Inhibition of neuronal uptake of noradrenaline in the isolated perfused rat heart by pancuronium and its homologues, Org. 6368, Org. 7268 and NC 45

Abstract

The cardiovascular effects of pancuronium may be caused partly by an interaction of this drug with the sympathetic nervous system. We examined one possible mechanism of interaction, the effect on the re-uptake processes for noradrenaline. Pancuronium and its closely related steroidal homologues, Org. 6368, Org. 7268 and NC 45, were studied at a high concentration (500 mumol litre-1) for inhibition of the uptake of tritiated noradrenaline into neuronal sites (Uptake1) and extraneuronal sites (Uptake2) in the isolated perfused rat heart. All drugs tested caused almost total inhibition of Uptake1. The bis-quaternary steroids pancuronium and Org. 6368 were selective for Uptake1 inhibition, the mono-quaternary steriods Org. 7268 and NC45 also produced significant inhibition of Uptake2. Uptake1 inhibition was investigated in detail using lesser concentrations of the compounds. All four steroids were found to cause a concentration-dependent inhibition of Uptake1. It seems likely, therefore, that inhibition of neuronal uptake of noradrenaline plays a significant role in the aetiology of the chronotropic actions of pancuronium in the rat.