Ventilatory effects of α2-adrenoceptor blockade in awake goats
Introduction
α2-Adrenoceptors (α2-ARs) are widely distributed in the CNS including brainstem sites associated with cardiorespiratory control (Guyenet et al., 1994, Rosin et al., 1996, Talley et al., 1996) where they are localized not only post-synaptically, but also pre-synaptically, as inhibitory receptors on non-adrenergic neurons (heteroreceptors) and on noradrenergic neurons themselves (autoreceptors). Several lines of evidence strongly suggest a role for α2-ARs in the regulation of respiratory rhythm. Clonidine, an α2-AR agonist, depresses the firing rate of central noradrenergic and serotonergic neurons (Svensson et al., 1975, Guyenet, 1980, Aghajanian and VanderMaelen, 1982, Andrade and Aghajanian, 1982, Feldman and Moises, 1988) and “pre-inspiratory” neurons of the rostral ventrolateral medulla (Arata et al., 1998). Furthermore, α2-AR mediated hyperpolarization has been described in neurons of the locus coeruleus (LC) (Aghajanian and VanderMaelen, 1982, Andrade and Aghajanian, 1985), dorsal motor nucleus of the vagus (Fukuda et al., 1987), hypoglossal nucleus (Parkis and Berger, 1997) and in sympathetic preganglionic neurons (Inokuchi et al., 1992). Data from neonatal rat in vitro brainstem-spinal cord preparations (Hilaire et al., 1989, Errchidi et al., 1990, Errchidi et al., 1991) have demonstrated that A5 noradrenergic modulation of the medullary respiratory rhythm generator is suppressed by α2-AR antagonists and may be mediated by α2-ARs located within the rostral ventrolateral medulla (Errchidi et al., 1991).
Clonidine and other α2-AR agonists inhibit breathing in cats (McCrimmon and Lalley, 1982, Haxhiu et al., 1995), dogs (Burton et al., 1990), rabbits (Zornow, 1991), horses (Lavoie et al., 1992), rats (Coles et al., 1998) and human subjects (Benhamou et al., 1991, Ooi et al., 1991, Penon et al., 1991, Belleville et al., 1992, Narchi et al., 1992). We have recently demonstrated that systemic administration of clonidine and other α2-AR agonists cause profound disturbances in respiratory pattern in awake goats (Hedrick et al., 1994, Hedrick et al., 1998, O'Halloran et al., 1999a, O'Halloran et al., 1999b, O'Halloran et al., 2000) that are not dependent on carotid body (Hedrick et al., 1994) or vagal afferent (O'Halloran et al., 1999b) feedback suggesting an effect on central α2-ARs. Dysrhythmic breathing induced by clonidine in the goat is reversed by systemic administration of a selective α2-AR antagonist (O'Halloran et al., 1999a, O'Halloran et al., 2000) but the ventilatory effects of α2-AR blockade have not been characterized.
The purpose of this study was to further elucidate the role of α2-ARs in the control of respiratory rhythm. We sought to determine if α2-AR pathways exert a tonic influence on respiratory rhythm under normal physiological conditions. The ventilatory effects of α2-AR blockade with SKF-86466 were studied in awake adult goats.
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Animals
Studies were conducted on adult female goats (56–80 kg body wt.) of mixed breed. The surgical and experimental protocols were approved by the Animal Care Committee of the University of Wisconsin–Madison.
Surgical preparation
Using aseptic techniques, under general anesthesia (induction with 15–20 mg/kg intravenous (IV) sodium thiopental for intubation, and maintenance with 1–5% halothane, 40% nitrous oxide, balance oxygen) each goat was prepared with a unilateral common carotid artery translocation to a subcutaneous
Antagonist effects of SKF-86466
Under control conditions (no drug treatment) systemic administration of clonidine (5 μg/kg) induced a highly dysrhythmic breathing pattern that was characterized by alternating episodes of tachypnea and slow irregular breathing patterns (prolonged and variable TE intervals) including periods of central apnea. The mean peak inhibitory ventilatory effect of clonidine is shown in Fig. 1A. Pretreatment with SKF-86466 (1000 μg/kg total cumulative dose) significantly attenuated the inhibitory (and
Discussion
The present study demonstrates that α2-AR blockade with SKF-86466 modulates respiratory rhythm and potentiates ventilatory responses to isocapnic hypoxia in awake adult goats. The antagonist effect of SKF-86466 at α2-ARs was demonstrated both as a reversal of the ventilatory disturbances induced by prior systemic administration of clonidine and as a rightward shift in the magnitude of the agonist-evoked response in animals pretreated with SKF-86466. However, it is now clear that imidazolines
Acknowledgements
We thank Gordon Johnson for excellent technical assistance. This work was supported by National Heart, Lung, and Blood Institute Grants HL-53969 and HL-10069.
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