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October 17, 2009
2:00 PM - 4:00 PM
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Carbachol Increases Respiration by Decreasing Expiration in the Working Heart Brainstem Preparation
  **   Ivo F. Brandes, M.D., Georg Stettner, M.D., Leszek Kubin, Ph.D., Dutschmann Mathias, Ph.D.
Zentrum fuer Anaesthesiologie, Rettungs- u. Intensivmedizin, UMG, Goettingen, Germany
Introduction: Maintenance of upper airway patency depends on hypoglossal motoneuron output and is compromised during sleep [1], anesthesia [2], and by analgesics and sedatives. Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder, characterized by nocturnal episodes of disturbance of the respiratory rhythm, upper airway collapse and hypoxia. Obstructive episodes are most severe during rapid eye movement sleep (REMS). During REMS, upper airway muscle tone is reduced parallel to the atonia of postural muscles, the respiratory rate is often increased. To assess the central neural mechanisms, pharmacological models have been used, including those in which a REMS-like state is elicited by microinjections of a cholinergic agonist, carbachol, into the pons [3]. Here we show that pontine carbachol injections elicit episodes of upper airway hypotonia associated with respiratory rate increases in the working heart-brainstem preparation (WHBP) of the rat.

Methods: The study was approved by the local Animal Care Committee and was in accordance with the German law on animal experimentation. In the rat WHBP [4] (P15-25, n=33), phrenic and hypoglossal nerve activities were obtained (PNA, HNA). Changes in the respiratory rhythm and pattern were analyzed before and after pontine carbachol microinjections (25-50 nl, 10 mM). Student's t-test was used to assess significance of carbachol effects (p<0.05). Pontamine sky blue was used to mark the injection sites for histological analysis.

Results: PNA and HNA exhibited phasic respiratory activity during control conditions. In 23/33 preparations, pontine injection of carbachol caused an almost complete depression of HNA within 142±26 s that lasted 16-24 min. During these episodes, the duration of the respiratory cycle (Ttot) decreased from 7.7±4.6 s to 4.9±2.5 s (p<0.05, n=13). The expiratory time (TE) was profoundly reduced from 6.5±4.1 s to 3.6±2.2 s (p<0.05), whereas the inspiratory time (TI) was only minimally decreased (from 1.2±0.5 s to 1.1±0.3 s; p = 0.4). Injections into the dorsomedial part of the nucleus pontis oralis corresponding to antero-posterior levels -8.16 to -8.76 from bregma [5] were most effective, whereas the ineffective sites were located ventral or lateral to the dorsomedial pontine tegmentum or in the nucleus pontis caudalis.

Conclusion: In the WHBP, carbachol microinjections into the nucleus pontis oralis elicit episodes of upper airway hypotonia associated with changes in the breathing pattern similar to those during REMS in OSA patients. Thus, the WHBP offers a novel model with which to pharmacologically manipulate cellular environment and study the cellular and neurochemical mechanisms of REMS-related respiratory disorders under stable experimental conditions not confounded by anesthesia.

Support: BCCN Goettingen and HL-047600.

1. Remmers JE et al, Pathogenesis of upper airway occlusion during sleep. J Appl Physiol, 1978. 44: 931-8.

2. Eastwood PR et al, Collapsibility of the upper airway during anesthesia with isoflurane. Anesthesiology, 2002. 97: 786-93.

3. Kubin L, Carbachol models of REM sleep: recent developments and new directions. Arch Ital Biol. 2001. 139:147-68

4. Paton JF, A working heart-brainstem preparation of the mouse. J Neurosci Meth, 65:63-8.

5 Paxinos G & Watson C, The Rat Brain in Stereotaxic Coordinates, 5th Ed, New York, Academic Press, 2005.

From Proceedings of the 2009 Annual Meeting of the American Society Anesthesiologists.