor blocker, was
injected through multibarrel micropipettes into the CVLM unilaterally. The dose of each drug was chosen based on previous studies (10, 20).
The area of CVLM was identified by administration of
L-glutamate (2 nmol/50 nl). In
other rats, injection of clonidine was performed 10 min after a prior
injection of SKF-86466 into the CVLM to determine whether the effects
of clonidine in the CVLM were mediated by the local
2-adrenoceptors. To clarify
whether the RVLM transmits actions of clonidine in the CVLM, clonidine
was injected into the CVLM unilaterally 5 min after bilateral
administration of muscimol (500 pmol/100 nl), a
GABAA agonist, into the RVLM.
Muscimol was injected bilaterally, because the projection from the CVLM to the contralateral RVLM was documented(14).
Each drug was dissolved in artificial cerebrospinal fluid (aCSF; in mM: 133.3 NaCl, 3.4 KCl, 1.3 CaCl2, 1.2 MgCl2, 0.6 NaH2PO4, 32.0 NaHCO3, and 3.4 glucose). Therefore, 50 nl of aCSF was injected as a control. At the end of each experiment, 10 nl of an emulsion of Alcian blue dye was used to mark the site of injection and hexamethonium (40 mg/kg) was administered intravenously to estimate noise level for RSNA.
Histological analysis. At the completion of each experiment, rats were perfused transcardially with 0.9% NaCl followed by phosphate-buffered 10% Formalin. The brain stem was removed, stored overnight in 10% phosphate-buffered Formalin, and then transferred to fixative containing 30% sucrose. Frozen brain tissue was sectioned in the coronal plane (50 µm) and stained with neutral red. Microinjection sites were identified by deposition of Alcian blue dye and referred to standard anatomic structures of the brain stem according to the atlas of Paxinos and Watson (19).
Statistical analysis. Data were expressed as means ± SE. Unpaired t-tests were used to compare the effects of clonidine or SKF-86466 with those of aCSF on mean arterial pressure (MAP), heart rate (HR), and RSNA. P values <0.05 were considered to be statistically significant.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Baseline values of MAP and HR were 101.3 ± 2.7 mmHg and 419 ± 16 beats/min in the rats injected with clonidine (n = 10) and 101.9 ± 3.6 mmHg and 424 ± 17 beats/min in the rats injected with SKF-86466 (n = 10). In the rats treated with aCSF (n = 6), baseline values were 100.9 ± 4.7 mmHg and 425 ± 25 beats/min, respectively.
Microinjection of clonidine and SKF-86466 into the CVLM. Unilateral microinjection of clonidine into the CVLM (n = 10) increased MAP and RSNA, whereas HR remained unaltered (Fig. 1). In contrast, microinjection of SKF-86466 into the CVLM (n = 10) decreased MAP, RSNA, and HR (Fig. 2). The responses occurred within 20 s of microinjection of clonidine or SKF-86466 and lasted at least 5 min. Table 1 summarizes onset times and peak latencies of the blood pressure to clonidine and SKF-86466 and also maximal changes in MAP, RSNA, and HR evoked by the microinjection of clonidine and SKF-86466. aCSF (n = 6) caused neither a cardiovascular effect nor a sympathetic response.
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The dose of clonidine used in this study had no local anesthetic effect
because the depressor response to
L-glutamate remained unaltered
at the peak of hypertensive action of the drug (before clonidine:
33.8 ± 3.1 mmHg, after clonidine: 35.5 ± 2.1 mmHg). Also, SKF-86466 in the dose used had no effect on pressor response to
glycine (10 nmol/50 nl) at the peak of hypotensive action of the drug
(before SKF-86466: 11.8 ± 2.4 mmHg, after SKF-86466: 12.2 ± 1.5 mmHg).
Effect of prior injection of selective
2-blockade in the CVLM on the
clonidine-induced pressor and sympathoexcitatory
effects. The prior injection of SKF-86466 into the CVLM
(n = 6) significantly attenuated but
did not totally abolish the increases in MAP and RSNA evoked by
clonidine (Figs. 1 and 3). In this series
of experiments, clonidine injection was carried out after the recovery
of the decreased MAP and RSNA to the prevailing levels.
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Effect of suppression of the RVLM on the clonidine-induced pressor and sympathoexcitatory effects. Figure 4 shows that the pressor and sympathoexcitatory effects of clonidine injected into the CVLM were abolished after the microinjection of muscimol into bilateral RVLM. Bilateral microinjection of muscimol into the RVLM (n = 5) decreased MAP and RSNA to 40.4 ± 3.1 mmHg and 60.9 ± 7.7% of the baseline activity, respectively. In these rats, microinjection of clonidine into the CVLM before the pretreatment of the RVLM with muscimol caused increases in MAP and RSNA by 14.4 ± 1.8 mmHg and 34.7 ± 6.0%, respectively. However, microinjection of clonidine into the CVLM following the muscimol injection into the RVLM did not alter MAP, RSNA, or HR (Figs. 4 and 5). Likewise, the depressor and sympathoinhibitory effects of SKF-86466 injected into the CVLM were abolished after the muscimol injection into the RVLM (Figs. 4 and 5).
