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 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 microM and 3.5 microM, respectively. 3. (+)-Propranolol (which has 100 times less beta-blocking activity than the (+/-) form) was approximately one third as effective as the (+/-) form at inhibiting isometric tension. 4. (+/-)-Propranolol (20 microM) 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 microM (+/-)-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 microM) that markedly depressed tetanic tension. 7. The results indicate that (+/-)-propranolol can decrease isometric tension independently of beta-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 microM), 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.
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School of Physiology and Pharmacology, University of New South Wales, Sydney, Australia.
Fryer
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D000200:Action Potentials / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects*; D011188:Potassium / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000319:Adrenergic beta-Antagonists; D002110:Caffeine; D011433:Propranolol; D011188:Potassium