ABSTRACT
The large-conductance Ca2+-activated K+ (BK) channel is widely expressed in the pulmonary blood vessels and plays a significant role in regulating pulmonary vascular tonus. It opens under membrane depolarization, increased intracellular Ca+2 concentration, and chronic hypoxia, resulting in massive K+ efflux, membrane hyperpolarization, decreased L-type Ca+2 channel opening, and smooth muscle relaxation. Several reports have demonstrated an association between BK channel dysfunction and pulmonary hypertension (PH) development. Decreased BK channel subunit expression and impaired regulation by paracrine hormones result in decreased BK channel opening, increased pulmonary vascular resistance, and pulmonary arterial pressure being the cornerstone of PH. The resulting right ventricular pressure overload ultimately leads to ventricular remodeling and failure. Therefore, it is unsurprising that the BK channel has arisen as a potential target for treating PH. Recently, a series of selective, synthetic BK channel agonists have proven effective in attenuating the pathophysiological progression of PH without adverse effects in animal models.
ABSTRACT
Anthracyclines are chemotherapeutic drugs widely used in the frontline of cancer treatment. The therapeutic mechanisms involve the stabilization of topoisomerase IIα, DNA, and the anthracycline molecule in a ternary complex that is recognized as DNA damage. Redox imbalance is another vital source of oxidative DNA damage. Together, these mechanisms lead to cytotoxic effects in neoplastic cells. However, anthracycline treatment can elicit cardiotoxicity and heart failure despite the therapeutic benefits. Topoisomerase IIß and oxidative damage in cardiac cells have been the most reported pathophysiological mechanisms. Alternatively, cardiac cells can undergo stress-induced senescence when exposed to anthracyclines, a state primarily characterized by cell cycle arrest, organelle dysfunction, and a shift to senescence-associated secretory phenotype (SASP). The SASP can propagate senescence to neighboring cells in an ongoing process that leads to the accumulation of senescent cells, promoting cellular dysfunction and extracellular matrix remodeling. Therefore, the accumulation of senescent cardiac cells is an emerging pathophysiological mechanism associated with anthracycline-induced cardiotoxicity. This paradigm also raises the potential for therapeutic approaches to clear senescent cells in treating anthracycline-induced cardiotoxicity (i,e, senolytic therapies).
Subject(s)
Anthracyclines , Cardiotoxicity , Humans , Anthracyclines/pharmacology , Senotherapeutics , Antibiotics, Antineoplastic , Cellular SenescenceABSTRACT
Global population aging is a major challenge to health and socioeconomic policies. The prevalence of diseases progressively increases with aging, with cardiovascular disease being the major cause of mortality among elderly people. The allostatic overload imposed by the accumulation of cardiac senescent cells has been suggested to play a pivotal role in the aging-related deterioration of cardiovascular function. Senescent cells exhibit intrinsic disorders and release a senescence-associated secretory phenotype (SASP). Most of these SASP compounds and damaged molecules are released from senescent cells by extracellular vesicles (EVs). Once secreted, these EVs can be readily incorporated by recipient neighboring cells and elicit cellular damage or otherwise can promote extracellular matrix remodeling. This has been associated with the development of cardiac dysfunction, fibrosis, and vascular calcification, among others. The molecular signature of these EVs is highly variable and might provide important information for the development of aging-related biomarkers. Conversely, EVs released by the stem and progenitor cells can exert a rejuvenating effect, raising the possibility of future anti-aging therapies.
Subject(s)
Allostasis , Extracellular Vesicles , Heart , Biological TransportABSTRACT
S17 is a clonogenic bone marrow stromal (BMS) cell line derived from mouse that has been extensively used to assess both human and murine hematopoiesis support capacity. However, very little is known about the expression of potassium ion channels and their function in cell survival and migration in these cells. Thus, the present study was designed to characterize potassium ion channels using electrophysiological and molecular biological approaches in S17 BMS cells. The whole-cell configuration of the patch clamp technique has been applied to identify potassium ion currents and reverse transcription polymerase chain reaction (RT-PCR) used to determine their molecular identities. Based on gating kinetics and pharmacological modulation of the macroscopic currents we found the presence of four functional potassium ion channels in S17 BMS cells. These include a current rapidly activated and inactivated, tetraethylammonium-sensitive, (IKV ) in most (50%) cells; a fast activated and rapidly inactivating A-type K + current (IK A -like); a delayed rectifier K + current (IK DR ) and an inward rectifier potassium current (IK IR ), found in, respectively 4.5%, 26% and 24% of these cells. RT-PCR confirmed the presence of mRNA transcripts for the alpha subunit of the corresponding functional ion channels. Additionally, functional assays were performed to investigate the importance of potassium currents in cell survival and migration. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analyses revealed a reduction in cell viability, while wound healing assays revealed reduced migration potential in cells incubated with different potassium channel blockers. In conclusion, our data suggested that potassium currents might play a role in the maintenance of overall S17 cell ionic homeostasis directly affecting cell survival and migration.
