Intracellular mechanism of quinidine action on muscle contraction

Summary The mechanism of quinidine action on rabbit cardiac and skeletal muscle was examined with functionally skinned muscle-fiber preparations. By using these preparations we could correlate measurements of muscle tension with the effect of quinidine on the Ca²⁺ activation of the contractile proteins and on the Ca²⁺ uptake and release from the sarcoplasmic reticulum (SR).Effect of quinidine on the contractile proteins. Quinidine concentrations above 0.5 mmol/l increased the maximal Ca²⁺-activated tension development 12% for papillary muscle and 5% for soleus (slow-twitch). Adductor magnus (fast-twitch) showed no significant change. Quinidine (0.1–1.0 mmol/l) also increased the submaximal Ca²⁺-activated tension development for the three muscle types (papillary muscle=soleus>adductor magnus) and shifted the [Ca²⁺]-tension curves to the left in a dose-dependent fashion.Effects of quinidine on the Ca²⁺ uptake and release from the SR. Sarcoplasmic reticulum of skinned fibers was loaded with Ca²⁺ (uptake phase), then Ca²⁺ was released by 25 mmol/l caffeine (release phase) giving a tension transient. The area under the tension transient was used to estimate the amount of Ca²⁺ released. Quinidine (>0.5 mmol/l) decreased the Ca²⁺ uptake (soleus>adductor magnus>papillary muscle) and increased the Ca²⁺ release [papillary muscle=soleus adductor magnus (only at 1.5 mmol/l, the highest concentration tested)] from the SR of all three muscles in a dose-dependent manner. Quinidine at low concentration (0.1 and 0.5 mmol/l) increased the caffeine-induced tension transient of papillary muscle and higher quinidine concentrations (1.0 and 1.5 mmol/l) decreased the caffeine-induced tension transient of soleus and adductor magnus during both the uptake and release phases. The decreased Ca²⁺ uptake of papillary muscle in 1.5 mmol/l quinidine was antagonized by increasing the free Mg²⁺ from 0.032 to 0.32 mmol/l.In summary, quinidine has similar mechanisms of action in all three muscles: increased Ca²⁺ activation of the contractile proteins, decreased Ca²⁺ uptake and increased Ca²⁺ release from the SR in functionally skinned muscle fibers. We conclude that quinidine-induced decreases in Ca²⁺ uptake by the SR could be responsible for quinidine-induced myocardial depression and that quinidine-induced increases in Ca²⁺ activation of the contractile proteins and Ca²⁺ release from the SR could be responsible for the increases in skeletal muscle contraction caused by quinidine.