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BackgroundChronic sympathetic stimulation drives desensitization and downregulation of β1 adrenergic receptor (β1AR) in heart failure. We aim to explore the differential downregulation subcellular pools of β1AR signaling in the heart.Methods and resultsWe applied chronic infusion of isoproterenol to induced cardiomyopathy in male C57BL/6J mice. We applied confocal and proximity ligation assay to examine β1AR association with L-type calcium channel, ryanodine receptor 2, and SERCA2a ((Sarco)endoplasmic reticulum calcium ATPase 2a) and Förster resonance energy transfer-based biosensors to probe subcellular β1AR-PKA (protein kinase A) signaling in ventricular myocytes. Chronic infusion of isoproterenol led to reduced β1AR protein levels, receptor association with L-type calcium channel and ryanodine receptor 2 measured by proximity ligation (puncta/cell, 29.65 saline versus 14.17 isoproterenol, P

Several ion currents in the mammalian ventricular myocardium are substantially regulated by the sympathetic nervous system via β-adrenergic receptor activation, including the slow delayed rectifier K+ current and the L-type calcium current. This study investigated the downstream mechanisms of β-adrenergic receptor stimulation by isoproterenol (ISO) on the inward rectifier (IK1) and the rapid delayed rectifier (IKr) K+ currents using action potential voltage clamp (APVC) and conventional voltage clamp techniques in isolated canine left ventricular cardiomyocytes. IK1 and IKr were dissected by 50 µM BaCl2 and 1 µM E-4031, respectively. Acute application of 10 nM ISO significantly increased IK1 under the plateau phase of the action potential (0–+20 mV) using APVC, and similar results were obtained with conventional voltage clamp. However, β-adrenergic receptor stimulation did not affect the peak current density flowing during terminal repolarization or the overall IK1 integral. The ISO-induced enhancement of IK1 was blocked by the calcium/calmodulin kinase II (CaMKII) inhibitor KN-93 (1 µM) but not by the protein kinase A inhibitor H-89 (3 µM). Neither KN-93 nor H-89 affected the IK1 density under baseline conditions (in the absence of ISO). In contrast, parameters of the IKr current were not affected by β-adrenergic receptor stimulation with ISO. These findings suggest that sympathetic activation enhances IK1 in canine left ventricular cells through the CaMKII pathway, while IKr remains unaffected under the experimental conditions used. [ABSTRACT FROM AUTHOR]

Dopamine (DA) and norepinephrine (NE) have been repeatedly implicated in neuropsychiatric vulnerability, in part via their roles in mediating the decision-making processes. Although two neuromodulators share a synthesis pathway and are coactivated under states of arousal, they engage in distinct circuits and modulatory roles. However, the specific role of each neuromodulator in decision-making, in particular the exploration–exploitation tradeoff, remains unclear. Revealing how each neuromodulator contributes to exploration– exploitation tradeoff is important in guiding mechanistic hypotheses emerging from computational psychiatric approaches. To under- stand the differences and overlaps of the roles of these two catecholamine systems in regulating exploration, a direct comparison using the same dynamic decision-making task is needed. Here, we ran male and female mice in a restless two-armed bandit task, which encourages both exploration and exploitation. We systemically administered a nonselective DA antagonist (flupenthixol), a nonselective DA agonist (apomorphine), a NE beta-receptor antagonist (propranolol), and a NE beta-receptor agonist (isoproterenol) and examined changes in exploration within subjects across sessions. We found a bidirectional modulatory effect of dopamine on exploration. Increasing dopamine activity decreased exploration and decreasing dopamine activity increased exploration. The modulatory effect of beta-noradrenergic receptor activity on exploration was mediated by sex. Reinforcement learning model parameters suggested that dopamine modulation affected exploration via decision noise and norepinephrine modulation affected exploration via sensitivity to outcome. Together, these findings suggested that the mechanisms that govern the exploration–exploitation transition are sensitive to changes in both catechol- amine functions and revealed differential roles for NE and DA in mediating exploration. [ABSTRACT FROM AUTHOR]

