Reversal of cardiac vagal effects of physostigmine by adjunctive muscarinic blockade

Pre-treatment with reversible acetylcholinesterase (AChE)
inhibitors is an effective strategy for reducing lethality following
organophosphate nerve agent exposure. AChE inhibition may have unwanted
cardiac side effects, which could be negated by adjunctive anticholinergic
therapy; however, direct study of this interaction is
difficult in vivo. The aims of the present study were to examine the
concentration-dependent effects of physostigmine on cardiac responses to
vagus nerve stimulation (VNS), to test whether adjunctive treatment with
hyoscine can reverse these effects and to assess the functional
interaction and electrophysiological consequences of a combined pretreatment.
Studies were performed in an isolated innervated rabbit heart
preparation. Physostigmine (1-1000nmol/L) was associated with a
concentration-dependent increase in the magnitude of heart rate slowing
during VNS, with an EC50 of 19nmol/L. Hyoscine was shown to be effective
at blocking the cardiac responses to VNS with an IC50 of 11nmol/L. With
concomitant perfusion of physostigmine, the concentration-response curve
for hyoscine was shifted downward and to the right, increasing the
concentration of hyoscine required to normalise (to control values) the
effects of physostigmine on heart rate. At the lowest concentration of
hyoscine examined (1nmol/L) a modest potentiation of heart rate response
to VNS (+15±3%) was observed. We found no evidence of cardiac dysfunction
or severe electrophysiological abnormalities with either physostigmine or
hyoscine alone, or as a combined drug-therapy. The main finding of this
study is that hyoscine, at concentrations greater than 10-8M, is
effective at reversing the functional effects of physostigmine on the
heart. However, low-concentrations of hyoscine may augment cardiac
parasympathetic control.