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

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-alpha) modulates stretch-induced electrophysiological abnormalities in rat atrial myocardium by a mechanism involving nitric oxide (NO)-dependent pathways. TNF-alpha (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-alpha application. Similar electrical effects were induced by stretching the preparations. A blocker of MGCs, Gd3+ (40 mu M), completely abolished action potential (AP) prolongations and electrical abnormalities caused by TNF-alpha or stretch. Further, a donor of exogenous NO, S-nitroso-N-acetylpenicillamine SNAP (300 mu M), evoked the same electrical abnormalities as TNF-alpha and tissue stretch. Both TNF-alpha 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 mu M). Thus, the present study shows (i) that TNF-alpha 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-alpha-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-alpha in mammalian organism.