Although there is a bulk of evidence on the favorable effect of probiotics on the cardiac system, their role in the management of myocardial infarction is not clear. Three viable probiotic bacterial strains, namely Lactobacillus reuteri, Bifidobacterium longum, and Bifidobacterium lactis, were gavaged to the rats daily for 28 days prior to the induction of myocardial injury. Myocardial injury was induced by the use of isoproterenol (ISO) in the probiotics, control and sham groups. The heart tissues were catheterized to evaluate the histopathological parameters and measure the expression of genes related to inflammation. Treatment with ISO caused subendocardial necrosis and rupture of cardiac myofibrils. Pretreatment with probiotics reduced the size of myocardial infarction caused by ISO. Also, in the probiotic group, a relative decrease in the amount of tissue fibrosis and rupture of cardiomyocytes fibers was seen. Pretreatment with probiotics partially ameliorated myocardial necrosis, edema and leukocyte infiltration. Also, a remarkable decrease was detected in the expression of tissue proinflammatory genes in the pretreated group with probiotics. Thus, viable probiotic supplementation may ameliorate or prevent cardiac injury. Additional preclinical and clinical studies are required to clarify the impact of probiotics in the prevention and management of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Data comparing the outcomes of loose versus rigorous validation strategies for pulmonary vein isolation (PVI) in patients with paroxysmal atrial fibrillation (PAF) are limited. We aimed to prospectively assess the effectiveness of loose versus rigorous validation for PVI in patients with PAF with a maintained sinus rhythm. Methods: Patients (n = 117) with PAF were randomized to receive either loose validation (n = 59) or rigorous validation (n = 58) after PVI. The presence of dormant conduction in loose validation was assessed only by adenosine administration followed by isoproterenol infusion. The complete absence of pulmonary vein (PV) potentials in rigorous validation was confirmed by the combination of the Lasso catheter with isoproterenol plus adenosine. Dormant conduction, revealed by validation after PVI, was ablated until all reconnections were eliminated. Results: The procedure time in the rigorous validation group was greater than that in the loose validation group (161.3 ± 52.7 min vs. 142.5 ± 37.6 min, p = 0.03, respectively). After successful PVI, the detection of dormant PV reconnections in the rigorous validation group was significantly greater than that in the loose validation group (69.0% vs. 37.3%, p = 0.001). However, after reisolation of the sites of dormant PV conduction, the postablation recurrence rates in 1.3 years were similar between the groups (79.2% vs. 83.6%, p = 0.67). Conclusion: Rigorous validation can reveal dormant conduction in more than two‐thirds of patients with PAF undergoing PVI. However, rigorous validation and additional ablation of the resulting connections do not improve long‐term outcomes when a protocol that includes electrophysiological confirmation and pharmacological validation is used. [ABSTRACT FROM AUTHOR]

