Reduction In Force Of Contraction Research Articles

Exposure to nanoplastics impairs collective contractility of neonatal cardiomyocytes under electrical synchronization

Nanoplastics are global pollutants that have been increasingly released into the environment following the degradation process of industrial and consumer products. These tiny particles have been reported to adversely affect various organs in the body, including the heart. Since it is probable that the less-developed hearts of newborn offspring are more vulnerable to nanoplastic insult during the infant feeding compared with mature hearts of adults, the acute effects of nanoplastics on the collective contractility of neonatal cardiomyocytes are to be elucidated. Here, we traced the aggregation of nanoplastics on the cell membrane and their internalization into the cytosol of neonatal rat ventricular myocytes (NRVMs) for 60 min in the presence of electrical pulses to synchronize the cardiac contraction in vitro. The time-coursed linkage of collective contraction forces, intracellular Ca2+ concentrations, mitochondrial membrane potentials, extracellular field potentials, and reactive oxygen species levels enabled us to build up the sequence of the cellular events associated with the detrimental effects of nanoplastics with positive surface charges on the immature cardiomyocytes. A significant decrease in intracellular Ca2+ levels and electrophysiological activities of NRVMs resulted in the reduction of contraction forces in the early phase (0–15 min). The further reduction of contraction force in the late phase (30–60 min) was attributed to remarkable decreases in mitochondrial membrane potentials and cellular metabolism. Our multifaceted assessments on the effect of positively surface charged nanoplastics on NRVM may offer better understanding of substantial risks of ever-increasing nanoplastic pollution in the hearts of human infants or adults.

Chloroform is a potent activator of cardiac and neuronal Kir3 channels.

Chloroform has been used over decades in anesthesia before it was replaced by other volatile anesthetics like halothane or sevoflurane. Some of the reasons were inadmissible side effects of chloroform like bradycardia or neural illness. In the present study, we identified members of the G protein-activated inwardly rectifying potassium channel family (Kir3) expressed in Xenopus oocytes as potential common molecular targets for both the neural and cardiac effects of chloroform. Millimolar concentration currents representing a 1:10000 dilution of commercially available chloroform were used in laboratories that augment neuronal Kir3.1/3.2 currents as well as cardiac Kir3.1/3.4. This effect was selective and only observed in currents from Kir3 subunits but not in currents from Kir2 subunits. Augmentation of atrial Kir3.1/3.4 currents leads to an effective drop of the heart rate and a reduction in contraction force in isolated mouse atria.

Mimicking Cardiac Fibrosis in a Dish: Fibroblast Density Rather than Collagen Density Weakens Cardiomyocyte Function

Cardiac fibrosis is one of the most devastating effects of cardiac disease. Current in vitro models of cardiac fibrosis do not sufficiently mimic the complex in vivo environment of the cardiomyocyte. We determined the local composition and mechanical properties of the myocardium in established mouse models of genetic and acquired fibrosis and tested the effect of myocardial composition on cardiomyocyte contractility in vitro by systematically manipulating the number of fibroblasts and collagen concentration in a platform of engineered cardiac microtissues. The in vitro results showed that while increasing collagen content had little effect on microtissue contraction, increasing fibroblast density caused a significant reduction in contraction force. In addition, the beating frequency dropped significantly in tissues consisting of 50% cardiac fibroblasts or higher. Despite apparent dissimilarities between native and in vitro fibrosis, the latter allows for the independent analysis of local determinants of fibrosis, which is not possible in vivo.

