The effect of propranolol and its analogs on Ca++ transport by sarcoplasmic reticulum vesicles

Vesicular fragments of sarcoplasmic reticulum were used as a model system to investigate the mechanism of propranolol inhibition on various steps of the Ca++ transport cycle, It was found that Ca++-dependent transfer of ATP terminal phosphate to the sarcoplasmic reticulum protein and formation of the phosphorylated enzyme intermediate are not inhibited by propranolol concentrations effective on Ca++ transport. Rather, a specific step following enzyme phosphorylation and corresponding to Ca++ translocation across the membrane is primarily inhibited. The consequent hydrolysis of phosphorylated enzyme is then secondarily inhibited, while "Ca++ independent" ATP hydrolysis remains unchanged. Comparison of the relative potencies of several propranolol analogs yields similar patterns for Ca++ transport inhibition in sarcoplasmic reticulum vesicles and negative inotropic effects on cardiac muscle. These patterns are at variant with those displayed by these agents with respect to beta adrenergic blockade.