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

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. British Journal of Pharmacology (1997) 122, 463–468; doi:10.1038/sj.bjp.0701405