Experimental Physiology Celebrating 100 years
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Experimental Physiology 91.1 pp 269-275
DOI: 10.1113/expphysiol.2005.031914
© The Physiological Society 2006
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
91/1/269    most recent
expphysiol.2005.031914v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kaczyñska, K.
Right arrow Articles by Szereda-Przestaszewska, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kaczyñska, K.
Right arrow Articles by Szereda-Przestaszewska, M.
Related Collections
Right arrow Respiratory

Clonidine-evoked respiratory effects in anaesthetized rats

Katarzyna Kaczyñska1 and Malgorzata Szereda-Przestaszewska1

1 Laboratory of Respiratory Reflexes, Polish Academy of Sciences Medical Research Centre, 5 Pawiñski Street, 02-106 Warsaw, Poland


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The respiratory effects of stimulation of {alpha}2-adrenergic receptors were studied in spontaneously breathing anaesthetized rats that were neurally intact, or bilaterally vagotomized, or subjected to bilateral combined midcervical vagotomy and section of the carotid sinus nerves. An intravenous clonidine bolus (15 µg kg–1) evoked a prolonged slowing of the respiratory rate in all the neural states explored. Vagotomy reduced the early clonidine-evoked decline, but not the augmentation of tidal volume that followed the decline. After section of the carotid sinus nerves, clonidine challenge continued to decrease the respiratory rate, but not the tidal volume. Blockade of {alpha}2-adrenergic receptors with intravenous doses of SKF 86466 (200 µg kg–1) abolished all respiratory effects of the clonidine challenge. In all the neural states studied, clonidine evoked a significant short-lived rise in mean arterial blood pressure followed by a decrease below the respective prechallenge value. The SKF 86466 pretreatment lowered mean arterial blood pressure control values and reduced the magnitude of postclonidine changes. These results indicate that: (i) clonidine-evoked activation of {alpha}2-adrenergic receptors affects the two components of the breathing pattern differently, and this occurs beyond the lung vagi; and (ii) changes in tidal volume result from excitation of the carotid bodies and are coupled with centrally mediated slowing of the respiratory rhythm.

(Received 11 August 2005; accepted after revision 7 November 2005; first published online 10 November 2005)
Corresponding author K. Kaczyñska: Laboratory of Respiratory Reflexes, Polish Academy of Sciences Medical Research Centre, 5 Pawiñski Street, 02-106 Warsaw, Poland. Email: kkacz{at}cmdik.pan.pl


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
{alpha}2-Adrenergic receptors came to the fore as regulators of exocytosis of a number of neurotransmitters, sympathetic nervous system function and blood pressure homeostasis (Philipp et al. 2002). Adrenergic pathways have been identified in the brain regions that belong to central respiratory network, such as nucleus tractus solitarii (NTS; Feldman & Moises, 1988; Hayward et al. 2002), nucleus ambiguus and ventral respiratory group (Ellenberger & Feldman, 1990). Their activation results in depression of ventilation, which implicates the involvement of {alpha}2-adrenergic receptors in the control of breathing (Burton et al. 1990; Rives & Bernard, 2001).

Clonidine is a non-specific {alpha}2-adrenergic receptor agonist that is widely used in clinical practice for the treatment of hypertension and postoperative pain, and in intensive care as a sedative and analgesic agent (Eisenach, 1988; Philipp et al. 2002). Some studies showed that clonidine produced depression of minute ventilation (Jarvis et al. 1992), snoring, obstructive sleep apnoea and episodes of arterial oxygen desaturation in man (Narchi et al. 1992).

While the effects of {alpha}2-adrenoceptor agonists on central cardiorespiratory activity are relatively well documented, few attempts have been made to demonstrate whether these agents are involved in the peripheral control of breathing and circulation. Intravenous clonidine administration in experimental animals evokes heterogeneous respiratory effects. Anaesthetized dogs (Burton et al. 1990) and goats (Hedrick et al. 1994) respond to clonidine with a slowing of the respiratory rhythm, whereas awake goats show an irregular pattern of breathing, including episodes of apnoea and tachypnoea (Hedrick et al. 1994).

