Mechano-electric Coupling Research Articles

Membrane Thickness Dependence of Non-Mammalian Prestins

Prestin is significant for voltage-dependent somatic motility of outer hair cells in the cochlea, which is important for mammalian hearing. This membrane protein undergoes conformational changes in response to changes in the membrane potential in a manner similar to piezoelectricity. Previously we have shown that mammalian prestin is sensitive to membrane thickness by changing membrane thickness by perfusion of gamma-cyclodextrin loaded with phosphatidylcholines with various hydrocarbon chain lengths. A reduction in membrane thickness led to a positive shift in the operating point of the membrane potential at which charge transfer associated with motile response takes place. The shift observed was up to 150 mV. An increase in membrane thickness had the opposite effect. Shifts were about +6 mV for 1% reduction in thickness. This result was interpreted as an indication that conformational change of prestin, namely the conformation with larger membrane area has thinner hydrophobic area that interfaces lipid bilayer. In the present study, we examined whether or not non-mammalian prestins are also sensitive to membrane thickness. We found that the membrane thickness dependence of platypus prestin was quantitatively similar to that of mammalian prestin. In contrast, chicken prestin did not show a systematic membrane thickness dependence. These results demonstrate that chicken prestin does not undergo conformational changes that are similar to those of mammalian or platypus prestin. These findings are therefore consistent with the presence of mechanoelectric coupling in platypus prestin and the absence of such coupling in chicken prestin.

Cardiac Electromechanical Models: From Cell to Organ

The heart is a multiphysics and multiscale system that has driven the development of the most sophisticated mathematical models at the frontiers of computational physiology and medicine. This review focuses on electromechanical (EM) models of the heart from the molecular level of myofilaments to anatomical models of the organ. Because of the coupling in terms of function and emergent behaviors at each level of biological hierarchy, separation of behaviors at a given scale is difficult. Here, a separation is drawn at the cell level so that the first half addresses subcellular/single-cell models and the second half addresses organ models. At the subcellular level, myofilament models represent actin–myosin interaction and Ca-based activation. The discussion of specific models emphasizes the roles of cooperative mechanisms and sarcomere length dependence of contraction force, considered to be the cellular basis of the Frank–Starling law. A model of electrophysiology and Ca handling can be coupled to a myofilament model to produce an EM cell model, and representative examples are summarized to provide an overview of the progression of the field. The second half of the review covers organ-level models that require solution of the electrical component as a reaction–diffusion system and the mechanical component, in which active tension generated by the myocytes produces deformation of the organ as described by the equations of continuum mechanics. As outlined in the review, different organ-level models have chosen to use different ionic and myofilament models depending on the specific application; this choice has been largely dictated by compromises between model complexity and computational tractability. The review also addresses application areas of EM models such as cardiac resynchronization therapy and the role of mechano-electric coupling in arrhythmias and defibrillation.

Mechanoelectrical coupling enhances initiation and affects perpetuation of atrial fibrillation during acute atrial dilation

Acute atrial dilation increases the susceptibility to atrial fibrillation (AF). However, the mechanisms by which atrial stretch may contribute to the initiation and perpetuation of AF remain to be determined. The purpose of this study was to use a novel multiscale model of atrial electromechanics and mechanoelectrical feedback to test the hypothesis that acute stretch increases vulnerability to AF by heterogeneous activation of stretch-activated channels. Human atria were represented by a triangular mesh obtained from magnetic resonance imaging data. Atrial trabecular bundle structure was incorporated by varying thicknesses of the atrial wall. Atrial membrane behavior was modeled by the Courtemanche-Ramirez-Nattel model with the addition of a nonselective stretch-activated cation current (I(sac)). Mechanical behavior was modeled by a series elastic, a contractile, and a parallel elastic element in which contractile force was related to intracellular concentration of free calcium and sarcomere length. Acute atrial dilation was simulated by increasing stretch throughout the atrial wall. Stimulation near the pulmonary vein ostia at an interval of 600 ms induced AF at an overall stretch ratio of 1.10. Initiation and perpetuation of AF in our model were related to increased dispersion of effective refractory period, conduction slowing, and local conduction block, all related to heterogeneous activation of I(sac). Upon local contraction, mechanoelectrical coupling affects perpetuation of AF by temporarily changing local excitability. During acute atrial dilation, heterogeneous activation of I(sac) enhances initiation and can affect perpetuation of AF.

