On the Mechanisms of the Cardiotoxic Effect of Lead Oxide Nanoparticles.

Lead compounds are one of the most common pollutants of the workplace air and the environment. In the occupational setting, the sources of their emission, including in nanoscale form, are various technological processes associated with lead smelting and handling of non-ferrous metals and their alloys, the production of copper and batteries. Both lead poisoning and lead exposure without obvious signs of poisoning have a detrimental effect on the cardiovascular system. The purpose of this research was to investigate the mechanisms of the cardiotoxic effect of lead oxide nanoparticles (PbO NPs). The toxicological experiment involved male albino rats subchronically exposed to PbO NPs (49.6 ± 16.0 nm in size) instilled intraperitoneally in a suspension. We then assessed post-exposure hematological and biochemical parameters of blood and urine, histological and ultrastructural changes in cardiomyocytes, and non-invasively recorded electrocardiograms and blood pressure parameters in the rodents. Myocardial contractility was studied on isolated preparations of cardiac muscles. We established that PbO NPs induced oxidative stress and damage to the ultrastructure of cardiomyocytes, and decreased efficiency of the contractile function of the myocardium and blood pressure parameters. We also revealed such specific changes in the organism of the exposed rats as anemia, hypoxia, and hypocalcemia.

Characteristics of the right atrial and right ventricular contractility in a model of monocrotaline-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) leads to changes in the pump function of the heart and causes right-sided myocardial hypertrophy and heart failure. This study was the first to compare the contractile characteristics of the multicellular myocardial preparations of the right atrium (RA) and right ventricle (RV) of male rats from the control group (CON) and the group with monocrotaline (MCT)-induced hypertrophy at the molecular and multicellular levels. In both RA and RV in MCT-treated rats, the fraction of motile filaments and the maximum sliding velocity of actin and reconstituted thin filaments over myosin decreased, and the ratio of α-/ß-myosin heavy chains (MHC) shifted towards ß-MHC. In the RA strips and RV trabeculae, the maximum shortening velocity, the extent of muscle shortening, the amplitude of isometric stress, the amount of work decreased. PAH leads to a greater drop in right atrial contractility than that of the ventricle.

Changes in the Cardiotoxic Effects of Lead Intoxication in Rats Induced by Muscular Exercise.

Exposure to lead is associated with an increased risk of cardiovascular diseases. Outbred white male rats were injected with lead acetate intraperitoneally three times a week and/or were forced to run at a speed of 25 m/min for 10 min 5 days a week. We performed noninvasive recording of arterial pressure, electrocardiogram and breathing parameters, and assessed some biochemical characteristics. Electrophoresis in polyacrylamide gel was used to determine the ratio of myosin heavy chains. An in vitro motility assay was employed to measure the sliding velocity of regulated thin filaments on myosin. Isolated multicellular preparations of the right ventricle myocardium were used to study contractility in isometric and physiological modes of contraction. Exercise under lead intoxication normalized the level of calcium and activity of the angiotensin-converting enzyme in the blood serum, normalized the isoelectric line voltage and T-wave amplitude on the electrocardiogram, increased the level of creatine kinase-MB and reduced the inspiratory rate. Additionally, the maximum sliding velocity and the myosin heavy chain ratio were partly normalized. The effect of exercise under lead intoxication on myocardial contractility was found to be variable. In toto, muscular loading was found to attenuate the effects of lead intoxication, as judged by the indicators of the cardiovascular system.

Omecamtiv mecarbil attenuates length-tension relationship in healthy rat myocardium and preserves it in monocrotaline-induced pulmonary heart failure.

