ATP-dependent interaction of propranolol and local anaesthetic with sarcoplasmic reticulum. Stimulation of Ca²⁺ efflux

Preincubation of sarcoplasmic reticulum (SR) with propranolol or tetracaine inhibits Ca²⁺ accumulation and stimulates ATPase activity by more than 2-fold. This effect is obtained only when the preincubation is carried out in the presence of ATP or other nucleoside triphosphates. The (ATP + drug)-induced inhibition of Ca²⁺ accumulation is pH-dependent, increasing as the pH rises above 7.5. The presence of micromolar concentrations of Ca²⁺ or Mg²⁺ during the preincubation prevents the inhibitory effect of ATP plus drug on Ca²⁺ accumulation or ATPase activity. The (ATP + drug) modification of SR vesicles resulted in stimulation of a rapid Ca²⁺ efflux from passively loaded vesicles. The ATP-dependent inhibition of Ca²⁺ accumulation by the drug is obtained with other local anaesthetics. The drug concentration required for 50% inhibition was 0.15 mM for dibucaine and 0.4 mM for both propranolol and tetracaine, whereas it was 5 mM, 8 mM and >10 mM for lidocaine, benzoicaine and procaine respectively. The heavy SR vesicles were only slightly affected by the incubation with propranolol or tetracaine in the presence of ATP, but their sensitivity increased markedly after storage at 0°C for 24-48 h. These results suggest that propranolol and some local anaesthetics, in the presence of ATP, stimulate Ca²⁺ efflux by modifying a protein factor(s) rather than the phospholipid bilayer.