Earlier studies in rats have shown an inhibitory action of clonidine (Fuxe et al. 1982) and an excitatory effect of {alpha}2-adrenergic blockade (Coles et al. 1998) on breathing rate. A contribution of peripheral afferents to ventilatory changes evoked by clonidine has not been described in this species. The present study was undertaken to determine the respiratory pattern evoked by I.V. clonidine administration in the rat, to asses the contribution of vagal and carotid body afferents to the respiratory effects observed, and to establish, with the use of the selective {alpha}2-antagonist SKF 86466, whether the respiratory effects of clonidine are due to stimulation of {alpha}2-adrenergic receptors.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All animal procedures were in accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the local ethics committee. Adult male Wistar rats (250–300 g body weight) were anaesthetized with an intraperitoneal injection of 600 mg kg–1 urethane (Sigma) and 120 mg kg–1 {alpha}-chloralose (Fluka AG). Supplementary urethane doses were administered I.V. as indicated by response(s) to nociceptive test stimuli. The animals were placed supine recumbency and breathed room air spontaneously. The trachea was exposed in the neck, sectioned below the larynx and cannulated. Catheters were inserted into the femoral vein for drug administration and into the femoral artery for blood pressure monitoring. Rectal temperature was maintained at 38°C with a heating pad. The midcervical segments of the vagi were isolated and prepared for vagotomy prior to measuring studied respiratory variables in neurally intact rats. The carotid region on both sides was dissected under an operating microscope, and carotid sinus nerves (CSNs) were prepared and cut bilaterally at their junctions with glossopharyngeal nerves later during the experiment. The carotid denervation was confirmed by the absence of any response to I.V. injection of 50 µg of NaCN, which dose elicits a brisk response in rats with intact CSNs. Baroreceptor denervation was completed when no hypertensive response occurred on clamping both common carotid arteries. Tidal volume (VT) signals were recorded with a model CS6 spirometer (Mercury) attached to the tracheal cannula. Arterial blood pressure was measured with a BP-2 monitor (Columbus Instruments). End-tidal CO2 concentration was measured with a capnograph (Engstrom Eliza Plus, Gambro). Electromyogram of the costal diaphragm was recorded with bipolar electrodes connected to a model NL 104 amplifier (Digitimer), and filtered and measured with a model AS 101 (Asbit) leaky integrator (time constant, 100 ms). The recordings were registered with an Omnilight 8M36 apparatus (Honeywell).

The respiratory effects of the stimulation of {alpha}2-adrenergic receptors were tested using single clonidine boluses in the following experimental designs: (i) before and after bilateral midcervical vagotomy in otherwise neurally intact rats (n = 8); (ii) before and after section of the CSNs in vagotomized rats (n = 10); and (iii) before and after blockade of {alpha}2-adrenergic receptors with SKF 86466 in vagotomized rats (n = 7). Clonidine hydrochloride (Sigma) was dissolved (18.8 µg ml–1) in 0.9% NaCl and injected at a dose of 15 µg kg–1 into the femoral vein. The dose was derived from our preliminary dose–response experiment, which revealed that this dose resulted in maximum while most uniform decline in the respiratory rate in neurally intact rats (see Fig. 1). SKF 86466 (6- chloro-3-methyl-2,3,4,5-tetrahydro-3-benzazepine, SmithKline Beecham) was dissolved (250 µg ml–1) in 0.9% NaCl solution and injected I.V. at a dose of 200 µg kg–1 (O'Halloran et al. 2001) 1 min before the clonidine bolus. Each drug bolus was immediately flushed with a 0.2 ml aliquot of the saline.