Subject(s)
Cell Movement , Mesenchymal Stem Cells/metabolism , Potassium Channels/metabolism , Potassium/metabolism , Animals , Cell Line , Cell Movement/drug effects , Cell Survival , Ion Channel Gating , Kinetics , Membrane Potentials , Mesenchymal Stem Cells/drug effects , Mice , Potassium Channel Blockers/pharmacology , Potassium Channels/drug effects , Potassium Channels/genetics , Signal TransductionABSTRACT
AIM: To investigate the effect of acute treatment with the anabolic steroid (AS) nandrolone decanoate in mitochondrial homeostasis and JAK-STAT3 signaling during the progression of cardiac ischemia/reperfusion injury (IR). METHODS: Male Wistar rats (2 months old) were randomly allocated into four experimental groups: Control (CTRL), IR, AS, and AS + AG490. All animals were euthanized 3 days after a single intramuscular injection of nandrolone at 10 mg/kg (AS and AS + AG490 groups) or vehicle (CTRL and IR groups). Baseline mRNA expression of antioxidant enzymes superoxide dismutase (SOD) 1 and 2, glutathione peroxidase, catalase, and myosin heavy chain (MHC) α and ß were compared between CTRL and AS groups. Isolated hearts were submitted to ex vivo ischemia and reperfusion, except for hearts from the CTRL group. Before the IR protocol, the JAK-STAT3 inhibitor AG490 was perfused in hearts from the AS + AG490 group. Heart samples were collected during reperfusion to investigate the effects on mitochondrial function. Results Antioxidant enzyme mRNA expression was unaffected, whereas the AS group exhibited decreased ß- MHC/α-MHC ratio versus the CTRL group. Compared to the IR group, the AS group exhibited better recovery of post-ischemic left ventricular (LV) end-diastolic pressure and LV-developed pressure levels, while infarct size significantly decreased. Furthermore, mitochondrial production, transmembrane potential, and swelling were improved, whereas ROS formation was decreased versus the IR group. These effects were prevented by the perfusion of JAK-STAT3 inhibitor AG490. CONCLUSION: These findings suggest that acute nandrolone treatment can provide cardioprotection by recruiting the JAK-STAT3 signaling pathway and mitochondrial preservation.
Subject(s)
Myocardial Reperfusion Injury , Nandrolone , Rats , Animals , Male , Antioxidants , Rats, Wistar , Mitochondria/metabolism , RNA, MessengerABSTRACT
BACKGROUND: The presence of G-type immunoglobulins with functional activity was previously demonstrated in chronic chagasic patients (CChP) with heart failure. Here we evaluated the profile and the arrhythmogenic effects of sera from CChP with preserved ventricular function. METHODS: Electrocardiography (ECG), Holter monitoring, exercise testing, and left ventricular ejection fraction of 40 CChP were measured. Serum from each patient was characterized in isolated rabbit hearts where ECG parameters were analyzed. RESULTS: From the total sera of the 40 CChP tested in rabbit hearts, 42.5% activated ß-adrenergic receptors (Ab-ß), 5% activated muscarinic receptors (Ab-M), and 30% activated both muscarinic and ß-receptors (Ab-Mß). In addition, 22.5% of the sera were not reactive (Ab-NR). Ab-ß patients presented more cases of arrhythmias in exercise testing (P < .001). In Holter, ventricular arrhythmias appeared more than twice as often in the Ab-ß group than in the Ab-NR group and in numbers similar to the Ab-Mß group (Ab-NR: 2; Ab-ß: 5; Ab-Mß: 3). Arrhythmias were induced by Ab-Mß in isolated rabbit hearts. Sera from patients with Ab-Mß, who had longer PR intervals, were able to reversibly prolong PR when perfused in isolated rabbit heart (r² = 0.74; P = .02). CONCLUSIONS: High prevalence of Ab-ß in CChP with preserved left ventricular function led to a greater incidence of ventricular arrhythmias in the patients.
