Many neural and neuromuscular systems in the body employ ACh as a neurotransmitter, and still other organs are influenced by ACh. Given the numerous physiological functions influenced by ACh, it is not surprising that perturbations of its function, resulting from AChE inhibition by PB, have numerous and diverse toxicological consequences. There are many recently published and ongoing studies that may elucidate the nature of the mechanisms of PB toxicity; however, many of the studies have yet to be confirmed. The following sections briefly review the available information on PB toxicity, including those studies that await replication.
The neuromuscular effects of PB are important for two reasons. First, impairment of neuromuscular function leads to muscle weakness. Second, experimental findings obtained from the readily accessible neuromuscular junction have long been interpreted to be applicable to other cholinergically innervated synapses in the central nervous system, which are much more difficult to access experimentally. Thus, events occurring at the neuromuscular junction have been thought to mirror those in the brain.
PB, as a ChE inhibitor, modifies physiological function at the sites of innervation of all types of muscle: smooth, cardiac, and skeletal (or striated). The neuromuscular effects of PB have been described almost exclusively for skeletal muscle, while those in other types of muscle are relatively less studied. The effects of PB on the skeletal neuromuscular junction have recently been reviewed in detail (Golomb, 1999). Effects of PB on cardiac muscle have been reported (Glass-Marmor et al., 1996).
Exposure to PB has pharmacological and/or toxicological consequences on neuromuscular function either by direct action of PB at low doses, acting as a weak agonist at the nicotinic ACh receptors (Sherby et al., 1984; Maelicke et al., 1993), or more importantly by accumulation of ACh resulting from inhibition of AChE. Acutely, PB leads to a facilitation (or augmentation) of the strength of contractile tension developed in skeletal muscle because ACh accumulation repetitively activates the contractile process. The relationship between the degree of ChE inhibition and the facilitation of twitch tension is complex. No twitch potentiation is seen until RBC AChE is at least 85 percent inhibited (Barber et al., 1979); this threshold is nearly identical to that noted for other ChE inhibitors. At inhibition levels of 85–98 percent there is a linear relationship between AChE inhibition and facilitation of twitch tension. Large doses of PB would normally be required to achieve these levels of RBC AChE inhibition, and it