View larger version (16K):
[in this window]
[in a new window]
  		Figure 1.  Respiratory rate changes evoked by I.V. clonidine challenge in neurally intact rats
Each clonidine dose was tested in a separate group of six rats. *P < 0.05 versus the respective preclonidine value.

 
Each individual value of VT, minute ventilation {eph_219_mu1} and respiratory rate was taken as an average over five consecutive breaths. The ventilatory data were derived from the integrated pneumotachograph signal and from the record of integrated diaphragm activity. The ventilatory parameters were assessed just before clonidine injection, during the early postclonidine phase (0–5 s after the saline flush), and at 30 s, 60 s and 2 min after the challenge. The data on clonidine dose effect on respiratory rate were analysed by Student's paired t test. All other experimental data were analysed by repeated measures two-way ANOVA, with time (prechallenge, early postclonidine phase, and 30 s, 60 s and 2 min after the challenge) and either innervation status (neurally intact and vagi cut, or vagi cut and vagi cut combined with CSNs cut) or SKF pretreatment (yes or no) as factors of repeated measures. Differences between individual time points and experimental situations were evaluated by planned comparisons. All statistical analyses were performed using Statistica for Windows v.5.1 software (StatSoft, Tulsa, OK, USA). In all cases, P < 0.05 was considered significant. All results shown are means ± 1S.E.M.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Figure 2 illustrates a typical response to the clonidine challenge (15 µg kg–1) in neurally intact rats. In these rats, intravenous clonidine injection produced distinct cardiorespiratory effects, mainly comprising biphasic changes in VT, significant and marked decreases in breathing frequency and {eph_219_mu2}, and a significant rise in arterial blood pressure. A similar respiratory response pattern was observed in midcervically vagotomized rats, except that the usual early postclonidine drop in VT was reduced or non-existent in some cases. Injection of an equal volume (0.2 ml) of the drug vehicle resulted in no respiratory effect, irrespectively of the neural state (not shown).



View larger version (16K):
[in this window]
[in a new window]
  		Figure 2.  A representative respiratory response pattern to I.V. administration of clonidine in a neurally intact rat
The injection time point is marked with an arrow above the upper trace. Note slowing of the breathing rate coupled with decreased VT ensued by augmentation, and apparent rise in blood pressure succeeded by a fall. VT, tidal volume; %CO2, end-tidal CO2; BP, systemic blood pressure; {int}Dia, integrated electromyogram of the diaphragm.

 
As shown in Table 1, clonidine challenge instantly evoked a significant but short-lived decrease in VT before, but not after vagotomy. There was, however, a significant early postclonidine decrease in VT in two more groups of vagotomized rats used in this study (see Table 2 and Fig. 3A, left panel), and statistical analysis of pooled VT data from all these groups (25 rats) has confirmed that clonidine challenge evokes a significant but relatively small early decrease in VT in vagotomized rats as well (–6.8 versus –10.8% in the neurally intact rats). At the later postclonidine time points there was a clear increase in VT that achieved significance at 2 min in the vagally intact and at 1 min in the vagotomized rats. The clonidine-evoked decrease in respiratory rate persisted at 2 min after the challenge both before and after vagotomy (Table 1). The decrease in {eph_219_mu3}, which always resulted from a significant reduction in the breathing rate, appeared immediately after the clonidine injection and persisted at 2 min postchallenge both before and after vagotomy. Both the pre- and postchallenge {eph_219_mu4} values were marginally higher after vagotomy (198 ± 18 and 122 ± 16 ml min–1, respectively, P < 0.001) than before this procedure (184 ± 20 and 97 ± 9 ml min–1, P < 0.01; see also Fig. 3A). Mean blood pressure was highest in the early phase of postclonidine breathing, changing from the baseline value of 82 ± 9 mmHg in the intact rats to 134 ± 11 mmHg (P < 0.001) and from 117 ± 8 to 166 ± 11 mmHg after vagotomy (P < 0.001). Two minutes after the challenge, a significant fall in blood pressure occurred both before and after vagotomy (P < 0.01).