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Histological analysis. Figure 6A is a composite of the locations where clonidine, SKF-86466, or aCSF was injected. Sites in which hypertensive responses of clonidine or hypotensive responses of SKF-86466 occurred were restricted to a region ventral to the nucleus ambiguus and dorsal to the lateral reticular nucleus. Figure 6B is a composite of the locations where muscimol was injected; the locations are in the dorsolateral aspect of the lateral paragigantocellular nucleus. According to the atlas of Paxinos and Watson (19), these regions represent medullary sections extended from 3.30 mm to 5.30 mm caudal to interaural line.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The principal findings in the present study are that clonidine injected
into the CVLM elevated arterial pressure and increased RSNA, whereas
SKF-86466, a selective blocker of
2-adrenoceptor, decreased
arterial pressure, HR, and RSNA on microinjection into the CVLM. The
effects of clonidine in the CVLM were significantly attenuated by a
prior injection of SKF-86466. Previous studies have demonstrated that
clonidine and its analogs elicit an hypotensive effect by inhibiting
the vasomotor neurons in the RVLM (2, 20). However, effects on blood
pressure and sympathetic activity of clonidine injected into the CVLM
have not been extensively studied. Our results clearly demonstrated
that clonidine exerts a pressor action in the CVLM associated with
sympathoexcitation. Because inhibition of the cardiovascular neurons in
the CVLM elevates blood pressure and increases peripheral sympathetic
activity (26), clonidine seems to act as a neuroinhibitory agent in the
CVLM as well as in the RVLM. In addition, the depressor and
sympathoinhibitory effects of SKF-86466 injected into the CVLM suggest
that endogenous 2-adrenoceptor-mediated
mechanisms act to tonically inhibit the cardiovascular neurons in the
CVLM. In fact, histological analysis of SKF-86466-responsive sites in
the CVLM placed them in a region where the specific
[3H]para-aminoclonidine
binding was shown (25).
The pressor and sympathoexcitatory actions of the drug injected into the CVLM demonstrated in this study might be independent of its systemically hypotensive action. However, the design of this study is not appropriate to address the question of whether the hypotensive effect of systemically administrated clonidine is buffered by an opposing effect in the CVLM.
Our results are in contrast, however, to the findings of McAuley et al. (15) that 10 and 20 nmol of clonidine dissolved in 100 nl of saline caused long-lasting depressor effects when injected into either the CVLM or the RVLM of Wistar-Kyoto rats. The data of McAuley et al. (15) suggest that clonidine act as a neuroinhibitory agent in the RVLM and as a neuroexcitatory agent in the CVLM to cause depressor response in both sites. However, an important aspect of our study differs from the study of McAuley et al. For microinjection, we used multibarrel glass micropipettes with tip diameters of 20-50 µm to enable injections to be made without causing substantial disruption to tissue, and also we verified the injection sites by typical depressor and sympathoinhibitory responses to L-glutamate and the deposition of Alcian blue dye. In contrast, McAuley et al. (15) utilized a 30-gauge needle, which might have damaged the medullary tissue. Furthermore they did not verify the injection sites by the typical responses to L-glutamate injection (15). Orer et al. (18) microinjected 1 nmol of clonidine dissolved in 100 nl of 0.9% saline into four sites in the CVLM in cats. Although the power of the 10-Hz rhythms in sympathetic discharge was almost eliminated by the clonidine injection, the total power of sympathetic nerve discharge and MAP was not significantly altered. Clonidine might have a different influence on the CVLM neurons in rat and cat. Further studies are definitely needed to clarify the species difference in the responsiveness of the CVLM neurons.
Clonidine binds to both
2-adrenoceptors and imidazole
receptors in the RVLM (9). There is a controversy concerning which receptors are primarily responsible for the hypotensive effects of
clonidine or clonidine analogs. In the RVLM, the fall in MAP elicited
by microinjection of clonidine analogs significantly correlated with
their affinities for imidazole receptors but not with their affinities
for 2-adrenoceptors (7), and
the depressor effects of locally injected clonidine were attenuated by
imidazole receptor antagonists but not by
2-selective adrenoceptor
antagonists (8, 10) and were mimicked by substances with imidazole
structures (3). However, -methylnorepinephrine, an agent with
similar affinities as clonidine for the
2-adrenoceptors but not for
imidazole receptors, exerted only negligible effects in ventrolateral
medulla of cats (3). These papers (3, 7, 8, 10) suggest functional
predominance of imidazole receptors in the RVLM. On the other hand,
iontophoretic application of -methylnorepinephrine exerted a similar
degree of inhibition of the vasomotor neurons in the RVLM as does
clonidine (1). Intravenous administration of
2-selective or nonselective
adrenoceptor antagonists reversed or antagonized the sympathoinhibitory
and hypotensive effects of clonidine and/or rilmenidine (1, 5,
12, 21). Furthermore, the hypotensive response to
2-adrenoceptor agonists was
lost in mice with a point mutation in the gene of the
2a-adrenoceptor subtype (13).
