Protection by tacrine and some adjuncts against the depressant effects of soman in guinea-pig atrium

Abstract

1. 1. The negative inotropic effects of soman have been reported previously. It was suggested that the depression in atrial force of contraction was a consequence of continuous muscarinic receptor activation by excessive acetylcholine (ACh) accumulation and also possibly through direct interactions at the receptor-associated K + channels by organophosphate (OP). 2. 2. In this study, the protective effects of tacrine (THA), an antimuscarinic as well as a K + channel blocker, against soman in guinea-pig atrium were investigated. 3. 3. It was found that tacrine could antagonize the negative inotropic effects of soman. This antagonism occurred in a concentration dependent manner, with effective concentrations (ECs) for tacrine ranging from 1.7 to 12.1 μM when the atrium was equilibrated with 0.05–10 μM soman. 4. 4. Inclusion of an oxime HI-6 (100 μM) in the regimen improved the efficacy of tacrine against soman (1 μM) by 16.1 fold. 5. 5. Addition of a potent antimuscarinic, either atropine or glycopyrrolate with tacrine also improved tacrine's efficacy against soman significantly. 6. 6. Atropine, at equivalent concentration, appeared to be the most effective of the three. At 0.1 μM concentration, atropine was 4.25 and 3.47 times more potent than HI-6 and glycopyrrolate respectively in enhancing THA efficacy. 7. 7. Our results suggested that the immediate suppression of the muscarinic manifestations and the reactivation of the enzyme acetylcholinesterase for the removal of excess ACh are both critical in maintaining the mechanical functions of a heart during acute OP poisoning. The blockade of K + channels by tacrine may also contribute to countering the depressant effects of soman.