View this table:
[in this window]
[in a new window]
  		Table 1. Changes in tidal volume (VT) and respiratory rate after intravenous clonidine challenge in neurally intact and vagotomized rats (n = 8)
 

View this table:
[in this window]
[in a new window]
  		Table 2. Effect of {alpha}2-adrenoceptor blockade on postclonidine pattern of breathing in vagotomized rats (n = 7)
 


View larger version (33K):
[in this window]
[in a new window]
  		Figure 3.  Effects of I.V. clonidine challenge and section of the CSNs on VT (A), respiratory rate (B) and {eph_219_mu8} (C) in bilaterally vagotomized rats (n = 10)
Two-way ANOVA revealed: (i) a significant effect of time (P < 10–5), but not section of the CSNs (P = 0.15), and a significant time x section of the CSNs interaction effect (P < 0.001) on VT; (ii) significant effects of time (P < 10–6), section of the CSNs (P < 0.001), and time x denervation interaction on respiratory rate (P < 0.01); and (iii) significant effects of time (P < 10–6), section of the CSNs (P < 0.01) and time x section of the CSNs interaction (P < 0.001) on {eph_219_mu9}. *P < 0.05, **P < 0.01 and ***P < 0.001 versus the respective preclonidine value; {dagger}P < 0.05, {dagger}{dagger}P < 0.01 and {dagger}{dagger}{dagger}P < 0.001 versus the corresponding pre-CSNs section value.

 
To determine whether the CSNs contribute to the response to I.V. clonidine challenge, we tested the effect of section of the CSNs on the respiratory effects of the drug in vagotomized rats. Our data show that the section of the CSNs abolished the clonidine-evoked depression and subsequent rise in VT (Fig. 3A). Moreover, while clonidine still lowered the frequency of breathing and depressed {eph_219_mu5} following deafferentation of the carotid bodies, these effects were significantly weaker after than before the neurotomy (Fig. 3B and C). The effect of neurotomy of the CSNs on the blood pressure response to clonidine in vagotomized rats is shown in Fig. 4A. After the section, mean arterial blood pressure (MAP) continued to increase immediately after the clonidine challenge and to decrease between 60 s and 2 min postchallenge; however, the response was significantly weaker compared to that before the section of the CSNs.



View larger version (14K):
[in this window]
[in a new window]
  		Figure 4.  Effects of sectionin the CSNs (A) and SKF 86466 pretreatment (B) on clonidine-evoked changes in blood pressure in vagotomized rats (n = 10 and n = 7, respectively)
Two-way ANOVA revealed: (i) significant effects of time (P < 10–6) and section of the CSNs (P < 0.01), but no significant time x section of the CSNs interaction effect (P = 0.059) on mean arterial blood pressure; and (ii) significant effects of time (P < 10–6) and time x SKF 86466 pretreatment interaction, but no significant effect of SKF 86466 pretreatment (P = 0.070) on mean arterial blood pressure. *P < 0.05, **P < 0.01 and ***P < 0.001 versus the respective preclonidine value; {dagger}P < 0.05, {dagger}{dagger}P < 0.01 and {dagger}{dagger}{dagger}P < 0.001 versus the corresponding pre-CSNs section value (A) or pre-SKF 86466 value (B).