Subject(s)
Arrhythmias, Cardiac/complications , Autoantibodies/immunology , Chagas Cardiomyopathy/complications , Heart Failure/complications , Receptors, Adrenergic, beta/metabolism , Ventricular Function, Left/physiology , Aged , Animals , Arrhythmias, Cardiac/immunology , Arrhythmias, Cardiac/physiopathology , Chagas Cardiomyopathy/immunology , Chagas Cardiomyopathy/physiopathology , Cross-Sectional Studies , Disease Models, Animal , Electrocardiography , Electrocardiography, Ambulatory , Female , Heart Failure/immunology , Heart Failure/physiopathology , Humans , Male , Middle Aged , Prognosis , RabbitsABSTRACT
Physical exercise is characterized by an increase in physical and metabolic demand in face of physical stress. It is reported that a single exercise session induces physiological responses through redox signaling to increase cellular function and energy support in diverse organs. However, little is known about the effect of a single bout of exercise on the redox homeostasis and cytoprotective gene expression of white adipose tissue (WAT). Thus, we aimed at evaluating the effects of acute aerobic exercise on WAT redox homeostasis, mitochondrial metabolism, and cytoprotective genic response. Male Wistar rats were submitted to a single moderate-high running session (treadmill) and were divided into five groups: control (CTRL, without exercise), and euthanized immediately (0 h), 30 min, 1 hour, or 2 hours after the end of the exercise session. NADPH oxidase activity was higher in 0 h and 30 min groups when compared to CTRL group. Extramitochondrial ROS production was higher in 0 h group in comparison to CTRL and 2 h groups. Mitochondrial respiration in phosphorylative state increased in 0 h group when compared to CTRL, 30 min, 1, and 2 h groups. On the other hand, mitochondrial ATP production was lower in 0 h in comparison to 30 min group, increasing in 1 and 2 h groups when compared to CTRL and 0 h groups. CAT activity was lower in all exercised groups when compared to CTRL. Regarding oxidative stress biomarkers, we observed a decrease in reduced thiol content in 0 h group compared to CTRL and 2 h groups, and higher levels of protein carbonylation in 0 and 30 min groups in comparison to the other groups. The levels returned to basal condition in 2 h group. Furthermore, aerobic exercise increased NRF2, GPX2, HMOX1, SOD1, and CAT mRNA levels. Taken together, our results suggest that one session of aerobic exercise can induce a transient prooxidative state in WAT, followed by an increase in antioxidant and cytoprotective gene expression.
Subject(s)
Adipose Tissue, White/metabolism , Homeostasis , Mitochondria/metabolism , Physical Conditioning, Animal , Adenosine Triphosphate/biosynthesis , Animals , Antioxidants/metabolism , Biomarkers/metabolism , Cell Respiration/genetics , Gene Expression Regulation , Lactic Acid/blood , Male , NADPH Oxidases/metabolism , Oxidation-Reduction , Oxidative Stress/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats, Wistar , Reactive Oxygen Species/metabolism , Retroperitoneal Space/physiologyABSTRACT
The bone marrow stromal cell line S17 has been used to study hematopoiesis in vitro. In this study, we demonstrate the presence of calcium and chloride currents in cultured S17 cells. Calcium currents were of low amplitude or barely detectable (50-100 pA). Hence to amplify the currents, we have used barium as a charge carrier. Barium currents were identified based on their distinct voltage-dependence, and sensitivity to dihydropyridines. S17 cells also exhibited a slowly activating outward current without inactivation, most commonly seen when the sodium of the extracellular solution was replaced either by TEA (TEA/Cs saline) or NMDG (NMDG saline), or by addition of amiloride to the extracellular solution. This current was abolished either by 500 microM SITS (4,4'-diisothiocyanatostilbene-2-2'-disulfonic acid) or 500 microM DPC (diphenylamine-2-carboxylic acid) a cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel blocker, identifying it as a Cl(-) current. RT-PCR identified the presence of ENaC and CFTR transcripts. CFTR blockade reduced cell proliferation, suggesting that this channel plays a physiological role in regulation of S17 cell proliferation.
Subject(s)
Bone Marrow Cells/metabolism , Calcium Channels, L-Type/metabolism , Calcium/metabolism , Cell Proliferation , Chlorides/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Stromal Cells/metabolism , 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester/pharmacology , 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid/pharmacology , Amiloride/pharmacology , Animals , Barium/metabolism , Bone Marrow Cells/drug effects , Calcium Channel Agonists/pharmacology , Calcium Channel Blockers/pharmacology , Calcium Channels, L-Type/drug effects , Calcium Channels, L-Type/genetics , Cell Line , Cystic Fibrosis Transmembrane Conductance Regulator/drug effects , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Epithelial Sodium Channels/metabolism , Kinetics , Membrane Potentials , Mice , Nifedipine/pharmacology , Patch-Clamp Techniques , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sodium/metabolism , Sodium Channel Blockers/pharmacology , Stromal Cells/drug effects , ortho-Aminobenzoates/pharmacologyABSTRACT
Heart rate variability (HRV) analysis consists in a well-established tool for the assessment of cardiac autonomic control, both in humans and in animal models. Conventional methods for HRV analysis in rats rely on conscious state electrocardiogram (ECG) recording based on prior invasive surgical procedures for electrodes/transmitters implants. The aim of the present study was to test a noninvasive and inexpensive method for ECG recording in conscious rats, assessing its feasibility for HRV analysis. A custom-made elastic cotton jacket was developed to fit the rat's mean thoracic circumference, with two pieces of platinum electrodes attached on its inner surface, allowing ECG to be recorded noninvasively in conscious, restrained rats (n=6). Time- and frequency-domain HRV analyses were conducted, under basal and autonomic blockade conditions. High-quality ECG signals were obtained, being feasible for HRV analysis. As expected, mean RR interval was significantly decreased in the presence of atropine (p <0.05) and increased in the presence of propranolol (p<0.001). Also, reinforcing the reliability of the method, low- and high-frequency HRV spectral powers were significantly decreased in the presence of propranolol (p <0.05) and atropine (p< 0.001), respectively. In summary, the present work describes a novel, inexpensive and noninvasive method for surface ECG recording in conscious rats.
