Microtubules are a major component of the cardiac myocyte cytoskeleton. Interventions that alter it may influence cardiac mechanical and electrical activity by disrupting the trafficking of proteins ...to and from the surface membrane by molecular motors such as dynein, which use microtubules as tracks to step along. Free tubulin dimers may transfer GTP to the α-subunits of G-proteins, thus an increase in free tubulin could increase the activity of G-proteins; evidence for and against such a role exists. There is more general agreement that microtubules act as compression-resisting structures within myocytes, influencing visco-elasticity of myocytes and increasing resistance to shortening when proliferated and resisting deformation from longitudinal shear stress. In response to pressure overload, there can be post-translational modifications resulting in more stable microtubules and an increase in microtubule density. This is accompanied by contractile dysfunction of myocytes which can be reversed by microtubule disruption. There are reports of mechanically induced changes in electrical activity that are dependent upon microtubules, but at present, a consensus is lacking on whether disruption or proliferation would be beneficial in the prevention of arrhythmias. Microtubules certainly play a role in the response of cardiac myocytes to mechanical stimulation, the exact nature and significance of this role is still to be fully determined.
The Frank-Starling law of the heart applies to all classes of vertebrates. It describes how stretch of cardiac muscle, up to an optimum length, increases contractility thereby linking cardiac ...ejection to cardiac filling. The cellular mechanisms underlying the Frank-Starling response include an increase in myofilament sensitivity for Ca2+, decreased myofilament lattice spacing and increased thin filament cooperativity. Stretching of mammalian, amphibian and fish cardiac myocytes reveal that the functional peak of the sarcomere length (SL)-tension relationship occurs at longer SL in the non-mammalian classes. These findings correlate with in vivo cardiac function as non-mammalian vertebrates, such as fish, vary stroke volume to a relatively larger extent than mammals. Thus, it seems the length-dependent properties of individual myocytes are modified to accommodate differences in organ function, and the high extensibility of certain hearts is matched by the extensibility of their myocytes. Reasons for the differences between classes are still to be elucidated, however, the structure of mammalian ventricular myocytes, with larger widths and higher levels of passive stiffness than those from other vertebrate classes may be implicated.
Background Many ion channels are preferentially located in caveolae where compartmentalisation/scaffolding with signal transduction components regulates their activity. Channels that are ...mechanosensitive may be additionally dependent on caveolar control of the mechanical state of the membrane. Here we test which mechanism underlies caveolar-regulation of the mechanosensitive ICl,swell channel in the adult cardiac myocyte. Methodology/Principal Findings Rat ventricular myocytes were exposed to solution of 0.02 tonicity (T; until lysis), 0.64T for 10–15 min (swelling), and/or methyl-β-cyclodextrin (MBCD; to disrupt caveolae). MBCD and 0.64T swelling reduced the number of caveolae visualised by electron microscopy by 75 and 50% respectively. MBCD stimulated translocation of caveolin 3 from caveolae-enriched buoyant membrane fractions, but both caveolin 1 and 3 remained in buoyant fractions after swelling. ICl,swell inhibition in control cells decreased time to half-maximal volume (t0.5,vol; 0.64T), consistent with a role for ICl,swell in volume regulation. MBCD-treated cells showed reduced time to lysis (0.02T) and t0.5,vol (0.64T) compared with controls. The negative inotropic response to swelling (an index of ICl,swell activation) was enhanced by MBCD. Conclusions/Significance These data show that disrupting caveolae removes essential membrane reserves, which speeds swelling in hyposmotic conditions, and thereby promotes activation of ICl,swell. They illustrate a general principle whereby caveolae as a membrane reserve limit increases in membrane tension during stretch/swelling thereby restricting mechanosensitive channel activation.
Mechanosensitivity is a property common to many cell types. Because channels gated by mechanical stimuli (mechanosensitive channels, MSCs) are implicated in many normal and pathological cellular ...responses, they present a valid target for therapeutic agents. However the process of mechanotranduction, the structure, function and pharmacology of eukaryotic MSCs are not well understood and matching experimental and in vivo stimuli is difficult. With respect to the pharmacology of these channels, a further complication arises because agents that modulate the activity of MSCs may not even bind to the channel itself, but may cause their effects by changing the properties of the tension-sensing lipid bilayer and/or cytoskeleton. MSCs in the myocardium are discussed in the context of their probable role in the generation of stretch-activated arrhythmias. The actions of the three most prominent agents used to study MSCs in the heart, the lanthanide gadolinium, the aminoglycosidic antibiotic streptomycin, and a peptide toxin isolated from tarantula venom, GsMTx-4, are compared. While all three can prevent mechanically-induced cardiac arrhythmias in experimental situations, only GsMTx-4 seems to have the potential as a novel therapeutic agent for the targeting of arrhythmias provoked by MSCs.
White discusses tapering the use of antidpressants. AD withdrawal has a long history in scientific literature, with many papers describing its occurrence and symptomatology. Most recently, Cosci and ...Chouinard provided a very detailed description of the myriad of symptoms people experience. Symptoms fall into many categories including affective, cognitive, gastrointestinal, neuromuscular, sleep, sexual, and even psychotic and behavioral. This level of complexity can often result in misdiagnosis. In addition, without careful management, protracted withdrawal can result in extended periods of suffering over many months and even years, and symptoms that are often untreatable. Recent research concluded that over half of people coming off ADs will suffer withdrawal symptoms, of which one in two cases will be severe. This suggests that AD withdrawal is likely to be something that GPs frequently see in their practice.