 
Clonidine given 1 min after the injection of SKF 86466 evoked no respiratory effects. As shown in Table 2, the SKF 86466-mediated {alpha}2-adrenoceptor blockade prevented the clonidine-evoked changes in VT and in the respiratory rate. Two-way ANOVA revealed a significant effect of time (P = 0.029), but not of SKF 86466 (P = 0.150), and a significant time x SKF 86466 pretreatment interaction effect (P = 0.0029) on {eph_219_mu6}. The significant depression of {eph_219_mu7} produced by clonidine (from 204.3 ± 23.4 to 128.8 ± 21.2 ml min–1 occurring in the early postclonidine phase, P < 0.001) was eliminated after the blockade of {alpha}2-adrenoceptors with SKF 86466 (before SKF 86466, 210.0 ± 43.2 ml min–1 and after SKF 86466, 204.9 ± 49.3 ml min–1, P = 0.71). The SKF 86466 pretreatment significantly affected blood pressure (P = 0.001), which was evidenced by the lower average MAP values before and up to 60 s after the injection of clonidine. The immediate clonidine-evoked rise in MAP was still present, yet the SKF 86466 pretreatment apparently prevented the hypotension that formerly occurred at 2 min after clonidine injections (Fig. 4B).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The present study showed that in anaesthetized rats the predominant effect of an I.V. injection of the {alpha}2-agonist clonidine was a prolonged slowing of the respiratory rhythm. In neurally intact rats, this response was associated with a short-lived decline in VT followed by an increase.

Midcervical vagal deafferentation of the lungs had little influence on the respiratory changes evoked by clonidine in our experiments. This observation is in general agreement with previously published results obtained in awake goats, which responded to I.V. infusion of clonidine with dysrhythmic breathing consisting of tachypnoeic and apnoeic episodes (Hedrick et al. 1994; O'Halloran et al. 1999a,b).

Yet it was shown that in response to clonidine challenge anaesthetized goats (Hedrick et al. 1994) and rats (Fuxe et al. 1982) displayed the depression of the respiratory rate which corresponds with prolonged slowing of breathing in our study. The paper by Fuxe et al. (1982) showed no data on clonidine effects on VT, and anaesthetized and artificially ventilated goats showed a stable amplitude of phrenic nerve discharge (Hedrick et al. 1994). The present study revealed a transient postclonidine decrease in VT, followed by an increase both before and after midcervical vagotomy. The immediate postclonidine drop in VT tended to be lesser in vagotomized compared to neurally intact rats and did not always reach significance. We presume that this biphasic pattern may be related to the use of a threefold higher dose of clonidine than that in the reports cited above. Midcervical neurotomy of the vagal nerves eliminated input from the lungs, revealing that clonidine might affect the volume component of the breathing pattern through chemoafferent nerves. Our next step, therefore, was to remove the input from the carotid body and carotid sinuses. This deafferentation abolished the decrease and the subsequent augmentation of VT but did not abrogate the decrease in the respiratory rate (Fig. 3). The latter finding falls in line with the depression of respiratory rate produced by clonidine challenge in anaesthetized goats that invariably occurs before and after vagotomy and chemosensory withdrawal (Hedrick et al. 1994). The carotid bodies are endowed with {alpha}2-adrenergic receptors (Kou et al. 1991; Almaraz et al. 1997), and the clonidine-evoked changes in VT observed in our study presumably resulted from the excitation of these {alpha}2-receptors. Earlier reports showed both inhibitory and stimulatory effects of I.V. clonidine on chemoreceptor activity. It was suggested that imidazoline I1 receptors are responsible for the excitatory effects, whereas the inhibition might be mediated by {alpha}2-adrenergic receptors (Ernsberger et al. 1998). Studies on the contribution of {alpha}2-adrenergic receptors to the posthypoxic decrease in respiratory rate in rats have produced inconsistent results (see Coles et al. 1998; Bach et al. 1999). Our study clearly demonstrated that the decline was succeeded by an increase in VT, and that the clonidine-evoked depression of the respiratory rate occurred exclusively via stimulation of the {alpha}2-adrenergic pathway, because pretreatment with the selective {alpha}2-antagonist SKF 86466 precluded all respiratory effects of the clonidine challenge. This result is in line with the effectiveness of this antagonist in reversing respiratory disturbances in goats (Hedrick et al. 1994; O'Halloran et al. 2001) and rats (Coles et al. 1998).

