title: TNF-α provokes electrical abnormalities in rat atrial myocardium via a NO-dependent mechanism.
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-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.
authors.affiliation: Department of Fundamental and Applied Physiology, Russian National Research Medical University, Ostrovitjanova 1, Moscow, 117997, Russia, abram340@mail.ru.
authors.forename: Denis V
authors.initials: DV
authors.lastname: Abramochkin
authors.forename: Vladislav S
authors.initials: VS
authors.lastname: Kuzmin
authors.forename: Vadim M
authors.initials: VM
authors.lastname: Mitrochin
authors.forename: Leonid
authors.initials: L
authors.lastname: Kalugin
authors.forename: Anton
authors.initials: A
authors.lastname: Dvorzhak
authors.forename: Ekaterina Y
authors.initials: EY
authors.lastname: Makarenko
authors.forename: Rudolf
authors.initials: R
authors.lastname: Schubert
authors.forename: Andre
authors.initials: A
authors.lastname: Kamkin
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D016275:Atrial Function / Q000187:drug effects / Q000502:physiology*; D004594:Electrophysiology; D005682:Gadolinium / Q000494:pharmacology; D006325:Heart Atria / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D010812:Physical Stimulation; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D005682:Gadolinium