We propose to take advantage of the fibrillation which spontaneously occurs in denervated skeletal muscle in order to study homeostatic and hormonal controls of electrical excitability. Intracellular recordings from fibrillating muscle fibers have revealed spontaneous fluctuations of membrane potential, called fibrillatory initiating events, which arise at a spatially restricted locus termed a "site of origin". Catecholamines have been found to greatly increase initiating event frequency. In order to define the altered electrical properties responsible for fibrillation, we will examine the effects of ionic and pharmacological manipulations on fibrillatory initiating events, which will be monitored both with a single microelectrode, inserted at a site of origin, and with a two microelectrode voltage clamp. These studies will define the role of the Na-K pump and time-varying conductance changes in the fibrillatory electrical activity of denervated muscle, and will also provide the framework for determining the mechanism by which catecholamines regulate initiating events. These studies promise to increase our understanding of the physiological control of electrical excitability not only in muscle but also in nerve and heart.
NIH ExPorter
NIH ExPorter