Subject(s)
Electrocardiography/methods , Heart Rate/physiology , Animals , Atropine/pharmacology , Propranolol/pharmacology , Rats , Reproducibility of ResultsABSTRACT
The purpose of this study was to investigate the cardiovascular effects of anabolic androgenic steroid (AAS) use, specifically the hemodynamic response, during maximal treadmill exercise testing by comparing the exercise response between users of AAS (U-AAS) and non-AAS users (N-AAS). Twenty-four men (n=12; 29+/-3.4 years and n=12; 29.5+/-8.2 years for the U-AAS and N-AAS groups, respectively) with regular participation in both resistance (mean=6 d.wk) and aerobic exercise (mean=2 d.wk) volunteered for the study. Both groups of subjects completed a ramp-protocol maximal treadmill exercise test to volitional fatigue. Several hemodynamic and metabolic measures were obtained before, during, and after testing. The results demonstrate for the first time that chronic administration of high doses of AAS (355.4+/-59.47 mg.wk) lead to hemodynamic and metabolic response impairment. In conclusion, the chronotropic significant incompetence in the current study was reflected by an exaggerated hemodynamic response to exercise. Furthermore, the findings suggest that nonusers of AAS showed increases in VO2max when compared to the AAS group. Therefore, this study provides a contraindication to AAS use, especially in those at increased risk of cardiovascular events.
Subject(s)
Anabolic Agents/adverse effects , Androgens/adverse effects , Exercise , Hemodynamics/drug effects , Testosterone/analogs & derivatives , Adult , Anabolic Agents/administration & dosage , Androgens/administration & dosage , Cardiovascular Diseases/chemically induced , Contraindications , Exercise Test , Humans , Male , Oxygen Consumption/drug effects , Resistance TrainingABSTRACT
Anabolic steroids (AS) are synthetic testosterone-derivatives developed by the pharmaceutical industry to mimic testosterone biological effects. So far, AS have been implicated in the treatment of pathological conditions, such as hypogonadism, anemia, and cachexia. Since their discovery, though, AS have been illicitly used by elite and recreational athletes, bodybuilders and weightlifters in order to enhance athletic and aesthetic performance. This practice is characterized by cycles of administration and withdrawal, the combination of different AS compounds, and administration of doses 50 - 1000 times higher than those recommended for therapeutic purposes. AS excess has been correlated to cardiovascular detrimental effects, including cardiac hypertrophy, arrhythmias, and hypertension. Particularly, acute myocardial infarction (AMI) has been extensively reported by clinical and post-mortem studies. Atherosclerosis, hypercoagulability state, increased thrombogenesis and vasospasm have arisen as potential causes of myocardial ischemia in AS users. Additionally, several experimental reports have demonstrated that AS can increase the susceptibility to cardiac ischemia/reperfusion injury, whereas the cardioprotection elicited by physical exercise and ischemic postconditioning is blunted. Altogether, these factors can contribute to increased AMI morbidity and mortality during AS excess, particularly when AS are combined with other compounds, such as thyroid hormones, growth hormones, insulin, and diuretics.
Subject(s)
Myocardial Infarction/chemically induced , Myocardial Reperfusion Injury/chemically induced , Testosterone Congeners/adverse effects , Animals , Atrial Remodeling/drug effects , Dose-Response Relationship, Drug , Humans , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury/pathology , Myocardial Reperfusion Injury/physiopathologyABSTRACT
AIM: The present study investigated the effects of anabolic steroid (AS) excess on blood pressure regulation. METHODS: Male Wistar rats were treated with nandrolone decanoate (AS) or vehicle (CTL) for 8 or 10 weeks. Saline (1.8%) and water intake were measured in metabolic cages. Urinary volume, osmolarity, Na+ and K+ concentrations, and plasma osmolarity were measured. The autonomic balance was estimated by heart rate variability at baseline or after icv injection of losartan. Cardiac function was assessed by echocardiography and ex vivo recordings. Myocardial collagen deposition was evaluated by Picrosirius-Red staining. Vascular reactivity and wall thickness were investigated in aortic sections. Blood pressure (BP) was assessed by tail-cuff plethysmography. Angiotensin II type I receptor (AT1R), renin, and mineralocorticoid receptor (MR) mRNA expression was measured in the kidneys and whole hypothalamus. RESULTS: AS group exhibited decreased urinary volume and Na+ concentration, while urinary K+ concentration, plasma osmolarity, and renal AT1R and renin mRNA levels were increased compared to CTL (p < 0.05). Water intake was increased, and saline intake was decreased in the AS group (p < 0.01). AS group exhibited increased low-frequency/high-frequency-ratio, while it was decreased by icv injection of losartan (p < 0.05) compared to baseline. Neither cardiac function nor vascular reactivity/morphology was affected by AS excess (p > 0.05). Ultimately, BP levels were not altered by AS excess (p > 0.05). CONCLUSION: AS excess promoted hydroelectrolytic and autonomic imbalance but did not alter vascular or cardiac function/morphology.
