The relationship between in situ changes in airway caliber and in vitro measurements of force of airway smooth muscle contracted remains unknown. The objective of these investigations is to determine the interrelationships between in situ changes in airway caliber induced by physiological and pharmacological stimuli and in vitro physiological, biochemical and morphological measurements of a) isometric smooth muscle contraction, b) receptor density, c) smooth muscle mass, and d) intrapulmonary forces. Three sets of experiments will be performed. 1) Graded response curves to pharmacological and physiological stimuli will generated in anesthetized dogs and assessed by tanatalum bronchography as change in airway caliber (Daw) simultaneously for generations 0 through 5 at each level of stimulation. The same airways will be excised for isometric fixation at the exact site measured during tantalum bronchography. Concentration-response curves will be generated in vitro and correlated to changes in Daw derived from the same dogs. 2) In separate experiments, sections of airway from generations 0 through 5 will be excised initially, and isometric measurements of airway response to methacholine, histamine, serotonin, epinephrine and potassium chloride will be generated in vitro. Contiguous tissue from each airway will be fixed in formalin for compuuterized morphometric determination of bronchial smooth muscle mass. Force of contraction for each airway will be assessed as a function of muscle mass: contractile force. Additionally, regional differences in receptor density, the role of lung interdependence and airway elastance on net changes in airway caliber will be determined and correlated with in situ data derived in Section 1. The geometric orientation of muscle for each generation of airway will be assessed and related to force and efficiency of smooth muscle contraction. 3) In a final set of experiments, contiguous strips of bronchus will be obtained as in section 2 for analysis of receptor density by ligand binding and autoradiographic techniques. Correlation of receptor density to physiological response in situ will be determined as a function of smooth muscle mass. Data derived from these studies will define the physiological and pharmacological significance of these correlates for the major resistance bronchi of the lung. Morphometric and biochemical data will define further the efficiency of bronchial contraction in terms of airway smooth muscle mass and geometric orientation of airway smooth muscle. These data will elucidate mechanisms that determine bronchomotor tone in normal and asthmatic humans.
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