Cardiac remodeling in rats with renal failure shows interventricular differences

Chronic renal failure (CRF) is associated with an increased incidence of cardiovascular diseases. Intensive research revealed a number of alterations in the heart during CRF; however, possible interventricular differences in CRF-induced cardiac remodeling have so far not been addressed. CRF was induced by two-stage surgical 5/6 nephrectomy (NX) in male Wistar rats. Cellular hypertrophy was quantified using immunohistological morphometric analysis. Contraction force and membrane potential were recorded in left and right ventricle papillary muscles with an isometric force transducer and high-resistance glass microelectrodes. Hypertrophy was present in the left ventricle (LV) of NX animals, but not in the right ventricle (RV) of NX animals, as documented by both ventricle/body weight ratios and cellular morphometric analysis of the cross-sectional area of myocytes. The contraction force was reduced in the LV of NX animals but increased in the RV of NX animals compared with sham-operated rats. Rest potentiation of contraction force was relatively more pronounced in the LV of NX rats. Fifty percent substitution of extracellular sodium with lithium significantly increased the contraction force only in the LV of NX animals. Action potential durations were shortened in both ventricles of CRF animals. Cardiac structural and contractile remodeling in CRF shows significant interventricular differences. CRF induces hypertrophy of the LV but not of the RV. LV hypertrophy was associated with a reduction of contraction force, whereas in the RV, the contraction force was enhanced. Partial recovery of contractile function of the LV by rest potentiation or lithium substitution indicates a role of the Na(+)/Ca(2+) exchanger in this phenomenon.

Basic Science of Cardiac Resynchronization Therapy

Electromechanical dyssynchrony can markedly worsen heart failure (HF) morbidity and mortality, independent of traditional risk factors.1–4 Depending on the metric used, current estimates of the prevalence of dyssynchrony vary from 25–30% in patients with HF (based on QRS widening) up to 60%, based on tissue Doppler or MRI measures of dyssynchronous contraction of the left ventricle (LV).5,6 Cardiac resynchronization therapy (CRT) or biventricular pacing has emerged as a promising option to treat patients with HF and dyssynchronous contraction.7–9 The past few decades have seen the rise of pharmacotherapy, primarily through agents that antagonize the effect of excessive concentrations of circulating neurohormones, yet, HF-related morbidity and mortality remain high.3–6 Biventricular stimulation has been demonstrated to improve contractile performance in patients with mechanical dyssynchrony acutely and chronically while also prolonging long-term survival—something not yet achieved by drug therapy.10 Although the clinical and mechanical effectiveness of CRT are well described, 30% of patients do not benefit from CRT and clinical criteria to identify CRT nonresponders remain elusive8,11,12 Currently, the most widely used predictor of reverse remodeling is the presence of marked mechanical dyssynchrony before CRT, as indexed by the width of the QRS.13 Mechanical dyssynchrony seems important, yet imaging-based measures have not predicted response well14 and even improvement in dyssynchrony after initiation of CRT only weakly predicts chronic response.15 Limited understanding of the molecular mechanisms underlying reverse cardiac remodeling induced by CRT has hampered the selection of potential responders. In this review, we focus on the electrophysiological aspects and molecular networks underlying the benefits of CRT. We will review how CRT homogenizes regional differences in stress kinase signaling and electric remodeling and then review its global effect on myocyte function and its …

Contributions of Neural Tone to In Vivo Passive Muscle–Tendon Unit Biomechanical Properties in a Rat Rotator Cuff Animal Model

Passive viscoelastic properties of muscle-tendon units are key determinants of intra- and post-operative success. Atrophied, retracted, and stiff muscle-tendon units are technically challenging to manipulate and perform poorly after surgical repair. This study employs botulinum neurotoxin A (BoNT-A)-mediated inhibition of presynaptic acetylcholine release to examine in vivo neural contributions to soft-tissue biomechanical properties. In vivo load-relaxation and active muscle contractile force testing protocols were performed in the rat rotator cuff model. The passive properties were assessed using linear regression analysis and Fung's quasi-linear viscoelastic (QLV) model. BoNT-A injected muscle--tendon units had a significant reduction in force of contraction (p = 0.001). When compared to saline injected controls, the BoNT-A significantly decreased parameter 'A' of the QLV model, which represents the linear elastic response (p = 0.032). The viscous properties in the BoNT-A treatment group were not significantly different from saline injected controls, as determined by comparison of QLV model parameters 'C,' 'τ(1),' and 'τ(2).' In conclusion, neural tone contributes significantly to muscle-tendon unit passive biomechanical properties. Pre-surgical treatment with BoNT-A may improve the rehabilitation of muscle by altering its passive elastic properties. Accordingly, pharmacological modulation of skeletal muscle stiffness with BoNT-A increases flexibility, potentially improving function. Chemical denervation with BoNT-A may also improve the manipulation of stiff and difficult to mobilize muscles during surgical procedures.