TREK‐1 K+ Channels in the Cardiovascular System: Their Significance and Potential as a Therapeutic Target

Potassium (K(+) ) channels are important in cardiovascular disease both as drug targets and as a cause of underlying pathology. Voltage-dependent K(+) (K(V) ) channels are inhibited by the class III antiarrhythmic agents. Certain vasodilators work by opening K(+) channels in vascular smooth muscle cells (VSMCs), and K(+) channel activation may also be a route to improving endothelial function. The two-pore domain K(+) (K(2P) ) channels form a group of 15 known channels with an expanding list of functions in the cardiovascular system. One of these K(2P) channels, TREK-1, is the focus of this review. TREK-1 channel activity is tightly regulated by intracellular and extracellular pH, membrane stretch, polyunsaturated fatty acids (PUFAs), temperature, and receptor-coupled second messenger systems. TREK-1 channels are also activated by volatile anesthetics and some neuroprotectant agents, and they are inhibited by selective serotonin reuptake inhibitors (SSRIs) as well as amide local anesthetics. Some of the clinical cardiovascular effects and side effects of these drugs may be through their actions on TREK-1 channels. It has recently been suggested that TREK-1 channels have a role in mechano-electrical coupling in the heart. They also seem important in the vascular responses to PUFAs, and this may underlie some of the beneficial cardiovascular effects of the essential dietary fatty acids. Development of selective TREK-1 openers and inhibitors may provide promising routes for intervention in cardiovascular diseases.

Models of stretch-activated ventricular arrhythmias

One of the most important components of mechanoelectric coupling is stretch-activated channels, sarcolemmal channels that open upon mechanical stimuli. Uncovering the mechanisms by which stretch-activated channels contribute to ventricular arrhythmogenesis under a variety of pathologic conditions is hampered by the lack of experimental methodologies that can record the 3-dimensional electromechanical activity simultaneously at high spatiotemporal resolution. Computer modeling provides such an opportunity. The goal of this review is to illustrate the utility of sophisticated, physiologically realistic, whole heart computer simulations in determining the role of mechanoelectric coupling in ventricular arrhythmogenesis. We first present the various ways by which stretch-activated channels have been modeled and demonstrate how these channels affect cardiac electrophysiologic properties. Next, we use an electrophysiologic model of the rabbit ventricles to understand how so-called commotio cordis, the mechanical impact to the precordial region of the heart, can initiate ventricular tachycardia via the recruitment of stretch-activated channels. Using the same model, we also provide mechanistic insight into the termination of arrhythmias by precordial thump under normal and globally ischemic conditions. Lastly, we use a novel anatomically realistic dynamic 3-dimensional coupled electromechanical model of the rabbit ventricles to gain insight into the role of electromechanical dysfunction in arrhythmogenesis during acute regional ischemia.

Single mechano‐gated channels activated by mechanical deformation of acutely isolated cardiac fibroblasts from rats

Mechanosensitive conductances were reported in cardiac fibroblasts, but the properties of single channels mediating their mechanosensitivity remain uncharacterized. The aim of this work was to investigate single mechano-gated channels (MGCs) activated by mechanical deformations of cardiac fibroblasts. Currents through single MGCs and mechanosensitive whole-cell currents were recorded from isolated rat atrial fibroblasts using the cell-attached and whole-cell patch-clamp configurations respectively. Defined mechanical stress was applied via the patch pipette used for the whole-cell recordings. Under resting conditions occasional short openings of two types of single MGCs with conductances of 43 and 87 pS were observed. Both types of channels displayed a linear current-voltage relationship with the reversal potential around 0 mV. Small (1 microm) mechanical deformations affected neither single nor whole-cell mechano-gated currents. Cell compressions (2, 3 and 4 microm) augmented the whole-cell currents and increased the frequency and duration of single channel openings. Cell stretches (2, 3 and 4 microm) inactivated the whole-cell currents and abolished the activity of single MGCs. Gd(3+) (8 microm) blocked the whole-cell currents within 5 min. No single channel activity was observed in the cell-attached mode when Gd(3+) was added to the intrapipette solution. Cytochalasin D and colchicine (100 microm each) completely blocked both the whole-cell and single channel currents. These findings show that rat atrial fibroblasts express two types of MGCs whose activity is governed by cell deformation. We conclude that fibroblasts can sense the direction of applied stress and contribute to mechano-electrical coupling in the heart.

