Effect of atropine and bispyridinium oximes on respiratory and circulatory function in guinea-pigs poisoned by sarin

Abstract

During the past decade the oxime HI 6(l-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydroxyimino)methyl] pyridinium dichloride) was shown to improve survival in nerve agent poisoning (in combination with atropine). Recent studies indicate, that HLö 7 (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2,4-bis[(hydroxyimino)methyl]pyridinium diiodide or dimethanesulfonate) is also an effective antidote in nerve agent poisoning but, with both oximes, data on restoration of respiration and circulation are scarce. The ability of HLö 7 or HI 6 with atropine to improve the respiratory and circulatory function in sarin-poisoned guinea-pigs was therefore investigated. Female Dunkin-Hartley guinea-pigs were anaesthetised with urethane (1.8 g/kg) and the arteria carotis, vena jugularis and trachea were cannulated. After baseline measurements the animals received 100 or 200 μg/kg sarin, and 2 min later the antidotes (all i.v.): 10 mg/kg atropine sulfate or a combination of atropine and HLö 7 or HI 6 (30 μmnol/kg, each). Respiratory and circulatory parameters were recorded for the whole experimental period of 60 min or until the death of the animal. Brain and diaphragm acetylcholinesterase (AChE) activity was determined in each animal after the experiment. Poisoning by sarin resulted in a rapid respiratory arrest within 5 min. Atropine treatment was only partially effective in improving respiration after 100 μg/kg sarin but was ineffective after 200 μg/kg sarin. Therapy of sarin-poisoned animals with atropine plus oxime further improved respiration to various extents, restored circulation and increased survival time, HLö 7 being more effective than HI 6. Diaphragm and brain AChE were reactivated by HLö 7 and, to a minor extent, by HI 6. The results of this investigation suggest, that at equimolar doses (30 μmol/kg) the new bispyridinium dioxime HLö 7 has a higher therapeutic efficacy in sarin-poisoned guinea-pigs when compared to HI 6 (both in combination with atropine).