The cardiac-specific myosin activator, omecamtiv mecarbil (OM), is an effective inotrope for treating heart failure but its effects on active force and Ca2+ kinetics in healthy and diseased myocardium remain poorly studied. We tested the effect of two concentrations of OM (0.2 and 1 µmol/L in saline) on isometric contraction and Ca-transient (CaT) in right ventricular trabeculae of healthy rats (CONT, n = 8) and rats with monocrotaline-induced pulmonary heart failure (MCT, n = 8). The contractions were obtained under preload of 75%-100% of optimal length (tension-length relationship). The 0.2 µmol/L OM did not affect the diastolic level, amplitude, or kinetics of isometric contraction and CaT, irrespective of the group of rats or preload. The 1 µmol/L OM significantly suppressed active tension-length relationships in CONT but not in MCT, while leading in both groups to a significantly prolonged relaxation. CaT time-to-peak was unaffected in CONT and MCT, but CaT decay was slightly accelerated in its early phase and considerably prolonged in its late phase to a similar extent in both groups. We conclude that the substantial prolongation of CaT decay is due to enhanced Ca2+ utilisation by troponin C mediated by the direct effect of OM on the cooperative activation of myofilaments. The lack of beneficial effect of OM in the healthy rat myocardium may be due to a relatively high level of activating Ca2+ in cells with normal Ca2+ handling, whereas the preservation of the tension-length relationship in the failing heart may relate to the diminished Ca2+ levels of sarcoplasmic reticulum.

Cardioinotropic Effects in Subchronic Intoxication of Rats with Lead and/or Cadmium Oxide Nanoparticles.

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 ß-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.

Differing effects of estrogen deficiency on the contractile function of atrial and ventricular myocardium.

Estrogen deficiency has a significant influence on the excitation-contraction coupling in the ventricular myocardium but its impact on the atrial contractile function has not been studied. We have compared the effects of estrogen deficiency on the contractility and cytosolic Ca2+ transient of single cardiomyocytes isolated from the left atrium (LA) and the left ventricle (LV) of rats subjected to ovariectomy (OVX) or sham surgery (Sham). The characteristics of actin-myosin interaction were studied in an in vitro motility assay. We found that OVX decreased the contractility of LV single cardiomyocytes but increased that of LA myocytes. The disturbance of ventricular mechanical function may be explained by the acceleration of Ca2+ transient and reduced Ca2+ sensitivity of the actin-myosin interaction. The augmentation of LA contractility may be explained by accelerated cross-bridge kinetics and increased end-diastolic sarcomere length, which may lead to elevated tension in atrial cells due to the Frank-Starling mechanism.

Force-velocity characteristics of isolated myocardium preparations from rats exposed to subchronic intoxication with lead and cadmium acting separately or in combination.

This investigation continues our study of the effects of Pb-Cd poisoning on the heart, extending the enquiry from isometric to auxotonic contractions, thereby examining the effect on the ability of myocardial tissues to perform mechanical work. Different shifts were revealed in myocardial force-velocity relations following subchronic exposure of rats to lead acetate and cadmium chloride acting separately, in combination, or in combination with a bioprotective complex (BPC). The experiments were conducted on isolated preparations of trabecules and papillary muscles of the right ventricle in physiological loading conditions and on isolated heart muscle contractile proteins examined by the in vitro motility assay. The results of the latter correlate with the shifts in the ratio of cardiac myosin isoforms. The amount of work performed by the myocardium was calculated on the basis of the tension-shortening loop area and was found to be similar in the preparations from all experimental groups. This fact presumably reflects adaptive capacity of the myocardial function even when contractility is damaged due to the metallic intoxication of a moderate severity. Some characteristics of rat myocardium altered by the impact of lead-cadmium intoxication became fully or partly normalized if intoxication developed against background administration of a bioprotective complex (BPC). Together with previously reported results obtained in the isometric mode of contractility, all these results strengthen the scientific foundations of risk assessment and risk management projects in the occupational and environmental conditions characterized by human exposure to lead and/or cadmium.

The first deaf-blind patient in Russia with Argus II retinal prosthesis system: what he sees and why.

OBJECTIVE: In this study, we propose a new method for evaluating the functional results based on the sizes of phosphenes that the patient drew which were then digitalized. We also describe the methodology of psychological testing and support for a deaf-blind patient. APPROACH: A 59-year-old man with retinitis pigmentosa and hearing loss (clinical Usher syndrome) underwent surgery to implant the Argus II retinal prosthesis system in his right eye. MAIN RESULTS: Correlation analysis showed a weak dependency between the size of a phosphene and the perceptual threshold. Significant correlations between a phosphene and the height of the interface, impedance or retinal thickness was not found. The patient with the retinal prosthesis felt more independent and confident, and more healthy. This is the first case of retinal implant surgery in Russia. SIGNIFICANCE: The results of this study add to the understanding in the field of retinal implants functioning. The experience of the successful rehabilitation of the deaf-blind patient after implantation of Argus II allowed us to design a methodology that can be used in future similar cases.

