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

Article

关键词: NA+/CA2+ EXCHANGE CURRENT;    CARDIAC MYOCYTES;    SMOOTH-MUSCLE;    CELLS;    MECHANISMS;    BLOCK;    MODE;    RAT;   

DOI  :  10.1161/01.CIR.0000028587.85711.F6

来源: SCIE

【 摘 要 】

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. Methods and 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 &PLUSMN; 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.kg(-1).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 approximate to40 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 approximate to60%, but had no significant effect on NCX-dependent Ca2+ extrusion. Conclusion-NCX-mediated Ca2+ influx plays an important role in acute, AF-induced AERP shortening.

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