The diaphragm, like limb muscles, fatigues when its workload is excessive and that diaphragm fatigue, in turn, may produce hypercapneic respiratory failure in patients with lung disease. The mechanisms responsible for the development of diaphragm fatigue remain, however, unclear. While a reduction in the contractility of the diaphragm per se has been shown to contribute to this process, recent studies have suggested that some conditions that result in diaphragm fatigue may reflexly elicit alterations in efferent respiratory motor outflow. Under conditions in which this reflex acts to increase the rate or depth of ventilation, hypercapneic failure may be forestalled; if, however, a reflex inhibition of motor outflow is elicited, the development of respiratory failure may be accelerated. Although electrophysiological studies have documented the existence of afferent phrenic reflex pathways capable of producing complex alterations in the level and timing of respiratory motor outflow, the role of phrenic afferent pathways in altering drive under physiological conditions remains unclear. The purpose of the experiments outlined in the present proposal is to examine the role played by phrenic afferent reflexes in influencing the development of respiratory muscle fatigue. We hypothesize that (a) strenuous diaphragmatic contractions induce metabolically mediated alterations in the character of afferent phrenic nerve activity and this altered afferent input reflexly changes efferent respiratory motor outflow, (b) these reflex alterations in drive may modulate the rate of development of diaphragm fatigue, (c) the power spectral shifts seen during the development of diaphragmatic fatigue are largely a result of reflex alterations in motor outflow, (d) the magnitude of the reflex response to a given phrenic afferent stimulus is modulated by the prevailing level of other sensory respiratory inputs, (e) activation of phrenic afferents reflexly alters cardiac output and regional vascular resistance, and (f) there are adaptive alterations in the """"""""gains"""""""" of the reflex responses to phrenic afferent stimulation following sustained, chronic increases in the respiratory workload. Four groups of studies are planned. In Objective I we will use a canine in situ diaphragm strip model to examine the character of the alterations in phrenic afferent activity and the reflex alterations in diaphragm motor outflow that occur during the development of diaphragm fatigue. In Objective II we plan to activate phrenic afferents with chemical stimuli to identify the effects of metabolic substances known to be released during strenuous muscle contractions; in this series of canine studies we will also examine the effect of afferent activation on the distribution of cardiac output and on the distribution of motor outflow to the various respiratory muscles. In Objective III we will determine if and how the response to activation of phrenic afferent pathways is altered in an animal model of elastase induced emphysema. In Objective IV we will look for evidence of fatigue- induced alterations in motor outflow in patients with lung disease. We believe these studies will provide useful information concerning the mechanisms of development of diaphragm fatigue and may identify new therapeutic approaches for the management of respiratory failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL025830-11A1
Application #
3858893
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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