Use of ion channel blockers in the exploration of possible mechanisms involved in the myopathy of diabetic mice.

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 Ca(2+)-mobilizing agent, selenite. The K(+)-channel blockers (UO2(2+) 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/l 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 UO2(2+) 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.(ABSTRACT TRUNCATED AT 250 WORDS)