Respiratory failure is a major cause of morbidity in the newborn period. Evidence from our work and that of others suggests that in this age group diaphragmatic fatigue contributes to this failure, and that neuromuscular transmission (NMT) is an important site of failure. Based on recent data from our laboratory the probable mechanism underlying NMT failure is inadequate neurotransmitter. Although calcium is known to play a pivotal in transmitter release, little is known regarding the maturation of this process with development. Also, little is known regarding how the hypoxia that is associated with respiratory failure modulates NMT in this age group. Hence we hypothesize that: 1) NMT failure is secondary to presynaptic mechanisms at the motor nerve terminal. Ca2+ plays an important role in the development of NMT failure because of structural and/or functional immaturity of specific subtypes of Ca2+ channels in the presynaptic nerve terminal. This will be tested in the isolated rat diaphragm a) using electrophysiological techniques to assess transmitter release in the presence of blockers of Ca2+ channel subtypes; and b) morphologically assessing Ca2+ channel subtypes using immunocytochemistry and molecular techniques. 2) Chronic hypoxia delays the maturation of the NM junction. This is associated with delayed functional maturity of the synapse and decreased synaptic efficacy. This will be tested by comparing the: a) morphology; b) force response; c) action potentials failures; d) quantal content and safety factor; and e) Ca2+ channels of diaphragms of rats raised in chronic hypoxia to control littermates at several time points during the first postnatal month. We believe that these studies will provide a better understanding of the mechanisms underlying diaphragmatic fatigue and respiratory failure in the newborn.
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