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

• Published in: European journal of pharmacology Vol. 576; no. 1; pp. 122 - 131
• Main Authors: Wolkowicz, Paul E., Grenett, Hernan E., Huang, Jian, Wu, Hsien Chin, Ku, David D., Urthaler, Ferdinand
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 08.12.2007; Elsevier
• Subjects: 2-APB; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester - pharmacology; Animals; Atrial fibrillation; Atrial tachycardia; Benzazepines - pharmacology; Biological and medical sciences; Boron Compounds - pharmacology; Calcium - physiology; Calcium Channel Agonists - pharmacology; Cardiac dysrhythmias; Cardiology. Vascular system; Cardiotonic Agents - pharmacology; Cyclic Nucleotide-Gated Cation Channels - genetics; Heart; Heart Atria - drug effects; Heart Atria - metabolism; Heart Atria - physiopathology; I f; In Vitro Techniques; Male; Medical sciences; Na/Ca-exchanger; Ouabain - pharmacology; Pharmacology. Drug treatments; Pyrimidines - pharmacology; Pyrroles - pharmacology; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Ryanodine - pharmacology; Tachycardia - chemically induced; Tachycardia - drug therapy; Tachycardia - physiopathology; Atrial tachycardia; Na/Ca-exchanger; Atrial fibrillation; 2-APB; I f; Arrhythmia; Calcium; Rat; Rodentia; Cardiovascular disease; Inorganic element; Excitability disorder; Vertebrata; Mammalia; Na; Heart disease; Animal; exchanger; Models; If; Ca
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2007.08.004

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 ((4 S)-1,4-Dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluormethyl)phenyl]-3-pyridinecarboxylic acid methyl ester), (iv) 300 nM FPL-64176 (2,5-Dimethyl-4-[2-(phenylmethyl)benzoyl]-1 H-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 (I f) inhibitors blunt this ectopic activity. Thus conditions that increase atrial calcium load increase the frequency of spontaneous mechanical activity. Decreasing extracellular sodium and I f inhibitors suppress this spontaneous tachycardia suggesting forward-mode sodium–calcium exchange and I f-like activities underlie this activity. This model may help define cell pathways that trigger atrial tachyarrhythmias.