Excitation-Contraction Coupling: The Effect of Calcium Channel Antagonistic Drugs on Reprimed and Inactivated Skinned Skeletal Muscle Fibers
Fill, Michael David
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https://hdl.handle.net/2142/71453
Description
Title
Excitation-Contraction Coupling: The Effect of Calcium Channel Antagonistic Drugs on Reprimed and Inactivated Skinned Skeletal Muscle Fibers
Author(s)
Fill, Michael David
Issue Date
1987
Department of Study
Physiology and Biophysics
Discipline
Physiology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Animal Physiology
Abstract
Contracture of skinned (sarcolemma removed), skeletal muscle fibers can be elicited by sudden changes in the ionic composition of the myoplasm. The bulk of evidence in the literature suggests that such contracture of skinned fibers is triggered by depolarization of resealed transverse tubules. If this hypothesis is true, then such contractures of skinned fibers are analogous to K contractures on intact cells.
This study confirms that a phenomenon similar to contractile activation in intact cells stimulated by elevated potassium, occurs in ionically stimulated skinned fibers. Further, phenomena similar to contractile inactivation and repriming seen in intact cells occurs in these skinned fibers. The rate of repriming as well as the estimated potential range over which contractile activation and repriming occur are comparable to the same parameters measured in intact cells. Thus, it was concluded that contractures of ionically stimulated skinned fibers are analogous to K contractures of intact cells.
The effects of several calcium channel antagonists were explored. Both the dihydropyridines (DHPs) and D600 block ionically induced contracture of skinned fibers. The characteristics of D600 paralysis were identical to those described elsewhere in intact cells and skinned mammalian fibers. In addition, I report that D600 interacts preferentially with inactivated fibers. The characteristics of DHP paralysis were temperature dependent. At low temperature, DHP paralysis resembles that of D600 in that inactivated fibers are more susceptible to drug paralysis. In contrast, at room temperature DHP paralyzed reprimed and inactivated fibers indentically. Application of the D600 derivative D890 revealed that the D600/D890 binding site in reprimed fibers is accessible from the myoplasm. In inactivated fibers, however, the D600/D890 binding site is more accessible to lipid soluble drugs.
The dose-response relationships were determined for DHP and D600. A simple 1:1 binding scheme fits the DHP data collected at room temperature. All other data were fit by a two state (inactivated and reprimed) concerted (involving a dimer) scheme. A diagrammatical model, incorporating the information reported here, is presented.
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