Inhibition by neuromuscular blocking drugs of norepinephrine transporter in cultured bovine adrenal medullary cells

Pancuronium stimulates the cardiovascular system, whereas vecuronium, a derivative of pancuronium, has far fewer effects. The inhibition of norepinephrine transporter (NET) in the sympathetic nervous system may partly account for the stimulatory actions of pancuronium. To investigate the mechanism of action of pancuronium on NET, we examined the effects of pancuronium on NET activity by using cultured bovine adrenal medullary cells and compared pancuronium with other neuromuscular blocking drugs. Pancuronium (1-300 microM) inhibited desipramine-sensitive [(3)H]norepinephrine (NE) uptake in a concentration-dependent manner. Vecuronium (100-300 microM) and d-tubocurarine (300 microM) also decreased [(3)H]NE uptake but were less potent than pancuronium at clinical concentrations. Succinylcholine had little effect on [(3)H]NE uptake. Saturation analysis showed that pancuronium and vecuronium reduced an apparent maximum velocity (V(max)) of [(3)H]NE uptake without altering Michaelis-Menten constant, indicating noncompetitive inhibition. Pancuronium did not inhibit the specific binding of [(3)H]desipramine to plasma membranes isolated from bovine adrenal medulla. A protein kinase C inhibitor, GF109203X, did not affect the inhibition of [(3)H]NE uptake by pancuronium. Pancuronium enhanced the inhibition of NET induced by ketamine. These results suggest that pancuronium, with clinically relevant concentrations, inhibits NET activity by interacting with a site distinct from the recognition site for NE and the desipramine binding site on the transporter. In this study, pancuronium inhibited norepinephrine uptake and was the most potent of the neuromuscular blocking drugs we tested, including pancuronium, vecuronium, d-tubocurarine, and succinylcholine. Pancuronium may affect the sympathetic nervous system by inhibiting the activity of the presynaptic norepinephrine transporter at clinically relevant concentrations.