Over the past several years, we have been interested and have focussed on the study of respiratory muscle function, especially as it relates to the young. From our recent work, it has become evident that neuromuscular (NM) transmission failure may be one important site of diaphragmatic fatigue. This is particularly true in the immature who may be predisposed for developing respiratory failure due to transmission impairment. This has been recently demonstrated by our preliminary observations in an isolated diaphragm preparation in our laboratory. On the basis of these data and those of other investigators, we have formulated several hypotheses in this proposal: A) Neuromuscular transmission failure can play a significant role in the development of diaphragmatic fatigue in the newborn. This will be tested in the rat phrenic nerve-hemidiaphragm preparation in-vitro at several ages and examined by comparing the force generated by the muscle in response to direct and indirect (phrenic) stimulation and correlating the force level to the size, number and shape of action potentials. B) The mechanisms responsible for NM transmission failure in the newborn diaphragm are related to an imbalance between Acetylcholine (ACH) release and breakdown in the synaptic cleft. This will be tested by measuring the size of ACH quanta, the activity of specific and nonspecific esterases and by the use of blockade experiments. C) NM transmission failure in the immature is secondary to presynaptic rather than postsynaptic mechanisms and these are specific to the neuromuscular junction of specific muscle fiber types. This will be examined by analyzing the amplitude and number of end plate potentials and the safety factor of NM transmission at various frequency of stimulation and correlating these with muscle fiber type. D) NM transmission in the young is more resistant to the effects of acute stresses such as hypoxia or acidosis. In this proposal, we utilize state-of-the-art techniques and methodologies and these are either operative or currently being developed. Since proper functioning of the respiratory system is vitally dependent on the integrity of the respiratory muscles, we believe that understanding the mechanisms which lead to muscle failure will be crucial for the treatment and prevention of respiratory muscle fatigue and subsequent respiratory failure in the newly born.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050401-03
Application #
2226577
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1993-07-01
Project End
1997-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Yale University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kass, L J; Bazzy, A R (2001) Chronic hypoxia modulates diaphragm function in the developing rat. J Appl Physiol 90:2325-9
Breugelmans, J G; Bazzy, A R (1997) Developmental differences in endplate response to P-type calcium channel blockade in the rat diaphragm. Brain Res Dev Brain Res 101:277-81
Akiyama, Y; Garcia, R E; Bazzy, A R (1996) Effect of inspiratory training on mitochondrial DNA and cytochrome-c oxidase expression in the diaphragm. Am J Physiol 271:L320-5
Akiyama, Y; Garcia, R E; Prochaska, L J et al. (1994) Effect of chronic respiratory loading on the subunit composition of cytochrome c oxidase in the diaphragm. Am J Physiol 267:L350-5
Bazzy, A R (1994) Developmental changes in rat diaphragm endplate response to repetitive stimulation. Brain Res Dev Brain Res 81:314-7