Anticholinergic effect of 2-aminopyridine and its sulfonylcarbamide derivatives on electromechanical activity in guinea pig atrium

The aim of the study was to investigate the effect of class IA antiarrhythmic drug procainamide and its new derivatives PA20, PA23, PA28 and PA53 on carbachol-induced action potential duration and contraction force in guinea pig atrial muscles. Experiments were carried out using standard method of registration of myocardium electromechanical activity. Under control conditions (perfusion of atrial strips with Tyrode solution), mean action potential duration measured at 90% (AP90) and 50% (AP50) of repolarization were 92.5+/-4.5 ms and 44.4+/-2.9 ms (n=18), respectively, and contraction force was of 2.7+/-0.5 mN (n=12). Carbachol (10(-6) M), an agonist of muscarinic acetylcholine receptor and activator of K(Ach) channels, markedly decreased AP90 to 32.4+/-2.4%, AP50 - to 25.4+/-2.2% (n=18) (p<0.001) and contraction force - to 24.2+/-5.8% (n=16) (p<0.05), vs. control. Procainamide and its new sulfonylcarbamide derivatives PA20, PA23, PA28 (10(-5)-3x10(-3) M), and PA53 (10(-5)-10(-3) M) reversed the carbachol-induced action potential duration shortening at different extent: procainamide derivative PA20 (N-cyclohexylsulfonylcarbamide fragment is linked up to benzene ring) had the most potent anticholinergic effect on action potential duration and contraction force of guinea pig atrial muscles. N-ethylsulfonylcarbamide fragment in PA23 or permanent positive charge of aliphatic nitrogen in PA28 had a weaker anticholinergic effect (similar to procainamide action) on action potential duration and contraction force than PA20. The weakest anticholinergic effect was induced by procainamide derivative PA53 with isosteric form of sulfonylcarbamide.

Atrial, B-type and C-type natriuretic peptides enhance the sensitivity of bradycardic responses to the cardiogenic chemoreflex (von Bezold-Jarisch reflex) in sheep

Certain forms of hypertrophic cardiomyopathy (HCM), are associated with increased activity of the Gq/phospholipase C signaling pathway. To determine the role of Gq signaling in cardiomyopathy at specific times during development, we used the tetracycline transactivator system to conditionally express a mutationally activated form of GOeq (Gq*) in the hearts of transgenic mice. Gq* expression at high levels (3-fold more than wild-type G%) during embryogenesis caused embryonic lethality. Gq* mice survived embryogenesis when Gq* expression was suppressed during that time period. Adult mice (8 weeks old) survived the induction of Gq* expression over a 12-week period. However, adult mice expressing Gq* for over 16 weeks developed marked fibrosis and histopathology consistent with HCM. Force measurements in isolated cardiac muscle strips from mice expressing Gq* for 8 weeks showed a marked reduction in the maximal force of contraction and slowing of the rates of contraction and relaxation. Induction of Gq* expression in adult mice caused decreased basal heart rate and increased heart rate variability. MAP and Jun kinase studies demonstrated increased activity of specific kinase cascades that are thought to be downstream of the Gq signaling pathway. DNA-array analysis of heart tissue from mice with Gq*-induced HCM allowed for identification of over one hundred genes regulated in a distinct pattern from our recently described. Gcinduced model of dilated cardiomyopathy. Functional and genetic characterization of this inducible Gq* model of cardiomyopathy should provide new insights into the genetic cascade leading to HCM and should lead to the identification of new diagnostic markers and potential therapeutic targets.

