Inhomogenic effect of bepridil on atrial electrical remodeling in a canine rapid atrial stimulation model.
BACKGROUND
The antiarrhythmic or reverse remodeling effects of bepridil, a multi-ion channel blocker, have been recently reported, but inhomogeneity of the electrical remodeling and effects of bepridil have been observed in previous reports. In this study, the effect of long-term administration of bepridil on atrial electrical remodeling was evaluated in a comparison of the right and left atrium (RA and LA) in a canine rapid atrial stimulation model.


RESULTS
In 10 beagle dogs, rapid atrial pacing (400 beats/min) was delivered for 6 weeks and the atrial effective refractory period (AERP), conduction velocity (CV) and inducibility of atrial fibrillation (AF) were evaluated every week. In 5 of the pacing dogs, bepridil (10 mg . kg(-1) . day(-1)) was administered orally, starting 2 weeks after the initiation of the rapid pacing. At the end of the protocol, the hemodynamic parameters and extent of tissue fibrosis were evaluated and the mRNA of SCN5A, Kv4.3, the L-type Ca2+ channel (LCC) and connexin (Cx) 40, 43, and 45 in both atria were examined by quantitative real-time reverse transcriptase-polymerase chain reaction. In the pacing control group, AERP shortening, decreased CV, increased AF inducibility and downregulation of the expression of SCN5A and LCC were observed. In the bepridil group, the AERP exhibited a relatively quick recovery after bepridil was started in the first week and continued to recover gradually until the end of the protocol, but that recovery was smaller in the LA than in the RA. The CV was not affected by bepridil administration. AF inducibility was well suppressed in the RA in the bepridil group, but the induction of short-duration AF could not be suppressed in the LA. The mRNA downregulation of the LCC and SCN5A was negated by bepridil administration in the RA; but not in the LA; however, the data showed similar tendencies. There were no significant differences in the hemodynamic parameters or tissue fibrosis and the mRNA expression of Kv4.3, Cx40, 43, and 45 between the pacing control and bepridil groups.


CONCLUSIONS
Bepridil exhibited an anti-electrical remodeling effect in this study as previously reported, but the effect was inhomogeneous between the RA and LA, with the LA appearing to be more resistant to the effect of bepridil.
Fukaya
Hidehira
H
Department of Cardio-Angiology, Kitasato University School of Medicine, 1-15-1 Kitasato,Sagamihara 228-8555, Japan. hidehira@med.kitasato-u.ac.jp
Niwano
Shinichi
S
Satoh
Daisuke
D
Masaki
Yoshihiko
Y
Niwano
Hiroe
H
Kojima
Jisho
J
Moriguchi
Masahiko
M
Izumi
Tohru
T
D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015764:Bepridil / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000096:biosynthesis*; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D009124:Muscle Proteins / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D013997:Time Factors; D020257:Ventricular Remodeling / Q000187:drug effects*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D009124:Muscle Proteins; D012333:RNA, Messenger; D015764:Bepridil