Background: A growing interest in using Nigella sativa oil (NSO) in the prevention or treatment of several cardiovascular diseases has prompted this study. The research aims to investigate the effect of NSO on cardiac damage prevention after long-term administration in induced myocardial infarction (MI) in rats. Methods: NSO was analyzed for its fatty acids composition using gas chromatography-mass spectrometry (GC-MS) analysis and administered in rats before and after isoproterenol (45 mg/kg body weight) induced myocardial infarction. The following parameters were assessed: electrocardiograms, histopathological examination, serum biochemical aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase-myocardial band (CK-MB), serum and heart inflammation (tumor necrosis factor-alpha (TNF), interleukin 1 beta (IL-1b), and interleukin 6 (IL-6)), and tissue oxidative stress (total antioxidant capacity (TAC), total oxidative stress (TOS), nitric oxide (NO), malondialdehyde (MDA), and the total thiols (THIOL)). Results: Linoleic acid (C18:2n-6) and oleic acid (C18:1n-9) were approximately 89% of total fatty acids while palmitic acid (C16:0) was 6.10%. Administration of NSO for 28 days helped in preventing QT and QTc interval prolongation and reduced heart rate (HR), after MI induction. The histological assessment showed improvement in myofibrillary degeneration and necrosis and also better reduced inflammatory process in the groups treated with NSO. In serum, pro-inflammatory cytokines IL-1b and IL-6 were downregulated in chronic conditions (for IL-1b, NSO vs. control was 86.09vs 150.39 pg/mL, and for IL-6 NSO vs. control was 78.00 vs. 184.98 pg/ml). In the heart tissue, the downregulation was observed only for TNF in both acute and chronic conditions (acute NSO vs. control was 132.37 vs. 207.63 pg/mL, and chronic NSO vs. control was 135.83 vs. 183.29 pg/ml). The pro-oxidant parameters TOS, NO, MDA, and OSI, were reduced in the groups treated with NSO only after 14 days of treatment, suggesting that the NSO antioxidant effect is time-dependent. Conclusions: NSO administration might have a favourable impact on the regulation of oxidative stress and inflammation processes after MI induction in rats, and it is worth considering its administration as an adjuvant treatment. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular diseases rank as the top global cause of mortality, particularly acute myocardial infarction (MI). MI arises from the blockage of a coronary artery, which disrupts blood flow and results in tissue death. Among therapeutic approaches, bioactives from medicinal plants emerge as promising for the development of new medicines. Objectives: This study explored the effects of naringenin (NAR 100 mg/kg), a flavonoid found in citrus fruits, in normotensive (NTR) and spontaneously hypertensive (SHR) rats, both subjected to isoproterenol (ISO 85 mg/kg)-induced MI. Results: Post-treatment assessments indicated that NAR reduced blood pressure and minimized clot formation, particularly notable in the SHR group, which helps mitigate damage related to hypertension and ISO exposure. Additionally, NAR effectively restored KCl-induced contractility in the aortas of both NTR and SHR groups. NAR treatment reduced reduced glutathione (GSH) and lipid hydroperoxides (LOOH) values and recovered the activity of the antioxidant enzymes catalase (CAT) and glutathione-s-transferase (GST) in NTR groups. Moreover, myocardial damage assessed through histological analyses was reduced in groups treated with NAR. Conclusions: The results highlight significant pathophysiological differences between the groups, suggesting that NAR has protective potential against ISO-induced cardiac damage, warranting further investigation into its protective effects and mechanisms. [ABSTRACT FROM AUTHOR]

Background: Activation of β2 adrenergic receptors reduces cutaneous mechanical pain thresholds in rats. While β2 adrenergic receptor activation may contribute to mechanisms that underlie temporomandibular joint pain, its effect on masticatory muscle pain sensitivity is uncertain. Objectives: The current study sought to determine the extent to which β adrenergic receptors are expressed by masticatory muscle afferent fibres, and to assess the effect of local activation of these receptors on the mechanical sensitivity of masticatory muscle afferent fibres in rats. Methods: Trigeminal ganglion neurons that innervate the rat (n = 12) masseter muscle and lower lip were identified by tissue injection of fluorescent dyes and were then stained with antibodies against β1 or β2 adrenergic receptors. Extracellular recordings from 60 trigeminal ganglion neurons that innervate the masticatory muscle were undertaken in a second group of anaesthetised rats of both sexes (n = 37) to assess afferent mechanical activation thresholds. Thresholds were assessed before and after injection of the β adrenergic receptor agonists into masticatory muscle. Results: β1 and β2 adrenergic receptor expression was greater in labial skin than in masticatory muscle ganglion neurons (p <.05, one‐way ANOVA, Holm–Sidak test). There was a higher expression of β2 adrenergic receptors in masticatory muscle ganglion neurons in males than in females. The mixed β agonist isoproterenol increased afferent mechanical activation threshold in male but not female rats (p <.05, Mann–Whitney test). In male rats, salbutamol, a β2 selective agonist, also increased afferent mechanical activation threshold but hydralazine, a vasodilator, did not (p <.05, Mann–Whitney test). Conclusion: Activation of β2 adrenergic receptors decreases the mechanical sensitivity of masticatory muscle afferent fibres in a sex‐related manner. [ABSTRACT FROM AUTHOR]

