Chemical respiratory control and excitatory neural drive to the respiratoryrhythm generator by central chemoreceptors: Role of cholinergic neuronalmechanism

To clarify the role and identify the substrate of central chemoreceptors, we conducted in vivo and in vitro experiments using rodents. Central chemoreceptors are mainly located in the superficial rostral ventral medulla overlapping with the para-facial respiratory group (pFRG) region. Two types of cells are supposed to be important on the basis of c-fos immunohistochemistry; surface small (type I) cells are primary receptor cells, and sensed information is transmitted to the deep respiratory rhythm generator via subsurface relay (type II) neurons. Because type I cells are cholineacetyltransferase-positive, acetylcholine (ACh) is likely a neurotransmitter at the synapse from type I to II cells. To investigate the role of nicotinic ACh receptors (nAChRs) in chemoreception, we applied nicotine to the medulla and observed increases of respiratory output, similarly to the responses to CO₂. Application of nAChRs-antagonists then indicated that the nAChRs-subtype α₄β₂ is important. Analyses of ventilation in each subtype of muscarinic ACh receptors (mAChRs) gene knockout mice showed that M1/M3-compound subtypes were also important. We succeeded to augment chemoresponsiveness by increasing endogenous ACh action with a cholinesterase inhibitor donepezil, which is promising as a therapeutic medicine for blunted chemoresponsiveness. We conclude that both nAChRs and mAChRs are importantly involved in the chemical regulation and maintenance of respiratory rhythm as sources of excitatory neural drive. [Jpn J Physiol 55 Suppl:S63 (2005)]