An N-/L-type calcium channel blocker, cilnidipine, suppresses autonomic, electrical, and structural remodelling associated with atrial fibrillation. Issue 14 (22nd May 2019)

• Record Type: Journal Article
• Authors: Tajiri, Kazuko; Guichard, Jean-Baptiste; Qi, Xiaoyan; Xiong, Feng; Naud, Patrice; Tardif, Jean-Claude; Costa, Antoine Da; Aonuma, Kazutaka; Nattel, Stanley
• Is Part Of: Cardiovascular research. Volume 115:Issue 14(2019)
• Page Start: 1975
• Page End: 1985
• Publication Date: 2019-05-22
• Subjects: Atrial fibrillation -- N-type Ca2+ channel -- Ca2+ channel blocker -- Autonomic nervous system -- Cilnidipine -- Fibrosis; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvz136
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Autonomic dysfunction can promote atrial fibrillation (AF) and results from AF-related remodelling. N-type Ca 2+ -channels (NTCCs) at sympathetic nerve terminals mediate Ca 2+ -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 Ca 2+ -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. Graphical Abstract: