Published ahead of print on December 1, 2005, doi:10.1164/rccm.200509-1469OC Am. J. Respir. Crit. Care Med., Volume 173, Number 5, March 2006, 555-565 A more recent version of this article appeared on March 1, 2006
Submitted on September 20, 2005 Cyclic Nucleotides Modulate Genioglossus and Hypoglossal Responses to Excitatory Inputs in RatsCynthia R.A Aoki1,1 Department of Medicine, University of Toronto, Toronto, ON, Canada, 2 Department of Medicine, University of Toronto, Toronto, ON, Canada; Division of Respirology, Toronto General Hospital Research Institute of the University Health Network, Toronto, ON, Canada, 3 Department of Pharmacology, University of Toronto, Toronto, ON, Canada, 4 Department of Medicine, University of Toronto, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada * To whom correspondence should be addressed. E-mail: richard.horner{at}utoronto.ca.
Rationale: Previous studies modulating pharyngeal muscle activity with pharmacological approaches have targeted membrane receptors on pharyngeal motoneurons. Whether modulation of intracellular pathways can increase pharyngeal muscle activity, however, has not been investigated but is relevant to pharmacological treatments of obstructive sleep apnea. Objectives: To determine if modulating the second messenger cyclic adenosine-3'-5'-monophosphate (cAMP) at the hypoglossal motor nucleus (HMN) will increase genioglossus activity across sleep-wake states. Methods: Forty-eight rats were implanted with electroencephalogram and neck electrodes to record sleep-wake states, and genioglossus and diaphragm electrodes for respiratory muscle recordings. Microdialysis probes were inserted into the HMN to perfuse artificial-cerebrospinal-fluid and (a) forskolin (500µM, adenylyl cyclase activator to increase cAMP), (b) a cAMP analogue (500µM), (c) iso-butyl-methylxanthine (IBMX, 300µM, phosphodiesterase inhibitor) or (d) a cyclic guanosine-3'-5'-monophosphate (cGMP) analogue (500µM, 8-Br-cGMP). Measurements and Main Results: Forskolin and the cAMP analogue at the HMN increased respiratory-related and tonic genioglossus activities in wakefulness and non-REM sleep but not REM sleep. IBMX did not affect genioglossus activity awake or asleep. However, IBMX abolished the robust excitatory responses to serotonin and phenylephrine at the HMN but responses to non-N-methyl-D-aspartate receptor activation remained. These effects of IBMX were mimicked by 8-Br-cGMP. Conclusions: Genioglossus responses to manipulation of cAMP at the HMN are differentially modulated by sleep-wake state. Selective abolition of serotonin and phenylephrine responses after IBMX suggests that under conditions of non-specific phosphodiesterase inhibition the HMN is unresponsive to certain, otherwise potent, excitatory inputs. Similar responses with 8-Br-cGMP suggest this effect is likely mediated by cGMP pathways. Key words: Sleep, Hypoglossal Motor Nucleus, cAMP, Obstructive Sleep Apnea
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