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Subchronic intoxication was induced in outbred male rats by repeated intraperitoneal injections with lead oxide (PbO) and/or cadmium oxide (CdO) nanoparticles (NPs) 3 times a week during 6 weeks for the purpose of examining its effects on the contractile characteristics of isolated right ventricle trabeculae and papillary muscles in isometric and afterload contractions. Isolated and combined intoxication with these NPs was observed to reduce the mechanical work produced by both types of myocardial preparation. Using the in vitro motility assay, we showed that the sliding velocity of regulated thin filaments drops under both isolated and combined intoxication with CdO– NP and PbO–NP. These results correlate with a shift in the expression of myosin heavy chain (MHC) isoforms towards slowly cycling β–MHC. The type of CdO–NP + PbO–NP combined cardiotoxicity depends on the effect of the toxic impact, the extent of this effect, the ratio of toxicant doses, and the degree of stretching of cardiomyocytes and muscle type studied. Some indices of combined Pb–NP and CdO–NP cardiotoxicity and general toxicity (genotoxicity included) became fully or partly normalized if intoxication developed against background administration of a bioprotective complex. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. The work was carried out partly within the framework of the IIF UrB RAS themes No AAA?A18?118020590031?8 and AAAA?A18?118020590135?3. This work was performed using the equipment of the Shared Research Center of Scientific Equipment SRC IIP UrB RAS.

The slow force response (SFR) to stretch is an important adaptive mechanism of the heart. The SFR may result in ~ 20–30% extra force but it is substantially attenuated in heart failure. We investigated the relation of SFR magnitude with Ca 2+ transient decay in healthy (CONT) and monocrotaline-treated rats with heart failure (MCT). Right ventricular trabeculae were stretched from 85 to 95% of optimal length and held stretched for 10 min at 30 °C and 1 Hz. Isometric twitches and Ca 2+ transients were collected on 2, 4, 6, 8, 10 min after stretch. The changes in peak tension and Ca 2+ transient decay characteristics during SFR were evaluated as a percentage of the value measured immediately after stretch. The amount of Ca 2+ utilized by TnC was indirectly evaluated using the methods of Ca 2+ transient “bump” and “difference curve.” The muscles of CONT rats produced positive SFR and they showed prominent functional relation between SFR magnitude and the magnitude (amplitude, integral intensity) of Ca 2+ transient “bump” and “difference curve.” The myocardium of MCT rats showed negative SFR to stretch (force decreased in time) which was not correlated well with the characteristics of Ca 2+ transient decay, evaluated by the methods of “bump” and “difference curve.” We conclude that the intracellular mechanisms of Ca 2+ balancing during stretch-induced slow adaptation of myocardial contractility are disrupted in failing rat myocardium. The potential significance of our findings is that the deficiency of slow force response in diseased myocardium may be diminished under augmented kinetics of Ca–TnC interaction. © 2018, The Physiological Society of Japan and Springer Japan KK, part of Springer Nature.

The apelin peptide is described as one of the most potent inotropic agents, produced endogenously in a wide range of cells, including cardiomyocytes. Despite positive effects on cardiac contractility in multicellular preparations, as well as indications of cardio-protective actions in several diseases, its effects and mechanisms of action at the cellular level are incompletely understood. Here, we report apelin effects on dynamic mechanical characteristics of single ventricular cardiomyocytes, isolated from mouse models (control, apelin-deficient [Apelin-KO], apelin-receptor KO mouse [APJ-KO]), and rat. Dynamic changes in maximal velocity of cell shortening and relaxation were monitored. In addition, more traditional indicators of inotropic effects, such as maximum shortening (in mechanically unloaded cells) or peak force development (in auxotonic contracting cells, preloaded using the carbon fibre technique) were studied. The key finding is that, using Apelin-KO cardiomyocytes exposed to different preloads with the 2-carbon fibre technique, we observe a lowering of the slope of the end-diastolic stress-length relation in response to 10 nM apelin, an effect that is preload-dependent. This suggests a positive lusitropic effect of apelin, which could explain earlier counter-intuitive findings on an apelin-induced increase in contractility occurring without matching rise in oxygen consumption.

Preload-induced changes of active tension and [Ca2+]i are “dissociated” in mammalian myocardium. This study aimed to describe the distinct effects of preload at low and physiological [Ca2+]o. Rat RV papillary muscles were studied in isometric conditions at 25‡C and 0.33 Hz at 1 mM (hypo-Ca group) and 2.5 mM [Ca2+]o (normal-Ca group). [Ca2+]i was monitored with fura-2/AM. Increase of preload caused a rise of active tension in hypo-Ca and normal-Ca groups whereas peak fluorescence rose significantly only at low [Ca2+]o. End-diastolic tension, end-diastolic level of fluorescence, time-to-peak tension, but not time-to-peak of Ca2+ transient, progressively increased with preload. Mechanical relaxation decelerated with preload while Ca2+ transient decay time decreased in the initial phase and increased in the late phase, resulting in a prominent “bump” configuration. The “bump” was assessed as a ratio of its area to the fluorescence trace area. It was a new finding that the preload-induced rise of this ratio was twice as large in hypo-Ca. Our results indicate that preload-induced changes in active tension and [Ca2+]i are “dissociated” in rat myocardium, with relatively higher expression at low [Ca2+]o. Ca-dependence of Ca-TnC association/dissociation kinetics is thought to be a main contributor to these preload-induced effects.

Introduction: Information on the force-length relation of intact myocytes from different regions of the heart is scarce. We therefore studied myocytes, isolated from apical and basal areas of guinea pig left and right ventricles (cell numbers: LVA 22, LVB 29, RVA 11, RVB 12). Methods: Force-length relations were measured by attaching carbon fibers to myocytes, allowing application of diastolic stretch while measuring passive and active force.1 Cells were kept at 36±1°C and paced at 2 Hz. Recorded forces were normalized to cell cross-sectional area and used to construct end-diastolic, end-systolic and active tension-length relations (EDTL, ESTL and ATL=ESTL-EDTL; respectively). In addition, the ratio of the slopes of ESTL and EDTL was used as a cross-section independent factor to characterise the Frank-Starling Gain (FSG) in individual cells. Results: For all tissue regions ESTL, EDTL and, hence, ATL, are linear over the range of end-diastolic sarcomere lengths studied (1.88-2.15 μm). Plotting the slope values of ATL vs. EDTL for all cells shows a positive correlation (slope 1.29, R2=0.24, 74 cells). In addition, FSG is larger than one for all cells studied: RVB 3.91±0.54), RVA (2.84±0.30), LVB (2.77±0.17), and LVA (3.20±0.24). Conclusions: Using the carbon fiber technique, it is possible to probe length-dependence of passive and active tension at the single cell level, without the interference of extracellular structures. The Frank-Starling Gain varies between the different regions of the heart and the positive correlation between ATL and EDTL confirms that in intact cells passive force bearing structures (such as titin) are likely to play a role in modulating length dependent activation.[1] Iribe et al, Force-length relations in isolated intact cardiomyocytes subjected to dynamic changes in mechanical load. AJP 2007/292:1487-1497.