kb-r7943 and Atrial-Fibrillation

Pulmonary veins (PVs) are the most important focus for generation of atrial fibrillation. The Na(+)/Ca(2+) exchange (NCX) current is important in PV electrical activity and cardiac glycosides-induced arrhythmias. The purpose of this study was to investigate whether KB-R7943, a NCX current blocker with preferential inhibition of the Ca(2+) influx, may alter PV electrophysiological characteristics and reduce glycoside-induced arrhythmogenicity.. Conventional microelectrodes were used to record the effects of KB-R7943 on action potentials and contractility in isolated rabbit PV tissue specimens with and without administration of ouabain. The ionic currents and intracellular calcium were studied in isolated single cardiomyocytes before and after KB-R7943 by the whole-cell patch clamp and indo-1 fluorimetric ratio techniques.. KB-R7943 (0, 3, 10, 30 microM) concentration-dependently prolonged APD(50) and APD(90) and decreased the PV firing rates (2.3 +/- 1.2 Hz, 2.1 +/- 1.2 Hz, 1.9 +/- 0.9 Hz, 1.7 +/- 1.1 Hz, n = 7, p < 0.05) and incidences of delayed afterdepolarizations (DADs). KB-R7943 (3, 30 microM) decreased transient inward currents, Ca(2+) transient and sarcoplasmic reticulum Ca(2+) content. Ouabain (0, 0.1, 1 microM) concentration-dependently increased the PV firing rates and DADs in PVs with spontaneous activity (n = 7) and induced nonsustained spontaneous activity (1 microM) in the PVs without spontaneous activity (n = 14). However, in the presence of KB-R7943 (30 microM), ouabain (1 microM) did not increase the PV firing rates or induce spontaneous activity in the PVs without spontaneous activity (n = 7).. KB-R7943 reduces the PV arrhythmogenic activity and prevents the ouabain-induced arrhythmogenicity. Our findings support the role of the NCX current in the PV electrical activity.

Topics: Action Potentials; Animals; Atrial Fibrillation; Calcium; Dose-Response Relationship, Drug; Fluorescent Dyes; Fluorometry; Indoles; Muscle, Smooth, Vascular; Myocytes, Cardiac; Ouabain; Patch-Clamp Techniques; Pulmonary Veins; Rabbits; Sarcoplasmic Reticulum; Sodium-Calcium Exchanger; Thiourea

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

Topics: Acute Disease; Anesthesia; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Calcium; Cells, Cultured; Dogs; Female; Heart Atria; Heart Conduction System; Ion Transport; Kinetics; Male; Myocardium; Periodicity; Refractory Period, Electrophysiological; Sodium-Calcium Exchanger; Thiourea