KB-R7943 prevents acute, atrial fibrillation-induced shortening of atrial refractoriness in anesthetized dogs

• Published in: Circulation (New York, N.Y.) N.Y.), 2002-09, Vol.106 (11), p.1410-1419
• Main Authors: MIYATA, Akira, ZIPES, Douglas P, HALL, Stephen, RUBART, Michael
• Format: Article
• Language: English
• Subjects: Acute Disease; Anesthesia; Animals; Anti-Arrhythmia Agents - pharmacokinetics; Anti-Arrhythmia Agents - pharmacology; Atrial Fibrillation - metabolism; Atrial Fibrillation - physiopathology; Atrial Fibrillation - prevention & control; Biological and medical sciences; Calcium - metabolism; Cardiac dysrhythmias; Cardiology. Vascular system; Cells, Cultured; Dogs; Female; Heart; Heart Atria - physiopathology; Heart Conduction System - drug effects; Ion Transport - drug effects; Kinetics; Male; Medical sciences; Myocardium - metabolism; Periodicity; Refractory Period, Electrophysiological - drug effects; Sodium-Calcium Exchanger - antagonists & inhibitors; Thiourea - analogs & derivatives; Thiourea - pharmacokinetics; Thiourea - pharmacology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.0000028587.85711.f6

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. 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 (P0.05). 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. NCX-mediated Ca2+ influx plays an important role in acute, AF-induced AERP shortening.