Subject(s)
Anabolic Agents/pharmacology , Autonomic Nervous System/drug effects , Autonomic Nervous System/physiology , Blood Pressure/drug effects , Nandrolone Decanoate/pharmacology , Animals , Gene Expression Regulation/drug effects , Hypothalamus/drug effects , Hypothalamus/metabolism , Kidney/drug effects , Kidney/metabolism , Male , Mineralocorticoids/genetics , RNA, Messenger/genetics , Rats , Rats, Wistar , Receptor, Angiotensin, Type 1/genetics , Renin/geneticsABSTRACT
AIM: Investigate cardiac electrical and mechanical dysfunctions elicited by chronic anabolic steroid (AS) overdose. METHODS: Male Wistar rats were treated with nandrolone decanoate (DECA) or vehicle (CTL) for 8â¯weeks. Electrocardiography and heart rate variability were assessed at weeks 2, 4, and 8. Cardiac reactivity to isoproterenol was investigated in isolated rat hearts. Action potential duration (APD) was measured from left ventricular (LV) muscle strips. L-type Ca2+ current (ICaL), and transient outward potassium current (Ito) were recorded by whole-cell patch-clamp in LV cardiomyocytes. Sarcoplasmic reticulum (SR) Ca2+ mobilization and Ca2+-induced contractile response sensitivity were evaluated in skinned cardiac fibers. Muscarinic type 2 receptor (M2R), ß1-adrenergic receptor (ß1AR), sarcoplasmic Ca2+ ATPase (SERCA-2a), type 2 ryanodine receptor (RyR2), L-type Ca2+ channel (CACNA1), Kv4.2 (KCND2), and Kv4.3 (KCND3) mRNA expression levels were measured by quantitative RT-PCR. RESULTS: Compared with CTL group, DECA group exhibited decreased high frequency band power density (HF) and increased low frequency power density (LF), Cardiac M2R mRNA level was decreased. QTc interval at 2nd, 4th, and 8th week as well as APD30 and APD90 were increased by DECA. Ito density was decreased, while ICaL density was increased by DECA. SR Ca2+ loading and release were decreased by DECA, while contractile sensitivity to Ca2+ was increased versus CTL group. CONCLUSION: DECA overdose induced cardiac rhythmic and mechanical abnormalities that can be associated with autonomic imbalance, up-regulated ICaL and down-regulated Ito, abnormal SR Ca2+ mobilization, and increased contractile sensitivity to Ca2+.
Subject(s)
Autonomic Nervous System Diseases/chemically induced , Autonomic Nervous System Diseases/metabolism , Calcium/metabolism , Coronary Disease/chemically induced , Coronary Disease/metabolism , Nandrolone Decanoate/adverse effects , Animals , Autonomic Nervous System Diseases/diagnosis , Coronary Disease/diagnosis , Disease Models, Animal , Electrocardiography , Male , Nandrolone Decanoate/administration & dosage , Rats , Rats, WistarABSTRACT
Aging is followed by numerous physiological limitations that reduce health span, particularly cardiovascular and metabolic disorders. Testosterone supplementation therapy (TST) has been widely used in the treatment of aging dysfunctions in either adult or aged patients, although recent evidence have suggested that the incidence of myocardial infarction might be increased in elderly patients. So far, though, the effects of TST in the progression of cardiac ischemia/reperfusion (IR) injury in aged hearts remain unclear. Male aged (23-24 months old) and adult (6 months old) Wistar rats were treated with placebo (Old + Placebo n = 5 / Adult + Placebo n = 5) or TST (Old + TST n = 7 / Adult + TST n = 5) for 30 days. After euthanasia, artificially-perfused isolated rat hearts were submitted to IR. Cardiac expression levels of genes encoding α and ß myosin heavy chain (MHC), ryanodine receptor (RyR), brain-natriuretic peptide (BNP), sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA2a), glucose-regulated protein 78 kDa (GRP78), eukaryotic initiation factor 2α (eIF2α), C/EBP-homologous protein (CHOP), caspase 3 and B cell lymphoma 2 (Bcl-2) were accessed by qRT-PCR. Protein levels of CHOP, p-Akt, and p-glycogen synthase kinase 3ß (p-GSK-3ß) were measured by Western Blot. Compared to placebo-treated aged rats, Old + TST group exhibited increased heart weight and up-regulation of αMHC mRNA expression levels, whereas ßMHC mRNA expression (p < 0.05). During reperfusion, left ventricular developed pressure, dP/dt+, dP/dt-, and cardiac contractile function index were increased in Old + TST rat hearts (p < 0.05), whereas infarct size was increased (p < 0.05) in comparison with Old + Placebo group. p-Akt levels of Old + TST rat hearts were decreased when compared to Old + Placebo group. Conversely, TST did not promote significant effects in adult rat hearts. Taken together, these findings suggest that myocardial stunning and infarct size of aged hearts were distinctly affected by TST.
