TNF-α provokes electrical abnormalities in rat atrial myocardium via a NO-dependent mechanism

• Published in: Pflügers Archiv Vol. 465; no. 12; pp. 1741 - 1752
• Main Authors: Abramochkin, Denis V., Kuzmin, Vladislav S., Mitrochin, Vadim M., Kalugin, Leonid, Dvorzhak, Anton, Makarenko, Ekaterina Y., Schubert, Rudolf, Kamkin, Andre
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2013
• Subjects: Action Potentials - drug effects; Animals; Arrhythmias, Cardiac - chemically induced; Atrial Function - drug effects; Atrial Function - physiology; Biomedical and Life Sciences; Biomedicine; Cell Biology; Electrophysiology; Gadolinium - pharmacology; Heart Atria - metabolism; Human Physiology; Ion Channels; Male; Membrane Potentials - drug effects; Molecular Medicine; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - physiology; Neurosciences; Nitric Oxide - physiology; Physical Stimulation; Rats; Rats, Wistar; Receptors; Receptors and Transporters; S-Nitroso-N-Acetylpenicillamine - pharmacology; Tumor Necrosis Factor-alpha - pharmacology; Heart; Stretch; Atrium; NO; Action potential; Cytokine
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-013-1320-2

Stretch-induced depolarizations of cardiomyocytes, which are related to activity of mechano-gated cation channels (MGCs), can lead to serious arrhythmias. However, signaling pathways leading to activation of mechano-gated channels by stretch remain almost unexplored. Using standard sharp microelectrodes, the present study addresses the hypothesis that tumor necrosis factor-alpha (TNF-α) modulates stretch-induced electrophysiological abnormalities in rat atrial myocardium by a mechanism involving nitric oxide (NO)-dependent pathways. TNF-α (50 ng/ml) produced a marked prolongation of action potential, subsequently transforming into humplike depolarizations and, finally, leading to occurrence of arrhythmias. These effects developed slowly during 25 min of TNF-α application. Similar electrical effects were induced by stretching the preparations. A blocker of MGCs, Gd 3+ (40 μM), completely abolished action potential (AP) prolongations and electrical abnormalities caused by TNF-α or stretch. Further, a donor of exogenous NO, S -nitroso- N -acetylpenicillamine SNAP (300 μM), evoked the same electrical abnormalities as TNF-α and tissue stretch. Both TNF-α and stretch failed to produce their typical effects after pretreatment of the preparations with the NO-synthase inhibitor L-N G -nitroarginine methyl ester (L-NAME) (100 μM). Thus, the present study shows (i) that TNF-α and the NO-donor SNAP evoke MGC-mediated electrical abnormalities in rat atrial myocardium in the absence of stretch that is very similar to stretch-evoked electrical events and (ii) that the TNF-α-induced electrical abnormalities are mediated by NO synthase. In conclusion, our data suggest that NO is an endogenous modulator of MGCs and mediates proarrhythmic effects of TNF-α in mammalian organism.