INHIBITORY EFFECTS OF (+ -)-PROPRANOLOL ON EXCITATION-CONTRACTION COUPLING IN ISOLATED SOLEUS MUSCLES OF THE RAT/

1. The effect of a beta-adrenoceptor antagonist, propranolol, was inve stigated on excitation-contraction coupling in small, intact bundles o f soleus muscle fibres from the rat. 2. (+/-)-Propranolol significantl y inhibited twitch and tetanic tension with IC50 values of 6.7 mu M an d 3.5 mu M, respectively. 3. (+)-Propranolol (which has 100 times less beta-blocking activity than the (+/-) form) was approximately one thi rd as effective as the (+/-) form at inhibiting isometric tension. 4. (+/-)-Propranolol (20 mu M) 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 mu M (+/-)-proprano lol was not significantly different from control. However, this concen tration of (+/-)-propranolol significantly reduced both the peak ampli tude and the maximum rate of rise of the action potential. Both effect s were only partially reversible after extensive washing. 6. (+/-)-Pro pranolol perfusion caused a modest reduction in the amplitude of sub-m aximal K+ contractures at concentrations (5 mu M) that markedly depres sed tetanic tension. 7. The results indicate that (+/-)-propranolol ca n decrease isometric tension independently of beta-receptor occupation by (i) reducing the amplitude and rate of rise of the action potentia l and (ii) by directly inhibiting excitation-contraction coupling. The relatively low IC50 for the 'membrane-stabilizing' action of proprano lol on tetanic tension (3.5 mu M), combined with the ability of the dr ug to accumulate gradually in biological membranes, may contribute to a peripheral component of the tremorolytic and fatigue-inducing action s of propranolol on skeletal muscle.