Purkinje fibres (PFs) play an important role in some ventricular arrhythmias and acute ventricular stretch can evoke mechanically-induced arrhythmias. We tested whether Purkinje fibres, play a role ...in these arrhythmias. Pseudo-ECGs were recorded in isolated, Langendorff-perfused, rabbit hearts in which the left ventricular endocardial surface was also irrigated with Tyrode,
an indwelling catheter placed in the left ventricular lumen. The number and period of ectopic activations was measured during left ventricular lumen inflation
an indwelling fluid-filled balloon (500 μL added over 2 s and maintained for 15 s in total). Mechanically-induced arrhythmias occurred in 70% of balloon inflations: they were maximal in the first 5 s and ceased within 15 s. Brief, (10 s) irrigation of the left ventricular lumen with Lugol solution (IK/I
),
the indwelling catheter, reduced inflation-induced ectopics by 98% (
< 0.05). Ablation of endocardial PFs by Lugol was confirmed by Triphenyltetrazolium Chloride staining. Optical mapping revealed the left ventricular epicardial activation patterns of ectopics could have PF-mediated and focal sources.
modelling predicted ectopic sources originating in the endocardial region propagate to and through the Purkinje fibres network. Acute distention-induced ectopics are multi-focal, their attenuation by Lugol, their activation patterns and
modelling indicate a participation of Purkinje fibres in these arrhythmias.
Pulmonary arterial hypertension (PAH) results in hypertrophic remodeling of the right ventricle (RV) to overcome increased pulmonary pressure. This increases the O
consumption of the myocardium, and ...without a concomitant increase in energy generation, a mismatch with demand may occur. Eventually, RV function can no longer be sustained, and RV failure occurs. Beta-adrenergic blockers (BB) are thought to improve survival in left heart failure, in part by reducing energy expenditure and hypertrophy, however they are not currently a therapy for PAH. The monocrotaline (MCT) rat model of PAH was used to investigate the consequence of RV failure on myocardial oxygenation and mitochondrial function. A second group of MCT rats was treated daily with the beta-1 blocker metoprolol (MCT + BB). Histology confirmed reduced capillary density and increased capillary supply area without indications of capillary rarefaction in MCT rats. A computer model of O
flux was applied to the experimentally recorded capillary locations and predicted a reduction in mean tissue P
in MCT rats. The fraction of hypoxic tissue (defined as P
< 0.5 mmHg) was reduced following beta-1 blocker (BB) treatment. The functionality of the creatine kinase (CK) energy shuttle was measured in permeabilized RV myocytes by sequential ADP titrations in the presence and absence of creatine. Creatine significantly decreased the K
in cells from saline-injected control (CON) rats, but not MCT rats. The difference in K
with or without creatine was not different in MCT + BB cells compared to CON or MCT cells. Improved myocardial energetics could contribute to improved survival of PAH with chronic BB treatment.
In American political fantasy, the Founding Fathers loom large, at once historical and mythical figures. InThe Traumatic Colonel, Michael J. Drexler and Ed White examine the Founders as imaginative ...fictions, characters in the specifically literary sense, whose significance emerged from narrative elements clustered around them. From the revolutionary era through the 1790s, the Founders took shape as a significant cultural system for thinking about politics, race, and sexuality. Yet after 1800, amid the pressures of the Louisiana Purchase and the Haitian Revolution, this system could no longer accommodate the deep anxieties about the United States as a slave nation.Drexler and White assert that the most emblematic of the political tensions of the time is the figure of Aaron Burr, whose rise and fall were detailed in the literature of his time: his electoral tie with Thomas Jefferson in 1800, the accusations of seduction, the notorious duel with Alexander Hamilton, his machinations as the schemer of a breakaway empire, and his spectacular treason trial. The authors venture a psychoanalytically-informed exploration of post-revolutionary America to suggest that the figure of Burr was fundamentally a displaced fantasy for addressing the Haitian Revolution. Drexler and White expose how the historical and literary fictions of the nation's founding served to repress the larger issue of the slave system and uncover the Burr myth as the crux of that repression. Exploring early American novels, such as the works of Charles Brockden Brown and Tabitha Gilman Tenney, as well as the pamphlets, polemics, tracts, and biographies of the early republican period, the authors speculate that this flourishing of political writing illuminates the notorious gap in U.S. literary history between 1800 and 1820.
Rapid release of calcium from internal stores via ryanodine receptors (RyRs) is one of the fastest types of cytoplasmic second messenger signalling in excitable cells. In the heart, rapid summation ...of the elementary events of calcium release, 'calcium sparks', determine the contraction of the myocardium. We adapted a correlative super-resolution microscopy protocol to correlate sub-plasmalemmal spontaneous calcium sparks in rat right ventricular myocytes with the local nanoscale RyR2 positions. This revealed a steep relationship between the integral of a calcium spark and the sum of the local RyR2s. Segmentation of recurring spark sites showed evidence of repeated and triggered saltatory activation of multiple local RyR2 clusters. In myocytes taken from failing right ventricles, RyR2 clusters themselves showed a dissipated morphology and fragmented (smaller) clusters. They also featured greater heterogeneity in both the spark properties and the relationship between the integral of the calcium spark and the local ensemble of RyR2s. While fragmented (smaller) RyR2 clusters were rarely observed directly underlying the larger sparks or the recurring spark sites, local interrogation of the channel-to-channel distances confirmed a clear link between the positions of each calcium spark and the tight, non-random clustering of the local RyR2 in both healthy and failing ventricles.
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