and Specific Aims.) Although human airways are known to dilate during exercise, the neural mechanisms causing this increase in airway caliber have not yet been defined.
The first aim of this application is to determine the sources from which these bronchodilating mechanisms arise. The three candidates to be investigated are a reflex arising from contracting hindlimb muscle, central command whose locus is believed to be the subthalamic locomotor region, and the Hering-Breuer reflex, which arises from the stimulation of slowly adapting receptors in the lungs.
The second aim i s to develop an understanding about the central site of integration and the final common pathway causing the exercise-induced increases in airway caliber. An important candidate for the site of integration is the caudal ventrolateral medulla, an area which is just dorsal to the lateral reticular nucleus. Likewise, an important candidate for the site of the final common pathway is the vagal motor nucleus, the nucleus ambiguous. A dog model will be used to test the following hypotheses: 1) that activation of cells within the subthalamic locomotor region decreases both total lung resistance and transverse tension from the trachealis muscle by withdrawing cholinergic input to airway smooth muscle; 2) that activation of cells within the ventral tegmental field of the pons, which evokes extensor muscle tone, increase the magnitude of the bronchodilation evoked by activation of the subthalamic locomotor region; 3) that blockade of excitatory amino acid receptors in the caudal ventrolateral medulla prevents the decreases in total lung resistance and tracheal smooth muscle tension arising from the hindlimb muscle reflex, from the Hering-Breuer reflex and from the subthalamic locomotor region (i.e., central command); 4) that the cells of origin for the vagal preganglionic fibers, whose inhibition causes bronchodilation, can be located electrophysiologically in the external portion of the nucleus ambiguus; 5) that the impulse activity of these vagal preganglionic cells is inhibited by contraction of hindlimb muscle, by inflation of the lungs and by activation of cells in the subthalamic locomotor region; and 6) that blockade of excitatory amino acid receptors in the caudal ventrolateral medulla prevents the inhibition of vagal preganglionic bronchomotor cells by hindlimb muscle contraction, by lung inflation and by activation of cells in the subthalamic locomotor region.
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