Mechanosensitivity of a Voltage-Gated Ion Channel, Nav1.5

Voltage-gated ion channels are often found in tissues where electrical and mechanical stimuli coexist. The mechanosensitive, voltage-gated sodium channel Nav1.5 (encoded by SCN5A) is expressed in two such electromechanical organs, the heart and the gastrointestinal tract. Mutations in SCN5A are frequently pathogenic and may affect mechanoelectrical coupling. The aim of this study was to assess mechanical sensitivity of Nav1.5 at the molecular level. SCN5A was expressed in HEK cells and studied using a pipette pulled and fire polished to ensure that a small number (2-50) of channels were reliably present in cell-attached micropatches. This allowed resolution of both single channel events and averaged behavior. Both positive and negative pressures (up to 50mmHg) produced visible patch distention, an increase in patch current at all voltages and large hyperpolarizing shifts in steady-state voltage-sensitivity of activation and inactivation. From voltage dependence of activation at rest (V1/2 = −30mV at 0mmHg), pressure resulted in graded shifts of V1/2 for activation and inactivation of −0.71mV/mmHg and −0.72mV/mmHg, respectively. Channel kinetics were predictably affected by the voltage shifts, but channel opening and fast inactivation were otherwise unaffected by pressure. Single channel traces showed that unitary conductance was unaffected, rather peak currents appeared to increase due to an increase in the number of active channels in the patch. These effects were minimally reversible for as long as 30 minutes after a single stretch stimulus. Patch excision resulted in an immediate shift of activation V1/2=-75mV and loss of stretch sensitivity. Application of the inhibitor of actin polymerization, cytochalasin D, diminished sensitivity to stretch (−0.42mV/mmHg). Our work demonstrates that mechanical stress at physiologically relevant levels affects voltage sensing of Nav1.5 channels, without affecting the pore, channel gate and fast inactivation. Supported by NIH DK52766.

Probing Conformational Changes of Prestin with Thiol-Reactive Optical Switches

Thiol-reactive optical switch probes were used to examine conformational changes of prestin-based membrane motor. Because this motor is based on mechanoelectric coupling similar to piezoelectricity, the motile activity can be monitored by charge movements across the plasma membrane, which appears as nonlinear capacitance. When the plasma membrane is conjugated with the probes, optically induced spiro-merocyanine transition positively shifted nonlinear capacitance of outer hair cells and prestin-transfected cells by ∼10mV. These shifts were reversible and were eliminated by pretreatment with iodoacetamide. However, they were little affected by pretreatment with biotin maleimide, which cannot reach the cytoplasmic surface. Our results showed that merocyanine states, with a larger dipole moment, interact with the motor's extended conformation stronger than with the compact conformation by 1.6×10−21J/molecule. The interaction sites are near the cytoplasmic side of the motor protein.

Precordial Thump in the Catheterization Laboratory Experimental Evidence for Commotio Cordis

