Physostigmine inhibition of 3',5'-cyclic AMP phosphodiesterase from cat sciatic nerve

This study was designed to determine whether cholinergic drug interaction with cyclic (c) AMP phosphodiesterase (PDE) might account for part of the effects of this class of drugs at the neuromuscular junction. The activity levels of both high- and low-affinity forms of cAMP PDE from cat sciatic nerve were examined for drug inhibition or activation. Of the cholinergic drugs tested, only physostigmine and Tacrine produced significant cAMP PDE inhibition. Physostigmine was 10 times more potent than theophylline and half as potent as SQ 20,009 (known PDE inhibitors) in inhibiting motor nerve cAMP PDE. Tacrine inhibited this enzyme at concentrations comparable with theophylline. None of the other drugs tested (diisopropylfluorophosphate, edrophonium, neostigmine, ecothiophate, carbachol or d-tubocurarine) produced significant changes in cAMP PDE activity. The inhibitory effects of physostigmine were shown to be pH independent over a range of 7.0 to 8.5. Kinetic studies indicated a mixed form of inhibition for physostigmine and Tacrine comparable with that seen for theophylline. These data indicate that the anticholinesterase activity of physostigmine and Tacrine do not adequately describe the facilitatory actions of these drugs at the motor nerve ending.