Scattered reports (Kato et al., 1989; Glass-Marmor et al., 1996) suggest that ACh accumulation in cardiac muscle compromises mitochondrial function and thus impairs myocardial energetics in a manner similar to that observed in skeletal muscle (see discussion of neuromuscular effects). The doses of PB employed in these studies were 20 and 60 mg/kg, respectively.

Thermoregulation

Like other ChE inhibitors, PB is capable of altering cholinergically mediated thermoregulatory processes in the hypothalamus. The cholinergic component is demonstrated by the ability of atropine to block PB alterations in thermoregulation (Matthew et al., 1988). Compromised temperature regulation is most prominent at higher ambient temperatures. In rats, acute administration of PB produces hyperthermia, whereas chronic administration elicits much less elevation in body temperature, indicating the relatively rapid emergence of adaptive processes akin to heat acclimation during prolonged exposure (Matthew et al., 1994). In contrast, mice given 0.2 mg/kg PB have been reported to be hypothermic (Kaufer et al., 1999). It appears that hyperthermia (and the extent of debilitation) is correlated with the degree of brain ChE inhibition (and presumably with the extent of penetration of the ChE inhibitor through the blood–brain barrier) and, further, there are no significant effects on temperature regulation when plasma ChE inhibition is less than 30 percent (Francesconi et al. 1984, 1986; Matthew et al., 1988, 1994). This also appears to be true for humans exposed to PB (Seidman and Epstein, 1989).

The impact of physical conditions such as heat, alone and in combination with pharmacological agents, on task performance has been evaluated in both animals and military personnel. PB is of particular interest in this regard since sweating is under autonomic, muscarinic control. In monkeys, doses of PB that produce a 25–30 percent inhibition of serum ChE levels result in only transient alterations in physiological parameters (Avlonitou and Elizondo, 1988). Francesconi and colleagues (1986) reported that chronic (14-day) inhibition of ChE in rats to levels as high as 39 percent is without effect on thermoregulation or exercise performance. In human volunteers, single doses of 30 mg are without effect on psychomotor performance or thermoregulation (Wenger and Latzka, 1992) as were multiple doses (Seidman and Epstein, 1989; Izraeli et al., 1990; Arad et al., 1992a,b). Chronic administration of PB does not appear to alter thermoregulation at cold ambient temperatures (Sawka et al., 1994).

It has been reported (Sharma et al., 1992) that moderate heat stress (38°C for 4 hours) enhances the entry of tracers such as Evans blue into the brains of rats, adding to earlier evidence supporting the notion that stress augments the permeability of the blood–brain barrier (Belova and Jonsson, 1982; Ben-Nathan et al., 1991). Subsequent studies have failed to confirm these findings. Lallement and colleagues (1998) administered tritiated PB to guinea pigs maintained at an ambient temperature of 42.6°C for 2 hours and noted that even though those given PB succumbed to heat stress and exhibited high levels of plasma



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