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An N-/L-type Calcium Channel Blocker, Cilnidipine, Suppresses Autonomic, Electrical, and Structural Remodelling Associated With Atrial Fibrillation

An N-/L-type Calcium Channel Blocker, Cilnidipine, Suppresses Autonomic, Electrical, and Structural Remodelling Associated With Atrial Fibrillation

Kazuko Tajiri, Jean-Baptiste Guichard, Xiaoyan Qi, Feng Xiong, Patrice Naud, Jean-Claude Tardif, Antoine Da Costa, Kazutaka Aonuma, Stanley Nattel

Cardiovasc Res. 2019 Dec 1;115(14):1975-1985.

PMID: 31119260

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP132203704	Cilnidipine		132203-70-4	Price

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