Since clonidine easily penetrates the blood–brain barrier (Panagiotidis et al. 1993), its ability to depress the respiratory rate in CSNs-denervated vagotomized rats may imply a central origin of the response. The role of CNS {alpha}2-adrenergic receptors in regulation of breathing has been extensively investigated. Central application of {alpha}2-agonists inhibits respiration both in experimental animals (McCrimmon & Lalley, 1981; Burton et al. 1990; Errichidi et al. 1991) and in humans (Ooi et al. 1991; Narchi et al. 1992). In contrast, selective blockade of {alpha}2-adrenergic receptors stimulates respiration in dogs (Burton et al. 1990) and rats (Coles et al. 1998), presumably as a consequence of the absence of {alpha}2-adrenergic tonic inhibitory effects on the respiratory generator in the medulla. As mentioned in the Introduction, {alpha}2-adrenergic receptors are widespread in the neural circuits of the medulla oblongata that are engaged in the control of breathing (Guyenet et al. 1994; Schreihofer & Guyenet, 2000).

The depressive component of the respiratory response evoked by clonidine beyond the direct stimulation of {alpha}2-adrenergic receptors may be the result of interaction or interference with other neurotransmitter systems. Burton et al. (1990) proposed that depressant ventilatory effects of clonidine were due to inhibition of the cholinergic system. Moreover, it has been shown that activation of {alpha}2-adrenergic receptors reduces the release of L-glutamate (Kamisaki et al. 1993), an excitatory neurotransmitter involved in the control of breathing.

Intravenous administration of clonidine evoked a biphasic blood pressure response: a short-lived rise followed by prolonged hypotension. This type of response was observed after I.V. injections of {alpha}2-adrenergic receptor agonists in man (Kallio et al. 1989; Bloor et al. 1992) and experimental animals (Sannajust et al. 1992; Soares de Moura et al. 2000). It has been shown that the pressor component of the blood pressure effects depends on activation of {alpha}2-adrenergic receptors in the vascular smooth muscles, whereas hypotension is due to their excitation within the rostral ventrolateral medulla (Guimaraes & Moura, 2001; Yamazato et al. 2001). Indeed, neither vagotomy nor combined section of the vagi and CSNs prevented the clonidine-evoked blood pressure changes in our experiments. The significant SKF 86466 pretreatment x time interaction effect with the preserved but smaller initial increase in blood pressure in our study suggests that the {alpha}2-antagonist may counteract the clonidine-evoked hypotension. While this observation is consistent with the study in humans by Hayar & Guyenet (2000), the trend for a hypotensive effect of SKF 86466 (P = 0.07) in our study does not permit unequivocal acceptance of this interpretation.

In conclusion, this study has shown that I.V. clonidine challenge depresses ventilation, primarily due to the large decrease in respiratory rate. The depression is executed via activation of {alpha}2-adrenoceptors outside the lung vagi. Carotid chemoreceptors most probably constitute a crucial neural pathway for changes in VT, whereas the predominant effect of the timing component may rely on central {alpha}2-adrenergic mechanisms.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Almaraz L, Perez-Garcia MT, Gomez-Nino A & Gonzalez C (1997). Mechanisms of alpha2-adrenoceptor-mediated inhibition in rabbit carotid body. Am J Physiol 272, C628–C637.[Medline]

Bach KB, Kinkead R & Mitchell GS (1999). Post-hypoxia frequency decline in rats: sensitivity to repeated hypoxia and alpha2-adrenoceptor antagonism. Brain Res 817, 25–33.[CrossRef][Medline]

Bloor BC, Ward DC, Belleville JP & Maze M (1992). Effects of intravenous dexemedetomidine in humans. II. Hemodynamic changes. Anesthesiology 77, 1134–1142.[Medline]

Burton MD, Johnson DC & Kazemi H (1990). Adrenergic and cholinergic interaction in central ventilatory control. J Appl Physiol 68, 2092–2099.[Abstract/Free Full Text]

