Ninio Daniel M, Saint David A
Discipline of Physiology, School of Molecular & Biomedical Science, University of Adelaide, SA 5005, Australia.
Prog Biophys Mol Biol. 2008 Jun-Jul;97(2-3):401-16. doi: 10.1016/j.pbiomolbio.2008.02.016. Epub 2008 Feb 16.
The incidence of atrial fibrillation correlates with increasing atrial size. The electrical consequences of atrial stretch contribute to both the initiation and maintenance of atrial fibrillation. It is suggested that altered calcium handling and stretch-activated channel activity could explain the experimental findings of stretch-induced depolarisation, shortened refractoriness, slowed conduction and increased heterogeneity of refractoriness and conduction. Stretch-activated channel blocking agents protect against these pro-arrhythmic effects. Gadolinium, GsMTx-4 toxin and streptomycin prevent the stretch-related vulnerability to atrial fibrillation without altering the drop in refractory period associated with stretch. Changes the activity of two-pore K+ channels, which are sensitive to stretch and pH but not gadolinium, could underlie the drop in refractoriness. Intracellular acidosis induced with propionate amplified the change in refractoriness with stretch in the isolated rabbit heart model in keeping with the clinical observation of increased propensity to atrial fibrillation with acidosis. We propose that activation of non-specific cation stretch-activated channels provides the triggers for acute atrial fibrillation with high atrial pressure while activation of atrial two-pore K+ channels shortens atrial refractory period and increases heterogeneity of refractoriness, providing the substrate for atrial fibrillation to be sustained. Stretch-activated channel blockade represents an exciting target for future antiarrhythmic drugs.
心房颤动的发生率与心房增大相关。心房扩张的电生理后果有助于心房颤动的起始和维持。有人提出，钙处理改变和牵张激活通道活性可以解释牵张诱导的去极化、不应期缩短、传导减慢以及不应期和传导异质性增加的实验结果。牵张激活通道阻滞剂可预防这些促心律失常作用。钆、GsMTx-4毒素和链霉素可防止与牵张相关的心房颤动易感性，而不会改变与牵张相关的不应期缩短。对牵张和pH敏感但对钆不敏感的双孔钾通道活性变化可能是不应期缩短的基础。在离体兔心脏模型中，丙酸盐诱导的细胞内酸中毒放大了牵张引起的不应期变化，这与临床观察到的酸中毒时心房颤动倾向增加一致。我们提出，非特异性阳离子牵张激活通道的激活为高心房压时急性心房颤动提供触发因素，而心房双孔钾通道的激活缩短心房不应期并增加不应期异质性，为心房颤动的持续提供底物。牵张激活通道阻滞剂是未来抗心律失常药物的一个令人兴奋的靶点。