Background: Residual non-pulmonary vein (PV) foci are significantly associated with atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). However, we previously reported among patients with non-PV foci induced only once, none experienced AF recurrence. Thus, we aimed to investigate the correlation between the residual induction number of non-PV foci and ablation outcome in paroxysmal AF patients. Methods and results: We investigated 55 paroxysmal AF patients with residual non-PV foci after PVI and ablation of non-PV-foci. Study patients were classified into the residual one-time induction of non-PV foci (residual OTI-nPVF) group (n = 23) and residual repeatedly induced non-PV foci (residual RI-nPVF) group (n = 32). Furthermore, the residual RI-nPVF group was divided into the low inducibility group (n = 10) and high inducibility group (n = 22) according to the presence or absence of non-PV foci provoked by two sets of drug induction tests (non-PV foci inducibility). In addition, the latter was divided into the ablation group (n = 14) or observation group (n = 8). The 2-year AF recurrence‐free rate in the residual RI-nPVF group was significantly lower compared to the residual OTI-nPVF group (53% vs. 90%, p = 0.018). There was no significant difference of the 2-year AF recurrence‐free rates in the inducibility of non-PV foci (p = 0.913) and the presence or absence of ablation (p = 0.812) in the residual RI-nPVF group. Conclusions: Among paroxysmal AF patients, the presence of residual RI-nPVF was associated with higher AF recurrence compared to residual OTI-nPVF. Furthermore, within residual RI-nPVF subgroup, non-PV foci inducibility or ablation of some residual RI-nPVF did not affect ablation outcome. [ABSTRACT FROM AUTHOR]

This investigation evaluated the therapeutic benefit of apocynin in isoproterenol (ISO)‐induced cardiac damage in rats. ISO‐administered male Wistar rats were treated with apocynin for 2 weeks. Blood plasma and left ventricle of heart tissues were collected and analyzed for oxidative stress‐related parameters such as malondialdehyde (MDA), advanced oxidation protein product (AOPP), and nitric oxide (NO). The activities of endogenous antioxidant enzymes such as superoxide dismutase (SOD) and catalase were also measured. The gene expressions of oxidative stress‐related proteins such as Nrf‐2, HO‐1, and HO‐2 in cardiac tissues were also measured. In silico studies like molecular docking and molecular dynamics were also performed to detect how apocynin interacts with NADPH and nitric oxide synthase at the molecular level. This investigation revealed significant elevation of serum transferase enzymes and creatinine kinase‐Muscle Brain (CK‐MB) activities in ISO‐administered rats compared to the control. Apocynin effectively normalized the serum transferases and CK‐MB activities in the blood of ISO‐stressed rats. Moreover, ISO‐induced elevations of MDA, NO, and AOPP levels were also suppressed by apocynin treatment. Consistently, apocynin restored the reduced SOD and catalase activities in ISO‐administered rats. This restoration of enzyme activity might be due to the increased expression of Nrf‐2 and HO‐1 and reduced expression of iNOS and TNF‐α in ISO‐administered rats. Histological analysis revealed that apocynin treatment ameliorated the mononuclear cell adherence and fibrosis in the cardiac tissue of ISO‐administered rats. Computational studies also support the experimental findings. This study demonstrates that apocynin prevents ISO‐induced cardiac injury not only by preventing inflammation but also by empowering the antioxidant defense system. [ABSTRACT FROM AUTHOR]

