Differential effects of diazepam on rat hindlimb muscles

Abstract

The effects of diazepam on internal membrane potential and action potentials and the isometric twitch and tetanus have been examined in rat fast-twitch (extensor digitorum longus) and slow-twitch (soleus) fibres. Low concentrations of the drug encountered during clinical usage (about 10 μM) had no effect on the membrane electrical properties or contractile properties of the fibres. Higher concentrations of diazepam (100–800 μM) induced changes in action potentials and excitation–contraction coupling but not in the resting membrane potential. After exposure to diazepam there was a rapid, concentration-dependent increase in twitch tension, which was attributed to an effect on excitation–contraction coupling, since the action potential and membrane potential were not altered. Soleus fibres were most sensitive to the potentiating action of diazepam. The decay of the tetanus was prolonged in both types of fibre, which indicated that diazepam blocked calcium uptake by the sarcoplasmic reticulum. Unexpectedly, the decay of isometric twitches was sensitive to diazepam only in soleus fibres, suggesting that calcium uptake was rate-limiting for tension relaxation in slow- but not fast-twitch fibres. The amplitude of the twitch and tetanus fell below control levels after prolonged exposure to diazepam, and there was a parallel reduction in action potential overshoot, especially during tetanic stimulation. Fast-twitch fibres were most susceptible to the depressant effect of diazepam.