These papers (1, 5, 13, 12, 21) suggest that
2-adrenoceptors, especially of
2a-subtype, seem to play a
principal role in the hypotensive effect of clonidine or clonidine-like substances. In the present study, the attenuation of the pressor and
sympathoexcitatory effects of clonidine in the CVLM by a prior injection of SKF-86466 strongly suggests an involvement of local 2-adrenoceptors. However, a
slight but significant pressor and sympathoexcitatory effect was
observed in response to the microinjection of clonidine performed after
the pretreatment with SKF-86466 (Figs. 3 and 4). Therefore, the
possibility that imidazole receptors in the CVLM (22) also participate
in the pressor and sympathoexcitatory effects of locally injected
clonidine could not be excluded, although rilmenidine, having higher
selectivity for imidazole receptors compared with clonidine, had no
effect on arterial pressure or HR when injected into the CVLM (10).
Another important finding in the present study was that microinjection
of either clonidine or SKF-86466 into the CVLM after bilateral
administration of muscimol into the RVLM did not alter MAP, RSNA, and
HR. These findings underscore the requirement of vasomotor neurons of
the RVLM for the action of clonidine and the
2-adrenoceptor antagonist in
the CVLM. Because the cardiovascular neurons in the CVLM send tonically
inhibitory inputs, which are GABAergic, to the vasomotor neurons in the
RVLM (4), it is likely that clonidine diminishes and SKF-86466 enhances
the inhibitory input to the RVLM.
In summary, we show that clonidine administered into the CVLM increases
MAP and RSNA mainly by acting on local
2-adrenoceptors. These pressor
and sympathoexcitatory effects suggest a neuroinhibitory action of
clonidine on the CVLM neurons. In addition, SKF-86466, an
2-adrenoceptor blocker,
microinjected into the CVLM elicits depressor and sympathoinhibitory
effects. These results indicate that activation of
2-adrenoceptors by endogenous
ligand inhibits CVLM neurons. The cardiovascular and sympathetic
effects of clonidine and
2-antagonist injected into the
CVLM require integrity of the vasomotor neurons in the RVLM.
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ACKNOWLEDGEMENTS |
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The authors thank Rijiko Matayoshi for her technical assistance. SKF-86466 was a kind gift of SmithKline Beecham Pharmaceuticals.
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FOOTNOTES |
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This work was supported in part by Grants in Aid for Scientific Research (05670625 and 03670461) from the Ministry of Education, Science and Culture of Japan. Additional experiments were supported by a research grant from Ministry of Health and Welfare (9A-1).
Present address of H. Teruya and S. Takishita: National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565, Japan.
Address for reprint requests: S. Sesoko, Third Dept. of Internal Medicine, Univ. of The Ryukyus School of Medicine, 207 Uehara, Nishihara, Okinawa 903-01, Japan.
Received 3 June 1997; accepted in final form 25 December 1997.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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 M. Yamazato, A. Sakima, J. Nakazato, S. Sesoko, H. Muratani, and K. Fukiyama Hypotensive and sedative effects of clonidine injected into the rostral ventrolateral medulla of conscious rats Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R1868 - R1876. [Abstract] [Full Text] [PDF]
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A. M. Schreihofer and P. G. Guyenet Role of presympathetic C1 neurons in the sympatholytic and hypotensive effects of clonidine in rats Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2000; 279(5): R1753 - R1762. [Abstract] [Full Text] [PDF]
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 A. Hayar and P. G. Guyenet Prototypical Imidazoline-1 Receptor Ligand Moxonidine Activates Alpha2-Adrenoceptors in Bulbospinal Neurons of the RVL J Neurophysiol, February 1, 2000; 83(2): 766 - 776. [Abstract] [Full Text] [PDF]
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 A. Hayar and P. G. Guyenet alpha 2-Adrenoceptor-mediated presynaptic inhibition in bulbospinal neurons of rostral ventrolateral medulla Am J Physiol Heart Circ Physiol, September 1, 1999; 277(3): H1069 - H1080. [Abstract] [Full Text] [PDF]
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),
SKF-86466 (
), clonidine + SKF-86466 (
), or artificial
cerebrospinal fluid (
) in the CVLM.
B: injection sites of muscimol (
)
in the RVLM. Amb, nucleus ambiguus; IO, inferior olivary nucleus; LPGi,
lateral paragigantocellular nucleus; LRt, lateral reticular nucleus;
NTS nucleus of the solitary tract; 12, hypoglossal nucleus. Drawing is
according to the atlas of Paxinos and Watson (