Ventilatory effects of α2-adrenoceptor blockade in awake goats

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Abstract

We sought to determine the extent to which α2-adrenoceptor (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 examined in awake adult goats. The antagonist effect of SKF-86466 at α2-ARs was evident both as a reversal of the ventilatory disturbances produced by the α2-AR agonist clonidine (5 μg/kg IV) and as a rightward shift in the potency of the agonist-evoked response after SKF-86466 pretreatment. Systemic administration of SKF-86466 in cumulative doses (25–250 μg/kg) or as a single bolus injection (500 μg/kg) produced dose-dependent increases in breathing in all animals. The excitatory effect was primarily mediated by increases in respiratory frequency that persisted for at least 120 min after injection (500 μg/kg). The time course and magnitude of the ventilatory response to SKF-86466 was similar in carotid body denervated animals. The ventilatory response to isocapnic hypoxia but not normoxic hypercapnia was significantly elevated after SKF-86466 administration (500 μg/kg). SKF-86466 (25–1000 μg/kg) produced dose-dependent increases in heart rate in all animals but did not significantly change mean arterial blood pressure at any dose. The results demonstrate that α2-AR pathways exert a tonic inhibitory influence on respiratory rhythm in the awake goat.

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.

Section snippets

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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