The phenomena of mechanical interaction of segments of hypertrophied myocardium.

The main aims of adaptation mechanisms of heart contractility are to regulate the stroke volume and optimize the global heart function. These mechanisms manifest themselves in hearts of healthy animals and in hearts with severe hypertrophy in different ways. Severe right ventricle hypertrophy was induced by single treatment with monocrotaline. Young rats of both sexes were used to prevent influences of sex hormones on the development of right ventricular hypertrophy. Serial duplex method is used as a model of interaction of two ventricular wall segments. In serial duplex the muscles are in connection 'end-to-end' and subjected to mutual deformations during contractions. It is important to establish the fine-tuning phenomena and evaluate their expressiveness in healthy hearts and hearts with severe hypertrophy. Mild force transient processes occur on muscle connection to serial duplex and on muscle separation from duplex in all experimental groups. These transients manifest themselves as slow changes in the amplitude of muscle contraction from cycle to cycle. During the muscle interaction in the serial duplex, evident transient processes in the mutual amplitude of deformations in all experimental groups are observed. The greatest changes in the length occur in the relaxation phase of the contraction cycle. The loss of interaction between ventricular muscles of rats with severe heart hypertrophy is the most likely cause of an additional deterioration in the heart pumping function. New targets may occur for the recovery of contractility of hearts with severe hypertrophy.

The length-dependent activation of contraction is equally impaired in impuberal male and female rats in monocrotaline-induced right ventricular failure.

The length-dependent activation of contraction is attenuated in the failing myocardium of adult male rats. This pathological change is not seen in adult female rats, possibly because of a protective effect of sex hormones. The present study evaluated length-dependent changes in isometric twitch, Ca(2+) transient (CaT) and action potential (AP) in the right ventricular myocardium of impuberal healthy male and female rats (control) and in rats treated with a single injection of 50 mg/kg monocrotaline (MCT). Compared with sex-matched control rats, MCT-treated male and female rats exhibited increased right ventricular weight (134% and 142% of control, respectively), decreased left ventricular weight (72% and 79%), twitch attenuation (48.8 ± 2.7% and 57.5 ± 1.2%) and prolongation (125 ± 3% and 127 ± 2%), CaT attenuation (37.8 ± 0.4% and 39.1 ± 1.1%) and prolongation (114 ± 1% and 116 ± 1%) and AP prolongation at 90% repolarization (195 ± 2% and 203 ± 1%). The MCT-treated male rats exhibited a 50% lower integral magnitude and an approximately 25% larger time-to-peak 'bump' compared with control male rats. These parameters in MCT-treated female rats tended to show similar changes to those seen in the control female rats, with no significant difference between the two groups. In all groups, integral magnitude and time-to-peak 'bump' increased with length. In conclusion, the length-dependent activation of contraction was equally blunted in the failing right ventricular myocardium of impuberal male and female rats. This was related to changes in CaT and AP, which were similar between male and female rats. Therefore, puberty is necessary for manifestation of the protective effects of sex hormones on this remodelling.

Sex differences in stretch-dependent effects on tension and Ca(2+) transient of rat trabeculae in monocrotaline pulmonary hypertension.

We aim to compare the effects of stretch on isometric tension/Ca(2+) transient in the right ventricular trabeculae of control (CONT) and hypertensive (MCT, monocrotaline application) adult male and female rats. The treatment with MCT resulted in RV hypertrophy in males only. Blunted active force-length relation and substantially prolonged twitch were found in MCT-males but not MCT-females (vs same-sex CONT). Ca(2+) transient was prolonged in both MCT-treated groups but extremely so in the MCT-males. The gradual stretch resulted in a distinct "bump" on Ca(2+) transient decline in CONT and MCT-treated groups. The integral magnitude of the "bump" was unaffected by the treatment with MCT in males or females but was larger in males vs females. The rate of "bump" development was significantly slower in MCT-males. In conclusion, the sex-specific differences in the stretch-dependent regulation of [Ca(2+)] i may underlie preservation of the Frank-Starling mechanism in female rat myocardium in monocrotaline-induced pulmonary hypertension.