The overall objectives of the proposed research for this competitive renewal are to determine the central and peripheral autonomic and somatic neural mechanisms which regulate smooth muscle of the colon and internal anal sphincter and the striated muscle of the external anal sphincter during defecation and during continence. New experiments are proposed to study three neural control systems: 1) sacral parasympathetic pathway, 2) sacral somatic pathway, and 3) lumbar sympathetic pathways. The action of neuro-transmitters and peptides on smooth muscle will also be studied. The integrity of the sacral parasympathetic and sacral somatic pathways to the colon and external anal sphincter is essential for the normal performance of defecation and to maintain continence. 1) Sacral parasympathetic pathway. In vitro electrophysiological techniques applied to multicellular preparations and dispersed autonomic neurons located in parasympathetic colonic ganglia will be used. Studies with these techniques will be directed at central questions of a) to determine the action of potassium blocking agents on the active and passive properties and repetitive firing characteristics of neurons in parasympathetic colonic ganglia and b) the types of potassium channels of neurons in parasympathetic colonic ganglia and 2) Sacral somatic pathway to the external anal sphincter. In situ and in vitro isometric force measurements, histochemistry, histology and biochemical techniques will be used to determine contractile properties of single motor units, number of striated muscles per motor unit, and myosin isozyme patterns during normal muscle activity and after prolonged muscle inactivity. 3) Lumbar sympathetic pathways. An in vitro nerve-muscle preparation of distal colon and isolated muscle strips of internal anal sphincter will be used to determine actions of the lumbar sympathetic nerves on distal colon muscle and adrenergic opioid receptor types on internal anal sphincter. Action of neuro-transmitters and neuropeptides. In vitro current and voltage clamp techniques of acutely dispersed smooth muscle cells of distal colon, rectum and internal anal sphincter will be used to determine passive and active electrophysiological properties, characterize whole-cell voltage-dependent calcium and potassium ionic currents and determine the action of neurotransmitters and peptides on passive and active electrophysiological properties and who-cell ionic currents.
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