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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-[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, Gd^sup 3+^ (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^sup 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.[PUBLICATION ABSTRACT]