Kb-R7943 prevents acute, atrial fibrillation-induced shortening of atrial refractoriness in anesthetized dogs.
BACKGROUND
To test the hypothesis that Ca2+ influx via Na+/Ca2+ exchange (NCX) underlies atrial fibrillation (AF)-induced shortening of atrial effective refractory period (AERP), we examined the potential of KB-R7943 (KB), a selective inhibitor of Ca2+-influx mode NCX, to attenuate this effect.


RESULTS
Studies were performed in 41 isoflurane-anesthetized dogs. In sinus rhythm dogs, peak AERP changes resulting from intravenous KB infusion ranged from (mean+/-SEM) 4.4+/-0.4% (1 mg/kg) to 14.8+/-2.6% (5 mg/kg; ED50=1.9 mg/kg). AERP was maximally prolonged between 5 and 10 minutes after beginning of KB infusion and returned to baseline values within 30 minutes thereafter. Rapid atrial pacing-induced AF reversibly shortened AERP (P<0.001) in 5 dogs, averaging 14.9+/-2.1% after 90 minutes of AF. Both the time course and magnitude of mean AERP changes in 5 AF dogs receiving 5 mg/kg KB were indistinguishable from those in 5 sinus rhythm dogs receiving an equivalent KB dose (P>0.05). We measured cardiac tissue and arterial plasma KB concentrations produced by intravenous infusion (1 mg x kg(-1) x min(-1)) of 5 mg/kg KB. Plasma drug concentration peaked at the end of KB infusions (30.86+/-3.26 nmol/L; n=4 dogs) and declined to 0.56+/-0.19 nmol/L after 100 minutes. The cardiac tissue-to-plasma drug concentration gradient averaged approximately 40 at 100 minutes after start of KB infusion. KB at concentrations achieved in vivo irreversibly blocked NCX-mediated Ca2+ influx in isolated canine right atrial myocytes by approximately 60%, but had no significant effect on NCX-dependent Ca2+ extrusion.


CONCLUSIONS
NCX-mediated Ca2+ influx plays an important role in acute, AF-induced AERP shortening.
Miyata
Akira
A
Krannert Institute of Cardiology, Wishard Memorial Hospital, Indianapolis, Ind, USA.
Zipes
Douglas P
DP
Hall
Stephen
S
Rubart
Michael
M
D000208:Acute Disease; D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000378:metabolism / Q000503:physiopathology* / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004285:Dogs; D005260:Female; D006325:Heart Atria / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010507:Periodicity; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000889:Anti-Arrhythmia Agents; D019831:Sodium-Calcium Exchanger; D013890:Thiourea; D002118:Calcium