Objective: To discuss the effect of bone marrow mesenchymal stem cells (BMSCs) -derived exosomes (Exo) on isoproterenol (ISO) -induced myocardial fibrosis in the rats, and to clarify its mechanism. Methods: The Exo was isolated from the BMSCs and characterized by transmission electron microscope, nanoparticle tracking analysis, and Western blotting methods. Forty SD rats were divided into control group, model group, BMSCs-Exo group, and BMSCs-Exo+ferroptosis activator (Erastin) group, and there were 10 rats in each group. The myocardial fibrosis models were established by subcutaneous injection of ISO in all the rats except control group. The rats in BMSCs-Exo and BMSCs-Exo+Erastin groups were given BMSCs-Exo, and the rats in BMSCs-Exo+Erastin group were additionally injected with Erastin intraperitoneally. After 4 weeks, echocardiography was used to detect the left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end diastolic diameter (LVEDD), and left ventricular end systolic diameter (LVESD) of the rats in various groups; HE staining was used to observe the pathomorphology of myocardium tissue of the rats in various groups; Masson staining was used to observe the fibrosis degrees of myocardium tissue of the rats in various groups; immunohistochemistry was used to detect the positive expression rates of α-smooth muscle actin (α-SMA), type Ⅰ collagen (COL-Ⅰ), and type Ⅲ collagen (COL-Ⅲ) in myocardium tissue of the rats in various groups; colorimetry was used to detect the Fe2+ level in myocardium tissue of the rats in various groups; Western blotting method was used to detect the expression levels of acyl-CoA synthetase long chain family member 4 (ACSL4), ferritin heavy chain 1 (FTH1), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11) proteins in myocardium tissue of the rats in various groups. Results: The particles isolated from BMSCs had a typical lipid bilayer structure, and most particle sizes distributed around 100 nm. High expression levels of CD63, CD9, tumor susceptibility gene 101 (TSG101), and heat shock protein 70 (HSP70) proteins confirmed the particles as Exo. Compared with control group, the LVEF and LVFS of the rats in model group were significantly decreased (P<0. 05), LVEDD and LVESD were increased (P<0. 05), the myocardial cell arrangement was disordered, some nuclear shrinkage and necrosis were seen, the collagen volume fraction (CVF) was significantly increased (P< 0. 05), the positive expression rates of α -SMA, COL-Ⅰ, and COL-Ⅲ were significantly increased (P< 0. 05), the Fe2+ level in myocardium tissue was significantly increased (P<0. 05), the expression level of ACSL4 protein was significantly increased (P<0. 05), and the expression levels of FTH1, GPX4, and SLC7A11 proteins were significantly decreased (P<0. 05). Compared with model group, the LVEF and LVFS of the rats in BMSCs-Exo group were significantly increased (P<0. 05), the LVEDD and LVESD were significantly decreased (P<0. 05), the myocardial tissue damage was significantly alleviated, the CVF was significantly decreased (P<0. 05), the positive expression rates of α -SMA, COL- Ⅰ, and COL- Ⅲ were significantly decreased (P<0. 05), the Fe2+ level in myocardium tissue was significantly decreased (P<0. 05), the expression level of ACSL4 protein was significantly decreased (P<0. 05), and the expression levels of FTH1, GPX4, and SLC7A11 proteins were significantly increased (P<0. 05). Compared with BMSCs-Exo group, the LVEF and LVFS of the rats in BMSCs-Exo+Erastin group were significantly decreased (P<0. 05), the LVEDD and LVESD were significantly increased (P<0. 05), the myocardial cell edema and necrosis were seen, the CVF was significantly increased (P<0. 05), the positive expression rates of α -SMA, COL-Ⅰ, and COL-Ⅲ were significantly increased (P<0. 05), the Fe2+ level in myocardium tissue was significantly increased (P<0. 05), the expression level of ACSL4 protein was significantly increased (P<0. 05), and the expression levels of FTH1, GPX4, and SLC7A11 proteins were significantly decreased (P<0. 05). Conclusion: BMSC-derived Exo can improve the myocardial fibrosis in the rats induced by ISO, and its mechanism may be related to the inhibition of ferroptosis. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI) is considered one of the most common cardiac diseases and major cause of death worldwide. The prevalence of MI and MI‐associated mortality have been increasing in recent years due to poor lifestyle habits viz. residency, obesity, stress, and pollution. Synthetic drugs for the treatment of MI provide good chance of survival; however, the demand to search more safe, effective, and natural drugs is increasing. Plants provide fruitful sources for powerful antioxidant and anti‐inflammatory agents for prevention and/or treatment of MI. However, many plant extracts lack exact information about their possible dosage, toxicity and drug interactions which may hinder their usefulness as potential treatment options. Phytoconstituents play cardioprotective role by either acting as a prophylactic or adjuvant therapy to the concurrently used synthetic drugs to decrease the dosage or relief the side effects of such drugs. This review highlights the role of different herbal formulations, examples of plant extracts and types of several isolated phytoconstituents (phenolic acids, flavonoids, stilbenes, alkaloids, phenyl propanoids) in the prevention of MI with reported activities. Moreover, their possible mechanisms of action are also discussed to guide future research for the development of safer substitutes to manage MI. [ABSTRACT FROM AUTHOR]