HomeCirculationVol. 115, No. 11Precordial Thump in the Catheterization Laboratory Experimental Evidence for Commotio Cordis Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBPrecordial Thump in the Catheterization Laboratory Experimental Evidence for Commotio Cordis Guillaume Cayla, MD, Jean Christophe Macia, MD and Jean Luc Pasquie, MD, PhD Guillaume CaylaGuillaume Cayla From the CHU Montpellier, Clinique du Cœur et Des Vaisseaux, Hôpital Arnaud de Villeneuve, Montpellier, France. Search for more papers by this author , Jean Christophe MaciaJean Christophe Macia From the CHU Montpellier, Clinique du Cœur et Des Vaisseaux, Hôpital Arnaud de Villeneuve, Montpellier, France. Search for more papers by this author and Jean Luc PasquieJean Luc Pasquie From the CHU Montpellier, Clinique du Cœur et Des Vaisseaux, Hôpital Arnaud de Villeneuve, Montpellier, France. Search for more papers by this author Originally published20 Mar 2007https://doi.org/10.1161/CIRCULATIONAHA.106.667725Circulation. 2007;115:e332A 57-year-old man was admitted to our institution for a diagnostic coronarography. During the right coronary injection (Iomeron 350, Altana Pharma, Le Mée sur Seine, France), complete atrioventricular block occurred for 3 seconds. A precordial thump was performed to restart cardiac activation. Unfortunately, the precordial thump occurred during repolarization of the first ventricular escape rhythm, resulting in ventricular fibrillation, which required external cardioversion. This is the first case documented of ventricular fibrillation initiation in a man by mild chest trauma. In commotio cordis—infrequent sudden death in young athletes caused by blunt chest trauma—ventricular fibrillation is induced by a light blow delivered at a wide range of velocities, as documented in an animal model.1 This tracing (Figure) is highly remarkable in that precordial thump, a common resuscitation maneuver, was responsible for commotio cordis, resulting in ventricular fibrillation that necessitated immediate cardioversion. Download figureDownload PowerPointDuring the RCA injection, the tracing exhibits blocked P waves followed by ventricular escape rhythm. The precordial thump resulted in a +30 mm Hg aortic pressure and incidentally occurred during the repolarization of the first beat of the escape rhythm in a phase of supervulnerability and induced ventricular fibrillation. P indicates p waves; ER, escape rhythm.DisclosuresNone.FootnotesCorrespondence to Jean Luc Pasquié, Clinique du Cœur et des Vaisseaux, Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire, 34295 Montpellier Cedex 5, France. E-mail [email protected]Reference1 Link MS, Maron BJ, Wang PJ, VanderBrink BA, Zhu W, Estes NA 3rd. Upper and lower limits of vulnerability to sudden arrhythmic death with chest-wall impact (commotio cordis). J Am Coll Cardiol. 2003; 1: 99–104.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Quinn T and Kohl P (2021) Cardiac Mechano-Electric Coupling: Acute Effects of Mechanical Stimulation on Heart Rate and Rhythm, Physiological Reviews, 10.1152/physrev.00036.2019, 101:1, (37-92), Online publication date: 1-Jan-2021. Quinn T and Kohl P (2016) Rabbit models of cardiac mechano-electric and mechano-mechanical coupling, Progress in Biophysics and Molecular Biology, 10.1016/j.pbiomolbio.2016.05.003, 121:2, (110-122), Online publication date: 1-Jul-2016. Quinn T (2013) The importance of non-uniformities in mechano-electric coupling for ventricular arrhythmias, Journal of Interventional Cardiac Electrophysiology, 10.1007/s10840-013-9852-0, 39:1, (25-35), Online publication date: 1-Jan-2014. Osorio J, Dosdall D, Tabereaux P, Robichaux R, Stephens S, Kerby J, Stickney R, Pogwizd S and Ideker R (2012) Effect of Chest Compressions on Ventricular Activation, The American Journal of Cardiology, 10.1016/j.amjcard.2011.10.024, 109:5, (670-674), Online publication date: 1-Mar-2012. Madias C, Maron B, Alsheikh-Ali A, Rajab M, Estes N and Link M (2009) Precordial thump for cardiac arrest is effective for asystole but not for ventricular fibrillation, Heart Rhythm, 10.1016/j.hrthm.2009.06.029, 6:10, (1495-1500), Online publication date: 1-Oct-2009. Nolan J and Soar J (2009) Defibrillation in clinical practice, Current Opinion in Critical Care, 10.1097/MCC.0b013e32832931cb, 15:3, (209-215), Online publication date: 1-Jun-2009. Osorio J, Dosdall D, Robichaux R, Tabereaux P and Ideker R (2008) In a Swine Model, Chest Compressions Cause Ventricular Capture and, By Means of a Long-Short Sequence, Ventricular Fibrillation, Circulation: Arrhythmia and Electrophysiology, 1:4, (282-289), Online publication date: 1-Oct-2008. March 20, 2007Vol 115, Issue 11 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.106.667725PMID: 17372182 Originally publishedMarch 20, 2007 PDF download Advertisement SubjectsArrhythmiasCardiopulmonary Resuscitation and Emergency Cardiac Care

Simulation of mechanoelectrical coupling in cardiomyocytes under normal and abnormal conditions

Mathematical models of the electromechanical function of cardiomyocytes and muscle duplexes, the simplest mechanically inhomogeneous myocardial systems, are developed. Using these models, the contribution of mechanoelectrical feedbacks to the contractive activity of the myocardium in normal and abnormal conditions is studied. In particular, the influence of the mechanical conditions of contraction on the shape and duration of the action potentials is reproduced and interpreted. In this context, different types of mechanical heterogeneity of the myocardium are analyzed. It is established that this heterogeneity can play a positive or negative role depending on the distribution of heterogeneous properties and on the order the elements of the system are activated. Using the same models, the contribution of mechanical factors to arrhythmogenesis under calcium overload of cardiomyocytes due to the weakening of the sodium-potassium pump is studied. Methods for correction of the contractive activity of cardiomyocytes in the case of such abnormalities are outlined.

