Use of ion channel blockers in the exploration of possible mechanisms involved in the myopathy of diabetic mice
Journal
Naunyn-Schmiedeberg's Archives of Pharmacology
Journal Volume
348
Journal Issue
3
Pages
311-318
Date Issued
1993
Author(s)
Abstract
Changes in the muscle contractions of the phrenic nerve-diaphragm preparation from the diabetic mouse were investigated by means of K+- and Cl--channel blockers and the Ca2+-mobilizing agent, selenite. The K+-channel blockers (UO22+ and 4-aminopyridine) cooperated synergistically with the Cl--channel blockers (Cd2+ and 9-anthracenecarboxylic acid) in increasing normal muscle contraction as described previously, but failed to induce this effect in the diaphragm of the diabetic mouse. Treatment with a Cl--channel blocker alone in 0.25 mmol/1 Ca2+ Krebs solution induced a myotonic activity accompanied by stimulus-bound repetitive action potential firings. This effect was also diminished in the diaphragm from diabetic mice. The membrane potential of the muscle cells in the diaphragm of the diabetic mouse was slightly but significantly decreased. The membrane input resistance was also increased and was refractory to being further increased by either a Cl--channel blocker or a low Cl--medium. Furthermore, the membrane chloride conductance was found to be decreased, but the membrane K+ conductance remained unchanged in the muscle from diabetic mice. These changes of membrane properties in the muscles from diabetic mice were shown to be similar to those induced by either Cl--channel blockers or a low Cl--medium. In addition, the combined treatment of the diaphragm from diabetic mice with Cd2+ Plus UO22+ in 0.25 mmol/l Ca2+ Krebs solution and then stepwise replenishment of Ca2+ led to a greater restoration of muscle contractions at a lower cumulative Ca2+ concentration than that was found with the normal diaphragm. The sustained muscle contracture of the mouse diaphragm induced by U022+ plus selenite was partially inhibited in the diaphragm from diabetic mice, indicating that the Ca2+ mobilizing mechanism of the diaphragm of the diabetic mouse was also altered. All of these observations obtained with the diaphragm of the diabetic mouse can be attributed to the diabetic state, because most of them could be normalized by insulin administration in vivo. Therefore, it is concluded that diabetes-induced changes of sarcolemmal ion channels and ion transporters may cause inhibition of muscle contraction and eventually lead to diabetic myopathy. ? 1993 Springer-Verlag.
Subjects
Alloxan diabetes; Ca2+ mobilization; Cl- conductance; Myopathy
SDGs
Other Subjects
4 aminopyridine; 9 anthroic acid; alloxan; cadmium; chloride channel blocking agent; glucose; insulin; ion transport affecting agent; potassium channel blocking agent; sodium selenite; uranyl nitrate; alloxan diabetes mellitus; animal experiment; animal model; animal tissue; article; calcium mobilization; chloride conductance; controlled study; diaphragm; intracellular recording; ion transport; male; mouse; myopathy; nonhuman; phrenic nerve; priority journal; subcutaneous drug administration; Action Potentials; Animal; Blood Glucose; Body Weight; Cadmium; Chloride Channels; Diabetes Mellitus, Experimental; Insulin; Ion Channels; Male; Mice; Mice, Inbred ICR; Muscle Contraction; Muscular Diseases; Phrenic Nerve; Potassium Channels; Respiratory Muscles; Sodium Selenite; Support, Non-U.S. Gov't
Type
journal article