Subject(s)
Dietary Supplements/adverse effects , Myocardial Reperfusion Injury/pathology , Testosterone/adverse effects , Aging/drug effects , Animals , Disease Progression , Heart/drug effects , Heart/physiopathology , Male , Myocardial Reperfusion Injury/physiopathology , Proto-Oncogene Proteins c-akt/analysis , Rats, Wistar , Testosterone/therapeutic useABSTRACT
AIMS: The aim of this study was to investigate whether the sera from chronic chagasic patients (CChPs) with beta-1 adrenergic activity (Ab-beta) can modulate ventricular repolarization. Beta-adrenergic activity has been described in CChP. It increases the L-type calcium current and heart rate in isolated hearts, but its effects on ventricular repolarization has not been described. METHODS AND RESULTS: In isolated rabbit hearts, under pacing condition, QT interval was measured under Ab-beta perfusion. Beta-adrenergic activity was also tested in guinea pig ventricular M cells. Furthermore, the immunoglobulin fraction (IgG-beta) of the Ab-beta was tested on Ito, ICa, and Iks currents in rat, rabbit, and guinea pig myocytes, respectively. Beta-adrenergic activity shortened the QT interval. This effect was abolished in the presence of propranolol. In addition, sera from CChP without beta-adrenergic activity (Ab-beta) did not modulate QT interval. The M cell action potential duration (APD) was reversibly shortened by Ab-beta. Atenolol inhibited this effect of Ab-beta, and Ab- did not modulate the AP of M cells. Ito was not modulated by isoproterenol nor by IgG-beta. However, IgG-beta increased ICa and IKs. CONCLUSION: The shortening of the QT interval and APD in M cells and the increase of IKs and ICa induced by IgG-beta contribute to repolarization changes that may trigger malignant ventricular arrhythmias observed in patients with chronic chagasic or idiopathic cardiomyopathy.
Subject(s)
Action Potentials/drug effects , Chagas Cardiomyopathy/immunology , Electrocardiography , Heart/drug effects , Immunoglobulin G/pharmacology , Myocytes, Cardiac/drug effects , Receptors, Adrenergic, beta-1/physiology , Action Potentials/physiology , Animals , Anti-Arrhythmia Agents/pharmacology , Atenolol/pharmacology , Calcium Channels, L-Type/drug effects , Calcium Channels, L-Type/physiology , Chagas Cardiomyopathy/physiopathology , Chronic Disease , Guinea Pigs , Heart/physiology , Heart Rate/drug effects , Heart Rate/physiology , Heart Ventricles/drug effects , Humans , Longitudinal Studies , Myocytes, Cardiac/cytology , Myocytes, Cardiac/physiology , Patch-Clamp Techniques , Potassium Channels/drug effects , Potassium Channels/physiology , Rabbits , Rats , Receptors, Adrenergic, beta-1/immunology , Retrospective Studies , Ventricular FunctionABSTRACT
Perfusion of hearts with extracts of Ilex paraguariensis (IP/mate) appears to reduce ischemia/reperfusion (I/R) injury. To determine if oral consumption of IP/mate can provide similar cardioprotection, short-term consumption was investigated alone or in association with exercise in rats. Animals were grouped into control (C), IP/mate consumption (M), exercise (E), and exercise with mate (E+M). M and E+M groups consumed IP/mate (1 g·kg-1 body weight in 1 mL water) by gavage. E and E+M groups swam 7× per week for 30 min carrying an additional 5% of body weight. After 1 week, hearts were tested ex vivo to measure left ventricle developed pressure (LVDP), systolic and end diastolic pressure (LVSP/LVEDP), maximum velocity of contraction and relaxation (dP/dt+ and dP/dt-) during I/R and infarction size. In addition, cardiac tissue was analyzed for oxidative stress by lipid peroxidation and protein carbonyl levels along with activity of catalase and superoxide dismutase (SOD). LVDP was higher in hearts from M and E groups as well as decreased infarction sizes than others. At the end of reperfusion, dP/dt+ was increased in E and M and dP/dt- was higher in M. LVSP was higher in M and E compared with C. Protein carbonyl and thiobarbituric acid reactive substances levels were higher in M while SOD activity was increased in E. No differences were observed in other activities. The results suggest that short-term consumption of IP/mate has protective effects on heart I/R injury similar to exercise, but the combination of these interventions appears to contradict the beneficial adaptations from exercise.
