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.

Effects of interleukin-17A on the bioelectric activity of rat atrial myocardium under normal conditions and during gradual stretching

“…The effect of stretching on the bio-electrical activity of RAPs is described in detail in our previous study [7]. In control conditions, there was no significant change during the first hour of the experiment.…”

“…The effect of Gd 3+ on the stretch-induced electrical activity, was described in detail in our previous studies [7,10]. Briefly, the application of Gd 3+ at a concentration of 40 lM, completely abolished all SIDs, hump-like SIDs, and extra APs after 10 min, without significant alteration of the contractile activity.…”

“…This stimulus was used to provoke the electrophysiological response of the cardiomyocytes. Each step was applied for approximately 5 s. Since the relationship between the length changes and stretch force differs among preparations, we have used the increase in isometric force amplitude (DAF) to standardize the mechanical test stimulus (for details see [7]). …”

“…The last was actualized since we described a similar activity provoked by some of the cytokines like TNF-a and IL-18 [7,8]. Noteworthy, the effects of both mentioned cytokines included the alteration of the mechanically gated channels (MGCs) activity in compilation with increased nitric oxide (NO) production.…”

Possible relationship between certolizumab pegol and arrhythmias: report of two cases

“…TNFa also seems to affect the ion-potential currents of myocardiocytes. Experiments on mice treated with TNFa have highlighted a reduced intake of sarcoplasmic Ca2+, possibly related to the nitrosylation of RyR2 channels (12,13). This reduction in Ca2+ levels may be responsible for depressed cell contractility and the development of aberrant sparks or hump-like depolarizations, which are risk factors for the occurrence of an arrhythmic event.…”