Differential effects of stretch and compression on membrane currents and [Na+]c in ventricular myocytes

Abstract

Mechano-electrical feedback was studied in the single ventricular myocytes. A small fraction (approximately 10%) of the cell surface could be stretched or compressed by a glass stylus. Stretch depolarised, shortened the action potential and induced extra systoles. Stretch activated non-selective cation currents (I(ns)) showed a linear voltage dependence, a reversal potential of 0 mV, a pure cation selectivity, and were blocked by 8 microM Gd(3+) or 30 microM streptomycin. Stretch reduced Ca(2+) and K(+) (I(K)) currents. Local compression of broadwise attached cells activated I(K) but not I(ns). Cytochalasin D or colchicin, thought to disrupt the cytoskeleton, suppressed the mechanosensitivity of I(ns) and I(K). During stretch, the cytosolic sodium concentration increased with spatial heterogeneities, local hotspots with [Na(+)](c)>24 mM appeared close to surface membrane and t-tubules (pseudoratiometric imaging using Sodium Green fluorescence). Electronprobe microanalysis confirmed this result and indicated that stretch increased total sodium [Na] in cell compartments such as mitochondria, nuclear envelope and nucleus. Our results obtained by local stretch differ from those obtained by end-to-end stretch (literature). We speculate that channels may be activated not only by axial but also by shear stress, and, that stretch can activate channels outside the deformed sarcomeres via second messenger.

The slow force response to stretch in atrial and ventricular myocardium from human heart: Functional relevance and subcellular mechanisms

“…We have further substantiated this evidence by demonstrating, for the first time in human ventricle, a stretch-induced increase in [Na + ] i associated with the SFR. This finding is in line with previous studies revealing stretch-induced increases in [Na + ] i in rat, rabbit, and mouse ventricle (Alvarez et al, 1999;Isenberg et al, 2003;Kondratev and Gallitelli, 2003;Luers et al, 2005;Perez et al, 2001;Wilhelm et al, 2006), although one study failed to detect a stretch-induced [Na + ] i increase (Hongo et al, 1996). How NHE is stimulated by stretch, however, is unknown at present.…”

“…An unexpected finding was that SACs are apparently not involved in the SFR in human myocardium, neither in atrium nor ventricle, despite convincing evidence for the expression and functional relevance of SACs in atrium and ventricle of many mammalian species (Isenberg et al, 2003;Suchyna et al, 2000;Zeng et al, 2000) including humans , and evidence for the involvement of SACs in the SFR in rat ventricle (Calaghan and White, 2004;Niederer and Smith, 2007). We have used a specific blocker of SACs in this study, GsMtx-4, to evaluate the role of SACs in human atrium and ventricle for baseline force development and the SFR.…”

“…SACs in atrial and ventricular myocytes preferentially conduct monovalent cations (Isenberg et al, 2003;Kamkin et al, 2003;Zeng et al, 2000) and, to a lesser degree, also Ca 2+ (Suchyna et al, 2004). Thus, activation of SACs could increase force via influx of Na + and/or Ca 2+ .…”

“…Many previous studies have relied on either gadolinium or streptomycin to block SACs. Although both can indeed block SACs (Hamill and McBride, 1996;Isenberg et al, 2003), they also have effects on channels other than SACs and thus interpretation of results obtained with these substances alone is difficult. Recently, however, a peptide isolated from the venom of the tarantula Grammostola spatulata, GsMtx-4, was identified as a novel, highly potent and specific inhibitor of SACs (Bowman et al, 2007;Suchyna et al, 2000).…”

Cell cultures as models of cardiac mechanoelectric feedback

“…These threedimensional deformations also give rise to fluid shear stresses that result from the flow of interstitial fluids around cells (Lorenzen-Schmidt et al, 2006). In single ventricular myocytes, axial stretch, local indentation, and hypoosmotic swelling affect membrane currents in different ways (Isenberg et al, 2003;Sasaki et al, 1992), One of the impediments of the study of MEF at the cellular level is the technical complexity of the experiments (Kohl and Ravens, 2003), which involve application of a mechanical perturbation (the input) while monitoring a change in electrophysiology (the readout).…”