Reversal of cardiac vagal effects of physostigmine by adjunctive muscarinic blockade

Abstract

(242 words)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 anti-cholinergic therapy. 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 pre-treatment. Studies were performed in an isolated innervated rabbit heart preparation. The reduction in heart rate with VNS was augmented by physostigmine (1-1000nmol/L), in a concentration-dependent manner -with an EC 50 of 19nmol/L. Hyoscine was shown to be effective at blocking the cardiac responses to VNS with an IC 50 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 -8 M, is effective at reversing the functional effects of physostigmine on the heart. However, low-concentrations of hyoscine may augment cardiac parasympathetic control. Keywords acetylcholinesterase; organophosphate nerve agents; vagus nerve; physostigmine; hyoscine; scopolamine; eserine 3 IntroductionExposure to highly toxic organophosphate nerve agents results in irreversible inhibition of peripheral and central acetylcholinesterase (AChE) resulting in acetylcholine accumulation and over-stimulation of muscarinic and nicotinic receptors. Symptoms of nerve agent poisoning include hyper-secretion, convulsions, respiratory distress, coma and death.Numerous studies in non-primates and non-human primates have shown that pre-treatment with reversible cholinesterase inhibitors, with and without anticholinergics, improves survival and reduces incapacitation after nerve agent exposure. (Bonhage et al., 2009;Lim et al., 1991;Lim et al., 1988;Muggleton et al., 2003;Philippens et al., 1998;Philippens et al., 2000;von Bredow et al., 1991;Wetherell et al., 2002;Wetherell, 1994) Pyridostigmine (a quaternary compound restricted primarily to the peripheral nervous system) and physostigmine (a neutral compound which can more readily pass the blood brain barrier) are long acting, but reversible, AChE inhibitors that are effective pre-treatments for nerve-agent exposure. While both agents are effective in preventing lethality in animal studies, physos...