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An N-/L-type calcium channel blocker, cilnidipine, suppresses autonomic, electrical, and structural remodelling associated with atrial fibrillation.


ABSTRACT: 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.

SUBMITTER: Tajiri K 

PROVIDER: S-EPMC6873085 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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An N-/L-type calcium channel blocker, cilnidipine, suppresses autonomic, electrical, and structural remodelling associated with atrial fibrillation.

Tajiri Kazuko K   Guichard Jean-Baptiste JB   Qi Xiaoyan X   Xiong Feng F   Naud Patrice P   Tardif Jean-Claude JC   Costa Antoine Da AD   Aonuma Kazutaka K   Nattel Stanley S  

Cardiovascular research 20191201 14


<h4>Aims</h4>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 th  ...[more]

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