Summary: Purpose: Multiple Myeloma (MM) is considered an incurable, biologically heterogeneous disease of the plasma cells. The clinical data on the association between stress and the molecular mechanism of stress hormone receptor expression and its relationship with IL‑6 signaling pathway have not yet proposed a clear answer in MM. This study aims to explore the effect of isoproterenol and propranolol, which are beta-adrenergic agonists and antagonists, respectively on suppressor of cytokine signaling (SOCS) and IL-6/gp130 signaling in MM cell lines. Material and methods: Four different MM cell lines (KMM‑1, RPMI 8226, LP‑1, and L363) were treated with isoproterenol and propranolol. Optimal dosages of isoproterenol and propranolol were determined, and the mRNA expression levels of IL‑6, gp130, and SOCS‑1 were examined using qRT-PCR. Results: The analysis of our results indicated that propranolol, as a β-adrenoreceptor antagonist, could increase MM cell death and ameliorate IL‑6 and its receptor gp130 in addition to up-regulate SOCS‑1 gene expression. On the other hand, isoproterenol, as a β-adrenoreceptor agonist, could provoke MM cell viability and IL‑6 expression. Conclusions: β‑adrenergic signaling seems to affect cell viability through targeting IL-6/gp130 and SOCS‑1 signaling in MM, underscoring the importance of further studies on stress hormones and IL‑6 suppressors as potent candidates for MM therapy. [ABSTRACT FROM AUTHOR]

BackgroundNitric oxide (NO) has been identified as a signaling molecule generated during β-adrenergic receptor stimulation in the heart. Furthermore, a role for NO in triggering spontaneous Ca2+ release via S-nitrosylation of CaMKIIδ (Ca2+/calmodulin kinase II delta) is emerging. NO donors are routinely used clinically for their cardioprotective effects on the heart, but it is unknown how NO donors modulate the proarrhythmic CaMKII to alter cardiac arrhythmia incidence. We test the role of S-nitrosylation of CaMKIIδ at the Cysteine-273 inhibitory site and cysteine-290 activating site in cardiac Ca2+ handling and arrhythmogenesis before and during β-adrenergic receptor stimulation.MethodsWe measured Ca2+-handling in isolated cardiomyocytes from C57BL/6J wild-type (WT) mice and mice lacking CaMKIIδ expression (CaMKIIδ-KO) or with deletion of the S-nitrosylation site on CaMKIIδ at cysteine-273 or cysteine-290 (CaMKIIδ-C273S and -C290A knock-in mice). Cardiomyocytes were exposed to NO donors, S-nitrosoglutathione (GSNO; 150 μM), sodium nitroprusside (200 μM), and β-adrenergic agonist isoproterenol (100 nmol/L).ResultsBoth WT and CaMKIIδ-KO cardiomyocytes responded to isoproterenol with a full inotropic and lusitropic Ca2+ transient response as well as increased Ca2+ spark frequency. However, the increase in Ca2+ spark frequency was significantly attenuated in CaMKIIδ-KO cardiomyocytes. The protection from isoproterenol-induced Ca2+ sparks and waves was mimicked by GSNO pretreatment in WT cardiomyocytes but lost in CaMKIIδ-C273S cardiomyocytes. When GSNO was applied after isoproterenol, this protection was not observed in WT or CaMKIIδ-C273S but was apparent in CaMKIIδ-C290A. In Langendorff-perfused isolated hearts, GSNO pretreatment limited isoproterenol-induced arrhythmias in WT but not CaMKIIδ-C273S hearts, while GSNO exposure after isoproterenol sustained or exacerbated arrhythmic events.ConclusionsWe conclude that prior S-nitrosylation of CaMKIIδ at cysteine-273 can limit subsequent β-adrenergic receptor-induced arrhythmias, but that S-nitrosylation at cysteine-290 might worsen or sustain β-adrenergic receptor-induced arrhythmias. This has important implications for the administration of NO donors in the clinical setting.