The functional and morphological damage of ischemic reperfused skeletal muscle.

Skeletal muscle is frequently damaged by ischemia-reperfusion both caused by direct injury and also by surgery. The purpose of the present experiments was to examine how the different types of skeletal muscles (fast and slow) react functionally and morphologically after 1 and 2 h of ischemia followed by different periods of reperfusion. The fast-twitch (musculus extensor digitorum longus, EDL) and the slow-twitch (musculus soleus, SOL) muscle of Wistar rats were prepared. They were stimulated in vivo, either directly or indirectly at different reperfusion times following tourniquet ischemia, and the contraction force of the muscles was recorded. The morphological changes were examined by light microscopy. At early reperfusion times, the contraction force of the EDL muscle was reduced by 40 and 90% after 1 and 2 h of ischemia, respectively. The contraction force was about 50% at the end of a 2-week reperfusion period in the 1-hour ischemia group and it increased significantly (from 5 to 38%) during the second week if the ischemia lasted for 2 h. Reduction of contraction force in the SOL muscle was over 50 and 90% following 1 and 2 h of ischemia, respectively, and it started to improve from the 2nd week. Morphological changes of the two types of muscle were identical. At early reperfusion times granulocytes were seen in the blood vessels adhering to the endothelium. 24 h later neutrophil granulocytes migrated into the endomysium and thereafter into the perimysium. One week after 1 h of ischemia both muscles showed normal histology. However, the structural regeneration process only started at the end of the 1st week of reperfusion after 2 h of the ischemic damage. The following conclusions can be drawn. (1) There is functional morphological evidence of ischemic and reperfusion injury in both muscles after 24 h and also after 1 week of reperfusion. (2) Functionally, the two types of muscles regenerate differently, i.e. the SOL starts to regenerate earlier than the EDL. (3) Morphologically the two types of muscle show the same reactions. An increase in the time of ischemia from 1 to 2 h delays the regeneration processes.

Studies on electrical and mechanical activity in hypoxic papillary muscles of the guinea-pig.

The hypoxia-induced changes in transmembrane potentials and in force of contraction of isolated papillary muscles of the guinea-pig were studied. With different glucose concentrations in the hypoxic medium both the extent and the time course of the reduction in force of contraction and action potential duration could be modified. A time lag of 10 minutes was observed in the onset of action potential shortening. The membrane potential decreased only at advanced stages of hypoxia. Lack of glucose was tolerated for a considerable longer period of time when the preparations were mainly quiescent during hypoxia, although membrane depolarization could not be prevented. Memembrane depolarization was basent only if the mucles were completely unloaded when exposed to hypoxia. The dissociation of events during hypoxia is interpredted as evidence for compartmentalization of energy supply within the cells.

Influence of Glucose on the Transmembrane Action Potential of Anoxic Papillary Muscle

The response of the cat papillary muscle to anoxia has been found to alter depending on the glucose concentration in the medium. At a glucose concentration of 5 mM anoxia caused a marked reduction in force of contraction and action potential duration within 20 minutes. At a glucose concentration of 50 mM anoxia induced similar changes in the force of contraction but little or no change in action potential duration. Elevation of glucose concentration during an anoxic interval reversed the anoxia-induced changes in action potential but had little effect on force of contraction. This effect of glucose could be partially duplicated by xylose and 2-deoxyglucose and in addition, 2-deoxyglucose has been found to prevent the effect of subsequently added glucose. These sugars appear to be transported by a system responsible for glucose transport but are not metabolized to any extent. It would appear therefore that transport of glucose is in some way related to transport of potassium as increased potassium permeability is thought by many to be responsible for anoxia-induced changes in action potential duration.