The overall goals are to describe where and how chemoreceptors within the medulla sense PH and/or PC02 and alter breathing, how PH in the extracellular fluid of the brain is regulated, and the relationship of PH regulation to central chemoreception (CCR). Recent studies with the excitatory neurotoxin kainic acid suggest that neurons accessible via the rostral ventral lateral medullary surface are involved in the chemoreception process and also may provide tonic excitatory input to other respiratory neurons. This project will localise these cells more precisely, evaluate possible neurotransmitters and receptors involved in their function, ask whether they are chemosensitive, and whether this chemosensitivity is a function of imidazole-histidine. The strategy is to microinject (10-100 nl) neuroactive agents and correlate physiological responses with the precise anatomical injection site marked by fluorescent microbeads. Excitatory neurotoxins (kainate, ibotenate), excitatory and inhibitory amino acids, muscarinic agonists and antagonists (here emphasizing receptor subtypes), low pH fluids, and the imidazole-histidine blocking agent, diethyl pyrocarbonate will be used. Autoradiography with muscarinic antagonists will identify the receptor subtype distribution in the medulla to correlate with the physiologically responsive microinjection sites. Evaluation of pH regulation will utilize surface electrode measurements of pH, PC02, and chloride and local application of agents that inhibit known ionic mechanisms involved in large cavity cerebrospinal fluid pH regulation i.e., amiloride, DlDS, and DEPC. Most experiments are in anesthetized, paralyzed, vagotomized, and servo-ventilated cats with exposed ventral medullary surface using phrenic nerve output to evaluate breathing. Some experiments with lesions made in key region(s) will be carried out in conscious animals to evaluate the importance of the region under more physiological conditions. Abnormalities in CCR function may be a cause of the Sudden Infant Death Syndrome and variations in CCR function have been related to the degree of C02 retention in chronic lung disease. This same region of the ventro-lateral medulla is also of crucial importance in the regulation of blood pressure. lt is important to gain a better understanding of the role of this region in the control of breathing.
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