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Pflugers Arch - Eur J Physiol (2013) 465:17411752 DOI 10.1007/s00424-013-1320-2
ION CHANNELS, RECEPTORS AND TRANSPORTERS
TNF- provokes electrical abnormalities in rat atrial myocardium via a NO-dependent mechanism
Denis V. Abramochkin & Vladislav S. Kuzmin & Vadim M. Mitrochin & Leonid Kalugin &
Anton Dvorzhak & Ekaterina Y. Makarenko & Rudolf Schubert & Andre Kamkin
Received: 8 January 2013 /Revised: 9 June 2013 /Accepted: 22 June 2013 /Published online: 5 July 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract 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-) modulates stretch-induced electrophysiological abnormalities in rat atrial myocardium by a mechanism involving nitric oxide (NO)-dependent pathways. TNF- (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- application. Similar electrical effects were induced by stretching the preparations. A blocker of MGCs, Gd3+
(40 M), completely abolished action potential (AP) prolongations and electrical abnormalities caused by TNF- or stretch. Further, a donor of exogenous NO, S-nitroso-N-acetylpenicillamine SNAP (300 M), evoked the same electrical abnormalities as TNF- and tissue stretch. Both TNF- and stretch failed to produce their typical effects after pretreatment of the preparations with the NO-synthase inhibitor L-NG-
nitroarginine methyl ester (L-NAME) (100 M). Thus, the present study shows (i) that TNF- 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--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- in mammalian organism.
Keywords Heart . Atrium . Action potential . Cytokine . NO . Stretch
Introduction
Contractile failure of the heart due to cardiac arrhythmia is a major cause of cardiovascular mortality. Lethal arrhythmias, such as ventricular fibrillation, appear usually in persons suffering from myocardial infarction, myocarditis, or other severe cardiac pathologies. Mechanisms that underlie electrical instability (abnormality) of the diseased...