Morris Mariana, Key Mary P, Farah Vera
Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Highway, Dayton, OH 45435, USA.
Exp Neurol. 2007 Jan;203(1):110-5. doi: 10.1016/j.expneurol.2006.07.027. Epub 2006 Sep 25.
The aim was to evaluate the acute and delayed effects of low dose sarin exposure on cardiac autonomic and brainstem catecholaminergic function in mice. The rationale was to expand our knowledge of the cardiovascular effects of this neurotoxic, acetylcholinesterase (AChE) inhibitor. C57BL/6 male mice with telemetric arterial catheters were injected with saline or sarin (8 microg/kg, 0.05x LD(50); sc, two injections) with blood pressure (BP) measurements made at 1 and 10 weeks after sarin exposure. BP and pulse interval variability (PI) and low and high frequency spectral oscillations were measured using autoregressive spectral analysis. In situ hybridization (ISH) was used to quantify tyrosine hydroxylase (TH) mRNA expression in brainstem cardiovascular centers. Sarin had no effect on blood AChE activity, heart rate (HR) or BP. There was a biphasic response in PI variance, an early increase (+140%) and a delayed decrease (-62%) at more than 2 months after sarin exposure. There were no changes in BP variance. Assuming that increased PI variance is a positive outcome, the short-term response to sarin should be protective. This is opposite for the delayed decrease in PI variance which is associated with adverse cardiovascular effects. There was an increase in TH mRNA in both locus coeruleus (0.18+/-0.05 vs. 1.4+/-0.2 microCi/g; control vs. sarin) and dorsal vagal complex (0.09+/-0.06 vs. 1.17+/-0.03 microCi/g; control vs. sarin). Results show that a dose of sarin which had no peripheral cholinergic effects caused changes in autonomic modulation, a short-term enhancement followed by a delayed impairment in heart rate variability. Sarin-induced cardiac effects suggest a controversial aspect to the use of pharmacological agents which target AChE for management of cardiovascular risk.
目的是评估低剂量沙林暴露对小鼠心脏自主神经和脑干儿茶酚胺能功能的急性和延迟效应。其基本原理是扩展我们对这种神经毒性乙酰胆碱酯酶（AChE）抑制剂心血管效应的认识。给植入遥测动脉导管的C57BL/6雄性小鼠注射生理盐水或沙林（8微克/千克，0.05倍半数致死剂量；皮下注射，两次注射），并在沙林暴露后1周和10周测量血压（BP）。使用自回归谱分析测量血压和脉搏间期变异性（PI）以及低频和高频谱振荡。采用原位杂交（ISH）定量脑干心血管中枢中酪氨酸羟化酶（TH）mRNA的表达。沙林对血液AChE活性、心率（HR）或血压无影响。PI方差呈双相反应，沙林暴露后2个多月时早期增加（+140%），随后延迟降低（-62%）。血压方差无变化。假设PI方差增加是一个积极结果，那么沙林的短期反应应该具有保护作用。这与PI方差的延迟降低相反，后者与不良心血管效应相关。蓝斑（0.18±0.05对1.4±0.2微居里/克；对照组对沙林组）和迷走背核复合体（0.09±0.06对1.17±0.03微居里/克；对照组对沙林组）中TH mRNA均增加。结果表明，一剂无外周胆碱能效应的沙林引起自主神经调节变化，心率变异性先短期增强，随后延迟受损。沙林诱导的心脏效应提示了使用以AChE为靶点的药物来管理心血管风险存在争议的一面。
