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Postnatal development of central rhythm generation of breathing in mammals Marshall, Lieneke H.

Abstract

The objective of this thesis was to investigate some of the developmental changes that occur in central rhythm generation of breathing in mammals. Specifically, progressive hypothermia was used as a tool to investigate the mechanism of respiratory arrest at very low body temperatures and autoresuscitation upon re-warming. Both in vivo and in vitro techniques were used; the first to identify the point in development when the ability to autoresuscitate from hypothermia-induced respiratory arrest was lost in mammals and the second to determine if the ability of neonatal mammals to autoresuscitate was dependent upon the persistent sodium current (lNap). Experiments were conducted upon neonates and juveniles of a cold-intolerant species, the rat, and a cold-tolerant species, the hamster. In vivo experiments revealed that the ability to autoresuscitate was lost in rats between 14 and 20 days after birth and in hamsters between 28 days after birth and adulthood. The time scale over which the ability to autoresuscitate was lost was similar to the time scale over which these animals developed adult-type endothermy and homeothermy. It was hypothesised that the loss of the ability to autoresuscitate over development corresponded to changes in the mechanism of rhythm generation of breathing. Pacemaker properties, primarily dependent upon lNap , were hypothesised to be the mechanism by which autoresuscitation from hypothermia-induced respiratory arrest occurred. A shift in the relative important of pacemaker properties and network properties of rhythm generation of breathing during the postnatal development of mammals could explain the loss of the ability to autoresuscitate. In order to examine the role of lNap-dependent pacemaker properties in respiratory rhythm generation and the phenomenon of autoresuscitation from hypothermia-induced respiratory arrest, riluzole was used to block lNap in en bloc preparations from neonatal rats and hamsters. Riluzole of two concentrations was bath applied, both at constant temperature and after fictive respiratory arrest at very low temperatures. In neonatal rats, riluzole failed to inhibit rhythm generation and autoresuscitation and instead appeared to block network bursting properties, important for pattern generation. These results are consistent with the hypothesis that lNap-dependent pacemaker properties are not essential for rhythm generation in neonatal rats and that respiratory rhythm in this species is instead produced by a heterogenous population of pacemakers including both lNap-dependent and lNap-independent cells. In contrast, blockade of lNap with riluzole produced fictive respiratory failure in preparations from hamsters via a decline in the frequency of bursting indicating that lNap was essential for the generation of respiratory rhythm in this species. Blockade of lNap also blocked autoresuscitation entirely in 67% of hamster preparations. These findings are consistent with the hypothesis that lNap-dependent pacemaker properties are essential for the generation of respiratory rhythm in neonatal hamsters and that these properties are important in the process of autoresuscitation from hypothermia-induced respiratory arrest.

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