Local stretch of adult single ventricular myocytes can induce arrhythmias that resemble surface-recordings from whole hearts. Stretch modulates multiple current components, I(SAC) being the current with the largest arrhythmogenic potential. Stretch-sensitivity of I(SAC) is higher in hypertrophied than in control myocytes as can be expected from the observation that hypertrophy and failure increase the risk of stretch-induced arrhythmias.

It is well established that NO released from the endothelium plays an important role in the regulation of vascular tone. This was most stringently demonstrated by the generation of mice deficient in endothelial NO synthase (eNOS), which develop hypertension (Huang et al. 1995;Shesely et al. 1996;Gödecke et al. 1998). Besides its role in the regulation of organ perfusion, NO might also modulate cardiac function (for review see Kelly et al. 1996). The cytokine-mediated depression of cardiac contractility has been attributed to elevated inducible NO 1. The functional consequences of a lack of endothelial nitric oxide synthase (eNOS) on left ventricular force development and the anti-adrenergic effect of acetylcholine (ACh) were investigated in isolated hearts and cardiomyocytes from wild type (WT) and eNOS knockout (eNOS_/_) mice.2. eNOS expression in cardiac myocytes accounted for 20 % of total cardiac eNOS (Western blot analysis). These results were confirmed by RT-PCR analysis.3. In the unstimulated perfused heart, the left ventricular pressure (LVP) and maximal rate of left ventricular force development (dP/dt max ) of eNOS_/_ hearts were not significantly different from those of WT hearts (LVP: 97 ± 11 mmHg WT vs. 111 ± 11 mmHg eNOS_/_; dP/dt max : 3700 ± 712 mmHg s _1 WT vs. 4493 ± 320 mmHg s _1 eNOS_/_).4. The dobutamine (10-300 nM)-induced increase in LVP was enhanced in eNOS_/_ hearts. In contrast, L-type Ca 2+ currents (I Ca,L ) in isolated cardiomyocytes of WT and eNOS_/_ hearts showed no differences after b-adrenergic stimulation. Dibutyryl-cGMP (50 µM) reduced basal I Ca,L in WT cells to 72 ± 12 % while eNOS_/_ I Ca,L was insensitive to the drug. The prestimulated I Ca,L (30 nM isoproterenol) was attenuated by dibutyryl-cGMP in WT and eNOS_/_ cells to the same extent.5. The Ca 2+ (1.5-4.5 mM)-induced increase in inotropy was not different between the two experimental groups and b-adrenergic receptor density was increased by 50 % in eNOS_/_ hearts.6. The contractile effects of dobutamine could be inhibited almost completely by ACh or adenosine. The extent of the anti-adrenergic effect of both compounds was identical in WT and eNOS_/_ hearts. Measurement of I Ca,L in isolated cardiac myocytes yielded similar results.7. These data demonstrate that in the adult mouse (1) lack of eNOS is associated with increased cardiac contractile force in response to b-adrenergic stimulation and with elevated b-adrenergic receptor density, (2) the unaltered response of I Ca,L in eNOS_/_ cardiac myocytes to b-adrenergic stimulation suggests that endothelium-derived NO is important in mediating the whole-organ effects and (3) eNOS is unimportant for the anti-adrenergic effect of ACh and adenosine.

Compression of the isolated cardiac fibroblast caused depolarization of the membrane by activating inward currents through a non-selective cation conductance (G(ns)). Stretch hyperpolarizes the fibroblast, however, not by Ca(2+) activation of K(+)-conductance. Ion selectivity, E(rev,) and Gd(3+)-sensitivity of stretch suppressed currents suggest that stretch reduces G(ns) that is activated by compression.

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.

Stretch-activated non-selective cation currents ( I(SAC)) constitute a mechanism that can induce cardiac arrhythmias. We studied I(SAC) in mouse ventricular myocytes by stretching part of the cell surface between the patch-pipette and a motor-driven glass stylus. In non-clamped cells, local stretch depolarised and induced after-depolarisations and extrasystoles. In voltage-clamped cells (K(+) currents suppressed) I(SAC) activated by local stretch had a nearly linear voltage dependence and reversed polarity between -12 and 0 mV. Conductance G(SAC) increased with the extent of local stretch. I(SAC) was not a Cl(-) current (insensitivity to replacement of Cl(-) by aspartate(-)). I(SAC) was not a Ca(2+)-activated current (insensitivity to 5 mM intracellular BAPTA). G(SAC) was blocked by 5 micro M GdCl(3) or by 75 mM extracellular (e.c.) CaCl(2). Removal of e.c. CaCl(2) increased G(SAC) 2.5-fold, as if G(SAC) were sensitive to Ca(2+) and Gd(3+). Replacement of 150 mM e.c. Na(+) by 150 mM Cs(+), Li(+), tetraethylammonium (TEA(+)) or N-methyl d-glucosamine (NMDG(+)) yielded currents that suggested for the conductance a selectivity G(Cs)> G(Na)> G(Li)> G(TEA)> G(NMDG). I(SAC) was suppressed by cytochalasin D, as if an intact F-actin cytoskeleton were necessary for activation of I(SAC).

Cardiac arrhythmia is a serious clinical condition, which is frequently associated with abnormalities of mechanical loading and changes in wall tension of the heart. Recent novel findings suggest that fibroblasts may function as mechano-electric transducers in healthy and diseased hearts. Cardiac fibroblasts are electrically non-excitable cells that respond to spontaneous contractions of the myocardium with rhythmical changes of their resting membrane potential. This phenomenon is referred to as mechanically induced potential (MIP) and has been implicated in the mechano-electric feedback mechanism of the heart. Mechano-electric feedback is thought to adjust the frequency of spontaneous myocardial contractions to changes in wall tension, which may result from variable filling pressure. Electrophysiological recordings of single atrial fibroblasts indicate that mechanical compression of the cells may activate a non-selective cation conductance leading to depolarisation of the membrane potential. Reduced amplitudes of MIPs due to pharmacological disruption of F-actin and tubulin suggest a role for the cytoskeleton in the mechano-electric signal transduction process. Enhanced sensitivity of the membrane potential of the fibroblasts to mechanical stretch after myocardial infarction correlates with depression of heart rates. It is assumed that altered electrical function of cardiac fibroblasts may contribute to the increased risk of post-infarct arrhythmia.

No abstract

Fibroblasts in the heart can respond to mechanical deformation of the plasma membrane with characteristic changes of their membrane potential. Membrane depolarization of the fibroblasts occurs during the myocardial contractions and is caused by an influx of cations, mainly of sodium ions, into the cells. Conversely, application of mechanical stretch to the cells, i.e., during diastolic relaxation of the myocardium, will hyperpolarize the membrane potential of the fibroblasts due to reduced sodium entry. Thus, cardiac fibroblasts can function as mechano-electric transducers that are possibly involved in the mechano-electric feedback mechanism of the heart. Mechano-electric feedback refers to the phenomenon, that the cardiac mechanical environment, which depends on the variable filling pressure of the ventricles, modulates the electrical function of the heart. Increased sensitivity of the cardiac fibroblasts to mechanical forces may contribute to the electrical instability and arrhythmic disposition of the heart after myocardial infarction. Novel findings indicate that these processes involve the intercellular transfer of electrical signals between fibroblasts and cardiomyocytes via gap junctions. In this article we will discuss the recent progress in the electrophysiology of cardiac fibroblasts. The main focus will be on the intercellular pathways through which fibroblasts and cardiomyocytes communicate with each other.