A pharmacological model for calcium overload-induced tachycardia in isolated rat left atria

Academic Article

Abstract

  • Few experimental models produce spontaneous tachycardia in normal left atria to allow the study of the cellular mechanisms underlying this contributor to atrial fibrillation. We reported 2-aminoethoxydiphenyl borate (2-APB) that provokes sporadic spontaneous mechanical activity and calcium leak in isolated rat left atria. Since sarcoplasmic reticulum calcium leak in the presence of high calcium load may trigger tachyarrhythmias, we tested how conditions that increase calcium load affect 2-APB-induced ectopic activity. Exposing superfused rat left atria to (i) 30 nM isoproterenol, (ii) 3 μM forskolin, (iii) 300 nM (-)BayK 8644 ((4S)-1,4-Dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluormethyl)phenyl]-3-py ridinecarboxylic acid methyl ester), (iv) 300 nM FPL-64176 (2,5-Dimethyl-4-[2-(phenylmethyl)benzoyl]-1H-pyrrole-3-carboxylic acid methyl ester) or (v) 120 μM ouabain increases their force of contraction, evidence of calcium loading, but does not produce ectopic activity. Spontaneous mechanical activity occurs in left atria superfused with 20 μM 2-APB at 47 ± 6 contractions/min in the absence of pacing. Any of these five agents increase rates of 2-APB-induced spontaneous mechanical activity to > 200 contractions/min in the absence of pacing. Washing tachycardic left atria with superfusate lacking 2-APB restores normal function, demonstrating the reversibility of these effects. Decreasing superfusate sodium reverses this tachycardia and two hyperpolarization-activated current (If) inhibitors blunt this ectopic activity. Thus conditions that increase atrial calcium load increase the frequency of spontaneous mechanical activity. Decreasing extracellular sodium and If inhibitors suppress this spontaneous tachycardia suggesting forward-mode sodium-calcium exchange and If-like activities underlie this activity. This model may help define cell pathways that trigger atrial tachyarrhythmias. © 2007 Elsevier B.V. All rights reserved.
  • Digital Object Identifier (doi)

    Author List

  • Wolkowicz PE; Grenett HE; Huang J; Wu HC; Ku DD; Urthaler F
  • Start Page

  • 122
  • End Page

  • 131
  • Volume

  • 576
  • Issue

  • 1-3