Commotio Cordis—Sudden Cardiac Death with Chest Wall Impact

Commotio cordis (CC), sudden death as a result of a blunt, often innocent-appearing chest wall blow, is being reported with increasing frequency. The clinical spectrum is diverse; however, a substantial number of cases occur in youth athletics. In events that occur during sport, victims are struck by projectiles regarded as standard implements of the game. Sudden death is instantaneous and victims are most often found in ventricular fibrillation (VF). Overall survival is poor; however, successful resuscitation can be achieved with early defibrillation. Autopsy is notable for the absence of any significant cardiac or thoracic injury. Development of an experimental model has allowed for substantial insights into the underlying mechanisms of sudden death. In anesthetized juvenile swine, induction of VF is instantaneous following chest wall blows occurring during a vulnerable window before the T wave peak. Crucial variables including the velocity of impact, impact location, and hardness of the impact object have been identified. Rapid left ventricular (LV) pressure rise following chest impact likely results in activation of ion channels via mechano-electric coupling. The generation of inward current via mechano-sensitive ion channels likely results in augmentation of repolarization and nonuniform myocardial activation, and is the cause of premature ventricular depolarizations that are triggers of VF in CC. While softer-than-standard safety baseballs reduce the risk of CC, commercially available chest protectors are ineffective in preventing CC. The development of more effective chest protectors and more widespread use of automated external defibrillators at youth sporting events are needed.

P3-21: The effects of wall stress on the dynamics of ventricular fibrillation: A simulation study using a dynamic mechano-electric coupling model

P3-21: The effects of wall stress on the dynamics of ventricular fibrillation: A simulation study using a dynamic mechano-electric coupling model

Stretch-induced ventricular arrhythmias during acute ischemia and reperfusion.

Mechanical stretch has been demonstrated to have electrophysiological effects on cardiac muscle, including alteration of the probability of excitation, alteration of the action potential waveform, and stretch-induced arrhythmia (SIA). We demonstrate that regional ventricular ischemia due to coronary artery occlusion increases arrhythmogenic effects of transient diastolic stretch, whereas globally ischemic hearts showed no such increase. We tested our hypothesis that, during phase Ia ischemia, regionally ischemic hearts may be more susceptible to triggered arrhythmogenesis due to transient diastolic stretch. During the first 20 min of regional ischemia, the probability of eliciting a ventricular SIA (P(SIA)) by transient diastolic stretch increased significantly. However, after 30 min, P(SIA) decreased to a value comparable with baseline measurements, as expected during phase Ib, where most ventricular arrhythmias are of reentrant mechanisms. We also suggest that mechanoelectrical coupling may contribute to the nonreentrant mechanisms underlying reperfusion-induced arrhythmia. When coronary artery occlusion was relieved after 30 min of ischemia, we observed an increase in P(SIA) and the maintenance of this elevated level throughout 20 min of reperfusion. We conclude that mechanoelectrical coupling may underlie triggered arrhythmogenesis during phase 1a ischemia and reperfusion.

Mechanoelectrical feedback: role of beta-adrenergic receptor activation in mediating load-dependent shortening of ventricular action potential and refractoriness.

Augmented preload increases myocardial excitability by shortening action potential duration (APD). The mechanism governing this phenomenon is unknown. Because myocardial stretch increases intracellular cAMP, we hypothesized that load-dependent changes in myocardial excitability are mediated by beta-adrenergic stimulation of a cAMP-sensitive K(+) current. The effects of propranolol on load-induced changes in electrical excitability were studied in 7 isolated ejecting canine hearts. LV monophasic APD at 50% and 90% repolarization (MAPD(50) and MAPD(90)) and refractoriness were determined at low (9+/-3 mL) and high (39+/-4 mL) load before and after beta-adrenergic blockade. During control, the MAPD(50) decreased from 193+/-26 to 184+/-26 ms with increased load, as did the MAPD(90) (238+/-28 to 233+/-28 ms), P</=0.04. Similar changes were observed in ventricular refractoriness. Treatment with propranolol completely abolished these load-induced effects. Myocardial catecholamine depletion with reserpine in 2 hearts also abolished changes in MAPD and excitability in response to increased preload. Increases in ventricular load mediate a decrease in ventricular APD and refractoriness through activation of the beta-adrenergic receptor. An increase in a cAMP-mediated K(+) current, possibly the slowly activating delayed rectifier I(Ks), may account in part for this form of mechanoelectrical coupling.

