Inefficacy of a highly selective T-type calcium channel blocker in preventing atrial fibrillation related remodeling.

The T-type Ca(2+) channel (I(CaT)) blocker mibefradil prevents AF-promoting remodeling occurring with atrial tachycardia, an action that has been attributed to I(CaT) inhibition. However, mibefradil has other effects, including ability to inhibit L-type Ca(2+) channels, Na(+) channels and cytochromes. Thus, the relationship between I(CaT) inhibition and remodeling protection in AF is still unknown. To assess the effects of a novel highly selective Cav3 (I(CaT)) blocker, AZ9112, on atrial remodeling induced by 1-week atrial tachypacing (AT-P) in dogs. Mongrel dogs were subjected to AT-P at 400 bpm for 7 days, with atrioventricular-node ablation and right-ventricular demand pacing (80 bpm) to control ventricular rate. Four groups of dogs were studied in investigator-blinded fashion: (1) a sham group, instrumented but without tachypacing or drug therapy (n = 5); (2) a placebo group, tachypaced but receiving placebo (n = 6); (3) a positive control tachypacing group receiving mibefradil (n = 6); and (4) a test drug group, subjected to tachypacing during oral treatment with AZ9112 (n = 8). One-week AT-P decreased atrial effective refractory period (ERP) at 6 of 8 sites and diminished rate-dependent atrial ERP abbreviation. Mibefradil eliminated AT-P-induced ERP-abbreviation at 4 of these 6 sites, while AZ9112 failed to affect ERP at any. Neither drug significantly affected AF vulnerability or AF duration. I(CaT) blockade with the highly selective compound AZ9112 failed to prevent rate-related atrial remodeling. Thus, prevention of atrial electrophysiological remodeling by mibefradil cannot be attributed exclusively to I(CaT) blockade. These results indicate that I(CaT) inhibition is not likely to be a useful approach for AF therapy.

Kato T ，Iwasaki YK ，Duker G ，Fjellstrom O ，Giordanetto F ，Sundqvist M ，Wallin A ，Wang QD ，Nattel S ... -  《-》

The T-type Ca(2+) channel blocker mibefradil prevents the development of a substrate for atrial fibrillation by tachycardia-induced atrial remodeling in dogs.

Fareh S ，Bénardeau A ，Thibault B ，Nattel S ... -  《-》

Differential efficacy of L- and T-type calcium channel blockers in preventing tachycardia-induced atrial remodeling in dogs.

Fareh S ，Bénardeau A ，Nattel S 《CARDIOVASCULAR RESEARCH》

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

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. 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. Cilnidipine, a commercially available NTCC-blocking drug, prevents AF-induced autonomic, electrical and structural remodelling, along with associated AF promotion.

Tajiri K ，Guichard JB ，Qi X ，Xiong F ，Naud P ，Tardif JC ，Costa AD ，Aonuma K ，Nattel S ... -  《-》

A comparison between calcium channel blocking drugs with different potencies for T- and L-type channels in preventing atrial electrical remodeling.

Ohashi N ，Mitamura H ，Tanimoto K ，Fukuda Y ，Kinebuchi O ，Kurita Y ，Shiroshita-Takeshita A ，Miyoshi S ，Hara M ，Takatsuki S ，Ogawa S ... -  《JOURNAL OF CARDIOVASCULAR PHARMACOLOGY》