AIMS Autonomic dysfunction can promote atrial fibrillation (AF) and results from AF-related remodelling. N-type Ca2+-channels (NTCCs) at sympathetic nerve terminals mediate Ca2+-entry that triggers neurotransmitter release. AF-associated remodelling plays an important role in AF pathophysiology but the effects of NTCC inhibition on such remodelling is unknown. Here, we investigated the ability of a clinically available Ca2+-channel blocker (CCB) with NTCC-blocking activity to suppress the arrhythmogenic effects of AF-promoting remodelling in dogs. METHODS AND RESULTS Mongrel dogs were kept in AF by right atrial tachypacing at 600 bpm. Four groups were studied under short-term AF (7 days): (i) Shams, instrumented but without tachypacing (n = 5); (ii) a placebo group, tachypaced while receiving placebo (n = 6); (iii) a control tachypacing group receiving nifedipine (10 mg orally twice-daily; n = 5), an L-type CCB; and (iv) a cilnidipine group, subjected to tachypacing and treatment with cilnidipine (10 mg orally twice-daily; n = 7), an N-/L-type CCB. With cilnidipine therapy, dogs with 1-week AF showed significantly reduced autonomic changes reflected by heart rate variability (decreases in RMSSD and pNN50) and plasma norepinephrine concentrations. In addition, cilnidipine-treated dogs had decreased extracellular matrix gene expression vs. nifedipine-dogs. As in previous work, atrial fibrosis had not yet developed after 1-week AF, so three additional groups were studied under longer-term AF (21 days): (i) Shams, instrumented without tachypacing or drug therapy (n = 8); (ii) a placebo group, tachypaced while receiving placebo (n = 8); (iii) a cilnidipine group, subjected to tachypacing during treatment with cilnidipine (10 mg twice-daily; n = 8). Cilnidipine attenuated 3-week AF effects on AF duration and atrial conduction, and suppressed AF-induced increases in fibrous-tissue content, decreases in connexin-43 expression and reductions in sodium-channel expression. CONCLUSIONS Cilnidipine, a commercially available NTCC-blocking drug, prevents AF-induced autonomic, electrical and structural remodelling, along with associated AF promotion.

中文翻译：

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N- / L型钙通道阻滞剂西尼地平可抑制与房颤相关的自主性，电性和结构性重构。

AIMS自主神经功能障碍可促进心房颤动（AF），并且是由AF相关的重塑导致的。交感神经末梢的N型Ca2 +通道（NTCC）介导触发神经递质释放的Ca2 +进入。AF相关的重塑在AF病理生理中起着重要作用，但NTCC抑制对这种重塑的影响尚不清楚。在这里，我们调查了具有NTCC阻断活性的临床可用的Ca2 +通道阻断剂（CCB）抑制狗中促进房颤重塑的心律失常作用的能力。方法和结果杂种狗在600 bpm时通过右心房速动保持AF。在短期房颤（7天）下研究了四组患者：（i）带器械的假肢，但无心动过速（n = 5）；（ii）安慰剂组，在接受安慰剂的同时心动过速（n = 6）；（iii）服用硝苯地平（每日两次，每日两次，每次10 mg； n = 5），L型CCB的速动对照组。（iv）西尼地平组，服用速尼定并用N- / L型CCB西尼地平（每天口服两次10毫克； n = 7）进行治疗。在使用西尼地平治疗的情况下，患有1周房颤的狗表现出明显减少的自主神经变化，这反映在心率变异性（RMSSD和pNN50降低）和血浆去甲肾上腺素浓度上。此外，西尼地平治疗的犬比硝苯地平犬的细胞外基质基因表达降低。与以前的工作一样，房颤1周后仍未出现房颤，因此，在长期房颤（21天）后对另外三个组进行了研究：（ii）安慰剂组，在接受安慰剂的同时心动过速（n = 8）；（iii）西尼地平组，在接受西尼地平治疗期间（每天两次，两次10毫克； n = 8）进行tachypacing。西尼地平减弱了3周房颤对房颤持续时间和心房传导的影响，并抑制房颤引起的纤维组织含量增加，连接蛋白43表达减少和钠通道表达减少。结论西尼地平是一种市售的NTCC阻断药物，可防止AF引起的自主神经，电和结构重构以及相关的AF促进。