Subject(s)
Heart/drug effects , Ilex paraguariensis/chemistry , Myocardial Contraction/drug effects , Myocardial Reperfusion Injury/prevention & control , Physical Conditioning, Animal , Plant Extracts/pharmacology , Animals , Blood Pressure/drug effects , Glutathione/blood , Lipid Peroxidation/drug effects , Male , Nitrites/blood , Protein Carbonylation/drug effects , Rats , Rats, Wistar , Thiobarbituric Acid Reactive Substances/metabolismABSTRACT
BACKGROUND: Cardiac arrhythmias are one of the main causes of death in ChCP and other dilated cardiomyopathies. Previous studies demonstrated that ventricular arrhythmias are associated with the presence of autoantibodies with beta-adrenergic activity, Ab-ß. OBJECTIVES: The aim of this study was to investigate whether Ab-ß, present in chronic chagasic patients (ChCP), induce cardiac arrhythmias in the pharmacological type-2 long QT syndrome model (LQTS-2). METHODS/RESULTS: The LQTS2 was established by perfusion of Tyrode saline solution with a potassium channel blocker E-4031 (5µM) in isolated rabbit hearts or in rabbit cardiac strips, in order to record ECG or action potential, respectively. Autoantibodies from ChCP activating (Ab-ß) or not (Ab-NR) cardiac beta 1-adrenergic receptors were used. Ab-ß, but not Ab-NR, were able to significantly shorten QT, QTc and increase Tpeak-Tend interval in the LQTS-2. A positive correlation between higher QTc and Tpeak-Tend was found after Ab-ß perfusion in the same model. In addition, in the LQTS-2 model, in almost 75% (11/15) of the hearts perfused with Ab-ß, ventricular and atrio-ventricular electrical disturbances were observed. Atenolol abolished all Ab-ß-induced arrhythmias. Ab-ß, when perfused in a cellular LQTS-2, drastically reduced the action potential duration and evoked early afterdepolarization (EAD's), while Ab-NR did not modulate the AP properties in the LQTS-2. CONCLUSION: The results indicate that Ab-ß were able to induce cardiac arrhythmias and EAD's. This phenomenon can explain, at least in part, the cellular mechanism of Ab-ß-induced arrhythmias. Furthermore, atenolol is effective for the treatment of Ab-ß-induced arrhythmias.
Subject(s)
Arrhythmias, Cardiac/blood , Arrhythmias, Cardiac/physiopathology , Autoantibodies/blood , Chagas Cardiomyopathy/blood , Long QT Syndrome/physiopathology , Receptors, Adrenergic, beta-1/blood , Action Potentials/drug effects , Action Potentials/physiology , Animals , Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/therapeutic use , Anti-Arrhythmia Agents/toxicity , Arrhythmias, Cardiac/etiology , Electrocardiography/drug effects , Electrocardiography/methods , Heart/drug effects , Heart/physiopathology , Humans , Long QT Syndrome/chemically induced , Longitudinal Studies , Male , Rabbits , Retrospective StudiesABSTRACT
BACKGROUND: We investigated whether a chronic low-protein multideficient diet (BRD) from weaning turns on cardiovascular adaptive responses that could culminate in hypertension and heart failure. METHODS AND RESULTS: Systolic pressure (SP) and heart rate (HR) were determined in CTRL (normal diet) and BRD rats. Plasma albumin, plasma urea and urinary urea excretion decreased in BRD rats. In this group, echocardiography and the Langendorff technique showed: (i) increased HR and hypertension; (ii) decreased LVDP, dP/dtmax, dP/dtmin, cardiac output, ejection fraction, stroke volume and left ventricular diameter. BRD rats were less sensitive to isoproterenol (ISO) in LVDP and dP/dtmax, with unchanged dP/dtmin; Pressure-volume relationships indicated left-oriented shifts in LVDP, SP and DP, and decreased capacitance compared to CTRL. BRD rats had higher cardiac and lung indexes, accompanied by muscle atrophy and recent ventricular-infarcted areas, higher ventricular ß1-AR content, and decreased ß2-AR and α1-AR. Propranolol treatment gave similar ISO responses in both groups, disappearance of the infarcted regions and, except for ß2-AR, recovery of normal receptor expression. BRD rats had intense stimulation of plasma membrane Ca2+-ATPase (PMCA) activity, with increased Ca2+ affinity and inhibition of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA). Ventricular phospholamban increased and Na+/Ca2+ exchanger decreased. PMCA activity correlated with an increase in its PKC-mediated phosphorylation, overlying a decrease in PKA-catalyzed phosphorylation. Propranolol normalized PKC and PKA activities with recovery of PMCA but not SERCA. CONCLUSION: BRD triggers sympathetic exacerbation and dysfunction in Ca2+ handling, accompanied by early onset of hypertension and left ventricle congestive heart failure.