Coles SK, Ernsberger P & Dick TE (1998). Post-hypoxic frequency decline does not depend on {alpha}2-adrenergic receptors in the adult rat. Brain Res 794, 267–273.[CrossRef][Medline]

Eisenach JC (1988). Intravenous clonidine produces hypoxemia by a peripheral alpha-2 adrenergic mechanism. J Pharmacol Exp Ther 244, 247–252.[Abstract/Free Full Text]

Ellenberger HH & Feldman JL (1990). Subnuclear organization of the lateral tegmental field of the rat. I. Nucleus ambiguus and ventral respiratory group. J Comp Neurol 292, P202–P211.

Ernsberger P, Kou YR & Prabhakar NR (1998). Carotid body I1-imidazoline receptors: binding, visualization and modulatory function. Respir Physiol 112, 239–251.[CrossRef][Medline]

Errichidi S, Monteau R & Hilaire G (1991). Noradrenergic modulation of the medullary respiratory rhythm generation in the newborn rat: an in vitro study. J Physiol 443, 477–498.[Abstract/Free Full Text]

Feldman PD & Moises HC (1988). Electrophysiological evidence for {alpha}1- and {alpha}2-adrenoceptors in solitary tract nucleus. Am J Physiol 254, H756–H762.[Medline]

Fuxe K, Agnati LF, Härfstrand A, Lundberg J, Hökfelt T, Calza L, Kimmel J & Bernardi P (1982). Intracisternal administration of avian pancreatic polypeptide lowers respiration rate and enhances the clonidine induced reduction of respiration rate in {alpha}-chloralose anesthetized rats: possible interactions with an {alpha}2-adrenergic receptor. Acta Physiol Scand 15, 381–384.

Guimaraes S & Moura D (2001). Vascular adrenoceptors: an update. Pharmacol Rev 53, 319–356.[Abstract/Free Full Text]

Guyenet PG, Stornetta RL, Riley T, Norton FR, Rosin DL & Lynch KR (1994). Alpha2A-adrenergic receptors are present in lower brainstem catecholaminergic and serotonergic neurons innervating spinal cord. Brain Res 638, 285–294.[CrossRef][Medline]

Hayar A & Guyenet PG (2000). Prototypical imidazoline-1 receptor ligand moxonidine activates alpha2-adrenoceptors in bulbospinal neurons of the RVL. J Neurophysiol 83, 766–776.[Abstract/Free Full Text]

Hayward LF, Riley AP & Felder RB (2002). {alpha}2-Adrenergic receptors in NTS facilitate baroreflex function in adult spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 282, H2336–H2345.[Abstract/Free Full Text]

Hedrick MS, Ryan ML, Pizarro J & Bisgard GE (1994). Modulation of respiratory rhythm by {alpha}2-adrenoceptors in awake and anesthetized goats. J Appl Physiol 77, 742–750.[Abstract/Free Full Text]

Jarvis DA, Duncan SR, Segal IS & Maze M (1992). Ventilatory effects of clonidine alone and in the presence of alfentanil, in human volunteers. Anesthesiology 76, 899–905.[CrossRef][Medline]

Kallio A, Scheinin M, Koulu M, Ponkilainen R, Ruskoaho H, Vjinamaki O & Scheinin H (1989). Effects of dexemedetomidine, a selective alpha 2-adrenoceptor agonist, on hemodynamic control mechanisms. Clin Pharmacol Ther 46, 33–42.[Medline]

Kamisaki Y, Hamada T, Maeda K, Ishimura M & Itoh T (1993). Presynaptic {alpha}2 adrenoceptors inhibit glutamate release from rat spinal cord synaptosomes. J Neurochem 60, 522–526.[CrossRef][Medline]

Kou YR, Ernsberger P, Cragg PA, Cherniack NS & Prabhakar NR (1991). Role of {alpha}2-adrenergic receptors in the carotid body response to isocapnic hypoxia. Respir Physiol 83, 353–364.[CrossRef][Medline]

McCrimmon DR & Lalley PM (1981). Inhibition of respiratory neural discharges by clonidine and 5-hydroxytryptophan. J Pharmacol Exp Ther 222, 771–777.