The effects of tubulin-binding agents on stretch-induced ventricular arrhythmias

Stretch-activated ion channels have been identified as transducers of mechanoelectric coupling in the heart, where they may play a role in arrhythmogenesis. The role of the cytoskeleton in ion channel control has been a topic of recent study and the transmission of mechanical stresses to stretch-activated channels by cytoskeletal attachment has been hypothesized. We studied the arrhythmogenic effects of stretch in 16 Langendorff-perfused rabbit hearts in which we pharmacologically manipulated the microtubular network of the cardiac myocytes. Group 1 ( n=5) was treated with colchicine, which depolymerizes microtubules, and Group 2 ( n=6) was treated with taxol, which polymerizes microtubules. Stretch-induced arrhythmias were produced by transiently increasing the volume of a fluid-filled left ventricular balloon with a volume pump driven by a computer-controlled stepper motor. Electrical events were recorded by a contact electrode which provided high-fidelity recordings of monophasic action potentials and stretch-induced depolarizations. The probability of eliciting a stretch-induced arrhythmia increased (0.22±0.11 to 0.62±0.19, p=0.001) in hearts treated with taxol (5 μM), whereas hearts treated with colchicine (100 μM) showed no statistically significant change. We conclude that proliferation of microtubules increased the arrhythmogenic effect of transient left ventricle diastolic stretch. This result indicates a possible mode of arrhythmogenesis in chemotherapeutic patients and patients exhibiting uncompensated ventricular hypertrophy. The data would indicate that the cytoskeleton represents a possible target for antiarrhythmic therapies.

Microvillar Ion Channels: Cytoskeletal Modulation of Ion Fluxes

The recently presented theory of microvillar Ca2+signaling [Lange, K. (1999) J. Cell. Physiol.180, 19–35], combined with Manning's theory of “condensed counterions” in linear polyelectrolytes [Manning, G. S. (1969). J. Chem. Phys.51, 924–931] and the finding of cable-like ion conductance in actin filaments [Lin, E. C. & Cantiello, H. F. (1993). Biophys. J.65, 1371–1378], allows a systematic interpretation of the role of the actin cytoskeleton in ion channel regulation.Ion conduction through actin filament bundles of microvilli exhibits unique nonlinear transmission properties some of which closely resemble that of electronic semiconductors: (1) bundles of microfilaments display significant resistance to cation conduction and (2) this resistance is decreased by supply of additional energy either as thermal, mechanical or electromagnetic field energy. Other transmission properties, however, are unique for ionic conduction in polyelectrolytes. (1) Current pulses injected into the filaments were transformed into oscillating currents or even into several discrete charge pulses closely resembling that of single-channel recordings. Discontinuous transmission is due to the existence of counterion clouds along the fixed anionic charge centers of the polymer, each acting as an “ionic capacitor”. (2) The conductivity of linear polyelectrolytes strongly decreases with the charge number of the counterions; thus, Ca2+and Mg2+are effective modulator of charge transfer through linear polyelectrolytes. Field-dependent formation of divalent cation plugs on either side of the microvillar conduction line may generate the characteristic gating behavior of cation channels. (3) Mechanical movement of actin filament bundles, e.g. bending of hair cell microvilli, generates charge translocations along the filament structure (mechano-electrical coupling). (4) Energy of external fields, by inducing molecular dipoles within the polyelectrolyte matrix, can be transformed into mechanical movement of the system (electro-mechanical coupling). Because ionic transmission through linear polyelectrolytes is very slow compared with electronic conduction, only low-frequency electromagnetic fields can interact with the condensed counterion systems of linear polyelectrolytes.The delineated characteristics of microvillar ion conduction are strongly supported by the phenomenon of electro-mechanical coupling (reverse transduction) in microvilli of the audioreceptor (hair) cells and the recently reported dynamics of Ca2+signaling in microvilli of audio- and photoreceptor cells. Due to the cell-specific expression of different types and combinations of ion channels and transporters in the microvillar tip membrane of differentiated cells, the functional properties of this cell surface organelle are highly variable serving a multitude of different cellular functions including receptor-mediated effects such as Ca2+signaling, regulation of glucose and amino acid transport, as well as modulation of membrane potential. Even mechanical channel activation involved in cell volume regulation can be deduced from the systematic properties of the microvillar channel concept. In addition, the specific ion conduction properties of microfilaments combined with their proposed role in Ca2+signaling make microvilli the most likely cellular site for the interaction with external electric and magnetic fields.