Subject(s)
Diet, Protein-Restricted/adverse effects , Heart Failure/metabolism , Hypertension/metabolism , Malnutrition/metabolism , Protein Deficiency/metabolism , Animals , Calcium Signaling/physiology , Chronic Disease , Diet, Protein-Restricted/trends , Heart Failure/etiology , Heart Failure/pathology , Hypertension/etiology , Hypertension/pathology , Male , Malnutrition/pathology , Protein Deficiency/pathology , Protein Kinases/metabolism , Rats , Rats, Wistar , Time Factors , Urea/metabolismABSTRACT
Few data are available on adolescent users because most behavioral studies on anabolic-androgenic steroids (AAS) abuse have been performed in adults. Studies evaluating the impact of long-term effects of AAS abuse on the prepubertal phase are even more uncommon. Accordingly, this study was developed to test the hypothesis that changes induced by the use of AAS during the adolescent phase may be noted in the adult phase even when the AAS treatment cycle is discontinued. Therefore, not only behavioral changes but also possible autonomic and electrolyte disorders were evaluated. For this purpose, we used male prepubertal, 26-day-old (P26) Wistar rats that were treated with vehicle (control, n=10) or testosterone propionate (TP; 5 mg/kg intramuscular (IM) injection, AAS, n=10) five times per week for 5 weeks, totaling 25 applications during the treatment. Aggression tests were performed at the end of the cycle (P54-56), whereas open-field tests (OFTs), elevated plus maze (EPM) behavioral tests and measurements of heart rate variability (HRV), fluid intake and pathology were conducted in the adult phase (P87-92). The AAS group showed greater aggressiveness in the pubertal phase and higher levels of horizontal and vertical exploration and anxiety-related behavior in the adult phase than the control group (P<0.05). HRV tests showed an increase in sympathetic autonomic modulation, and hydroelectrolytic assessment showed lower basal intake levels of hypertonic saline than the control group (P<0.05), without statistically significant changes in the basal intake of water. These data together suggest that the use of AAS during the prepubertal phase induces behavioral, autonomic and hydroelectrolytic changes that manifest in the adult phase even when treatment is discontinued in late adolescence in rats.
Subject(s)
Anabolic Agents/pharmacology , Autonomic Nervous System/drug effects , Behavior, Animal/drug effects , Eating/drug effects , Heart Rate/drug effects , Testosterone Propionate/pharmacology , Age Factors , Aggression/drug effects , Animals , Animals, Newborn , Body Weight , Drinking/drug effects , Electrocardiography , Exploratory Behavior/drug effects , Male , Maze Learning/drug effects , Rats , Rats, Wistar , Sodium/metabolismABSTRACT
OBJECTIVES: In the present study, we investigated whether MSC-transplantation can revert cardiac dysfunction in streptozotocin-induced diabetic rats and the immunoregulatory effects of MSC were examined. BACKGROUND: Cardiac complications are one of the main causes of death in diabetes. Several studies have shown anti-diabetic effects of bone marrow mesenchymal stromal cells (MSC). METHODS/RESULTS: The rats were divided in three groups: Non-diabetic, Diabetic and Diabetic-Treated with 5 × 10(6) MSC 4 weeks after establishment of diabetes. Four weeks after MSC-therapy, systemic metabolic parameters, immunological profile and cardiac function were assessed. MSC-transplantation was able to revert the hyperglycemia and body weight loss of the animals. In addition, after MSC-transplantation a decrease in corticosterone and IFN-γ sera levels without restoration of insulin and leptin plasma levels was observed. Also, MSC-therapy improved electrical remodeling, shortening QT and QTc in the ECG and action potential duration of left ventricular myocytes. No arrhythmic events were observed after MSC-transplantation. MSC-therapy rescued the cardiac beta-adrenergic sensitivity by increasing beta-1 adrenergic receptor expression. Both alpha and beta cardiac AMPK and p-AMPK returned to baseline values after MSC-therapy. However, total ERK1 and p-ERK1/2 were not different among groups. CONCLUSION: The results indicate that MSC-therapy was able to rescue cardiac impairment induced by diabetes, normalize cardiac AMPK subunit expression and activity, decrease corticosterone and glycemia and exert systemic immunoregulation.