Narchi P, Benhamou D, Hamza J & Bouaziz H (1992). Ventilatory effects of epidural clonidine during the first 3 hours after Caesarean section. Acta Anaesthesiol Scand 36, 791–795.[Medline]

O'Halloran KD, Herman JK & Bisgard GE (1999a). Nonvagal tachypnea following {alpha}2-adrenoceptor stimulation in awake goats. Respir Physiol 118, 15–24.[CrossRef][Medline]

O'Halloran KD, Herman JK & Bisgard GE (1999b). Differential effects of clonidine on upper airway abductor and adductor muscle activity in awake goats. J Appl Physiol 87, 590–597.[Abstract/Free Full Text]

O'Halloran KD, Herman JK & Bisgard GE (2001). Ventilatory effects of {alpha}2-adrenoceptor blockade in awake goats. Respir Physiol 126, 29–41.[CrossRef][Medline]

Ooi R, Pattison J & Feldman SA (1991). The effects of intravenous clonidine on ventilation. Anesthesia 46, 632–633.[Medline]

Panagiotidis G, Stenstrom A & Lundquist I (1993). Effects of adrenergic and cholinergic stimulation on islet monoamine oxidase activity and insulin secretion in the mouse. Eur J Pharmacol 233, 285–2980.[CrossRef][Medline]

Philipp M, Brede M & Hein L (2002). Physiological significance of {alpha}2-adrenergic receptor subtype diversity: one receptor is not enough. Am J Physiol Regul Integr Comp Physiol 283, R287–R295.[Abstract/Free Full Text]

Rives JE & Bernard DG (2001). {alpha}2-Adrenergic receptors and the central control of breathing in the cane toad, Bufo marinus. Respir Physiol 125, 213–223.[CrossRef][Medline]

Sannajust F, Cerutti C, Koening-Berard E & Sassard J (1992). Influence of anaesthesia on the cardiovascular effects of rilmenidine and clonidine in spontaneously hypertensive rats. Br J Pharmacol 105, 542–548.

Schreihofer AM & Guyenet PG (2000). Role of presympathetic C1 neurons in the sympatholytic and hypotensive effects of clonidine in rats. Am J Physiol Regul Integr Comp Physiol 279, R1753–R1762.[Abstract/Free Full Text]

Soares de Moura RS, Leao MC, Castro Resende AC, Moreira CF, Sena KM, Silveira SS, Lima AF, Nunes FR & Mesquita Ferreira AG (2000). Actions of L-NAME and methylene blue on the hypotensive effects of clonidine and rilmenidine in the anesthetized rat. J Card Pharmacol 35, 791–795.[CrossRef][Medline]

Yamazato M, Sakima A, Nakazato J, Sesoko S, Muratani H & Fukiyama K (2001). Hypotensive and sedative effects of clonidine injected into the rostral ventrolateral medulla of conscious rats. Am J Physiol Regul Integr Comp Physiol 281, R1868–R1876.[Abstract/Free Full Text]


   Acknowledgements
 
We are indebted to Dr S. J.Chrapusta, Department of Experimental Pharmacology, for his critical reading of the manuscript. Mrs Teresa Warnawin is thanked for her excellent technical assistance and SmithKline Beecham Pharmaceuticals SA for the generous gift of SKF 86466.





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
91/1/269    most recent
expphysiol.2005.031914v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kaczyñska, K.
Right arrow Articles by Szereda-Przestaszewska, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kaczyñska, K.
Right arrow Articles by Szereda-Przestaszewska, M.
Related Collections
Right arrow Respiratory

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS