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The purpose of these investigations is to determine the modulating influences of mediators of anaphylaxis on parasympathetic activation in tracheal smooth muscle. Previous investigations have shown that atropine reduced the in vitro sensitivity of ragweed-sensitized tracheal smooth muscle to histamine and high-potassium induced tone. Spontaneous contractions, seen only in sensitized tracheal muscles strips, also were atropine-sensitive and spontaneous phasic contractile activity could be mimicked in muscle strips by addition of small concentrations of acetylcholine or by inhibiting acetylcholinesterase. These studies indicated possible presynaptic augmentation of acetylcholine release and/or reduced cholinesterase activity. We propose to study the parasympathetic innervation of airways with the specific aim of determining the role of histamine, serotonin, and products of arachidonic acid metabolism (prostanoids and leukotrienes) in the release of the neurotransmitter, acetylcholine. It is hypothesized that antigenic sensitization augments tracheal smooth muscle response to acetylcholine. Two mechanism for this effect are hypothesized: 1) increased basal/stimulated release of neurotransmitter and 2) decreased cholinesterase activity resulting from immune-sensitization. All studies will be conducted using tracheal smooth muscle from which the epithelium has been removed to eliminate confounding effects of epithelium-derived relaxing factors. We will 1) determine the normal release characteristics of neurotransmitter (both basal and neurally-activated release of acetylcholine 2) determine whether agents such as histamine, serotonin, prostaglandin F2a and leukotriene D4 augment basal and neurally activated release of acetylcholine 3) compare these date with neurotransmitter release from a sensitized population 4) determine basal acetylcholinesterase activities in homogenates of normal and sensitized tracheal smooth muscle, and 5) determine if agents of anaphylaxis have a modifying effect on cholinesterase activity. We will employ 14C-labeled choline as a precursor of acetylcholine and promote its uptake and turnover by electrical field stimulation in the presence of an incubating concentration of 14C-choline. The Basal efflux of 14C will be measured by liquid scintillation. Augmentation of acetylcholine release will be assessed after incubation with mediators (above) and comparisons will be made between control and sensitized populations. Cholinesterase activities will be measured using spectrophotometric techniques. In addition, total protein and non-collagen protein assays will be performed to enable comparisons to be made between different populations and among different ages. Protein estimations may in themselves reveal differences between normal and sensitized populations. Data derived from these studies will suggest factors influencing modulation of airway smooth muscle tone in vitro and have a direct application to therapeutic interventions in obstructive airways disease and asthma.
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