Mechanoelectric coupling as a fundamental surrogate in ventricular arrhythmia?

Mechanoelectric coupling as a fundamental surrogate in ventricular arrhythmia?

On the mechanoelectrical coupling in the cochlear outer hair cell.

Outer hair cell electromotility, a manifestation of the interconnection between the mechanical and electrical processes occurring in outer hair cells, is believed to be an important contribution to the active cochlea. Two modes of mechanoelectrical coupling in the outer hair cell wall are studied: the potential shift caused by mechanical loading under the wall charge preservation conditions and the current (transferred charge) caused by mechanical loading under the voltage-clamp conditions. By using the previously reported elastic moduli of the wall and components of the active force, the potential shift under the charge preservation conditions is derived. This shift is expressed in terms of the wall strains and the active force derivatives with respect to the wall potential. The magnitudes of the potential shift corresponding to the conditions of cell inflation, axial stretch (compression), and the micropipet aspiration are estimated. In the last case, the distribution of the potential shift along the cell wall is also demonstrated. The potential shift can reach -20(-)-40 mV under the conditions of the micropipet aspiration or cell inflation. Such shift is much smaller under the condition of cell stretch (compression). The current and the charge transfer caused by the cell stretch under the voltage-clamp conditions is analyzed, and shows good agreement of predictions with experimental data.

Stretch-induced changes in arrhythmogenesis and excitability in experimentally based heart cell models.

Mechanoelectric coupling in the heart is well documented and has been suggested as a cause of arrhythmia. One hypothesized mechanism for the stretch sensitivity of cardiac muscle is the presence of stretch-activated channels (SACs). This study uses modeling to explore the influence of SACs on cardiac resting potential, excitation threshold, and action potential in the context of arrhythmia. We added a putative SAC, modeled as a linear, time-independent conductance with reversal potential of -20 or -50 mV, to guinea pig and frog ventricular membrane models. Increased stretch conductance led to resting potential depolarization, a decreased excitation threshold, altered action potential duration, and, under certain conditions, early afterdepolarizations. We conclude that stretch increases cellular excitability, making the heart prone to ectopic activity. Regional effects of stretch on action potential duration can vary and are influenced by factors such as the SAC reversal potential, ionic conditions, and baseline currents, all of which may lead to an increased dispersion of refractoriness throughout the heart and therefore an increased risk of arrhythmia.

Membrane stretch evoked by cell swelling increases contractile activity in vascular smooth muscle through dihydropyridine-sensitive pathways.

Effects of the dihydropyridine calcium antagonist felodipine and of calcium reduction were studied on osmotically induced contractile responses in the vascular smooth muscle of the rat isolated portal vein. Previous studies have shown that changes in osmolarity that cause cell swelling are accompanied by increased contractile activity in this smooth muscle (Johansson & Jonsson 1968). A transient enhancement of the contractile activity developed in the portal vein on return to standard Krebs solution after exposure to 60 mM urea. This osmotic response was dependent on extracellular Ca2+ (abolished in Ca2+ free solution +0.1 mM EGTA) and was reduced in proportion to the decrease in spontaneous phasic contractile activity when Ca2+ was lowered from the standard 2.5 mM concentration. Felodipine, 3 nM, reduced the spontaneous activity to approximately 50% but showed an even more pronounced inhibitory effect on the osmotic responses which were reduced to less than 20% of control. Other calcium antagonists such as verapamil, 60 nM and diltiazem, 300 nM, were also more effective in inhibiting the osmotic responses than the spontaneous activity. In contrast, the K+ channel opener, pinacidil, 100-200 nM, reduced the spontaneous activity to 50% but had only minor inhibitory effect on the osmotic responses, about 75% still persisting. It is suggested that stretch of the cell membrane in response to variations in osmolarity induces contractile activity in vascular smooth muscle by mechano-electrical coupling involving dihydropyridine-sensitive pathways.