Inhibitory effects of (±)-propranolol on excitation-contraction coupling in isolated soleus muscles of the rat

Abstract

1. The effect of a β-adrenoceptor antagonist, propranolol, was investigated on excitation-contraction coupling in small, intact bundles of soleus muscle fibres from the rat. 2. (±)-Propranolol significantly inhibited twitch and tetanic tension with IC50 values of 6.7 μM and 3.5 μM, respectively. 3. (+)-Propranolol (which has 100 times less β-blocking activity than the (±) form) was approximately one third as effective as the (±) form at inhibiting isometric tension. 4. (±)-Propranolol (20 μM) had no significant effect on the amplitude of caffeine contractures, suggesting that it did not directly inhibit Ca2+ release from the sarcoplasmic reticulum. 5. The resting membrane potential measured after 15 min perfusion with 20 μM (±)-propranolol was not significantly different from control. However, this concentration of (±)-propranolol significantly reduced both the peak amplitude and the maximum rate of rise of the action potential. Both effects were only partially reversible after extensive washing. 6. (±)-Propranolol perfusion caused a modest reduction in the amplitude of sub-maximal K+ contractures at concentrations (5 μM) that markedly depressed tetanic tension. 7. The results indicate that (±)-propranolol can decrease isometric tension independently of β-receptor occupation by (i) reducing the amplitude and rate of rise of the action potential and (ii) by directly inhibiting excitation-contraction coupling. The relatively low IC50 for the 'membrane-stabilizing' action of propranolol on tetanic tension (3.5 μM), combined with the ability of the drug to accumulate gradually in biological membranes, may contribute to a peripheral component of the tremorolytic and fatigue-inducing actions of propranolol on skeletal muscle.