This study aimed to investigate the potential cardioprotective effects of moderate and high-intensity aerobic interval training (MIIT and HIIT) preconditioning. The focus was on histological changes, pro-oxidant-antioxidant balance, autophagy initiation, and apoptosis in myocardial tissue incited by isoproterenol-induced pathological cardiac remodeling (ISO-induced PCR). Male Wistar rats were randomly divided into control (n = 6), ISO (n = 8), MIIT (n = 4), HIIT (n = 4), MIIT + ISO (n = 8), and HIIT + ISO (n = 8) groups. The MIIT and HIIT protocols were administered for 10 weeks, followed by the induction of cardiac remodeling using subcutaneous injection of ISO (100 mg/kg for two consecutive days). Alterations in heart rate (HR), mean arterial pressure (MAP), rate pressure product (RPP), myocardial oxygen consumption (MVO2), cardiac hypertrophy, histopathological changes, pro-oxidant-antioxidant balance, autophagy biomarkers (Beclin-1, Atg7, p62, LC3 I/II), and apoptotic cell distribution were measured. The findings revealed that the MIIT + ISO and HIIT + ISO groups demonstrated diminished myocardial damage, hemorrhage, immune cell infiltration, edema, necrosis, and apoptosis compared to ISO-induced rats. MIIT and HIIT preconditioning mitigated HR, enhanced MAP, and preserved MVO2 and RPP. The pro-oxidant-antioxidant balance was sustained in both MIIT + ISO and HIIT + ISO groups, with MIIT primarily inhibiting pro-apoptotic autophagy progression through maintaining pro-oxidant-antioxidant balance, and HIIT promoting pro-survival autophagy. The results demonstrated the beneficial effects of both MIIT and HIIT as AITs preconditioning in ameliorating ISO-induced PCR by improving exercise capacity, hemodynamic parameters, and histopathological changes. Some of these protective effects can be attributed to the modulation of cardiac apoptosis, autophagy, and oxidative stress. [ABSTRACT FROM AUTHOR]

Objective: To investigate the cardioprotective potential of betulin in isoproterenol (ISO)-induced myocardial injury in rats. Methods: Wistar rats were divided into five groups (n=10): normal, ISO, nebivolol 5 mg/kg, and betulin (20 & 40 mg/kg). Nebivolol and betulin were administered orally for 29 days. ISO (85 mg/kg) was administered subcutaneously on day 27 and day 28 to induce myocardial injury. On day 29, blood was collected for determination of cardiac markers, and hemodynamic parameters were investigated. The levels of oxidative stress markers and the gene expressions of apoptotic markers and inflammatory mediators were evaluated. Moreover, 2,3,5-triphenyltetrazolium chloride staining and histopathological analysis were also performed. Results: Betulin reduced the size of myocardial infarction, decreased elevated levels of cardiac enzymes, and maintained hemodynamic functions. It also inhibited ISO-induced upregulation of Bax, caspase-3, NF-κB, and 1L-6, enhanced endogenous antioxidant enzymes, and reduced lipid peroxidation. Additionally, pretreatment with betulin alleviated myocardial ischemic damage, as reflected by reduced myonecrosis, edema, and inflammatory changes. Conclusions: Betulin exhibits strong cardioprotective activity against ISO-induced myocardial injury by anti-inflammatory, anti-apoptotic, and antioxidant activities.

The major contribution of myocardial damage to global mortalities raises debate regarding the exploration of new therapeutic strategies for its treatment. Therefore, our study investigated the counteracting effect of tiron against isoprenaline (ISO)-mediated cardiac infarction in mice. Tiron was administered tomice for 7 days prior to two consecutive injections of ISOon days 8 and 9 of the treatment protocol. Tiron significantly reduced the levels of CK-MB, LDH, and AST in serum samples of ISO-challenged mice. A considerable increase in the cardiac antioxidant response was observed in tiron-treated mice, as indicated by depletion of MDA and enhancement of antioxidant activities. Furthermore, tiron induced amarked decrease in NLRP3, ASC, and caspase-1 levels accompanied by weak immune reactions of IL-1β, NF-kB, TLR4, and iNOS in the infarct cardiac tissues. Histopathological screening validated these variations observed in the cardiac specimens. Thus, tiron clearly mitigated the oxidative and inflammatory stress by repressing the NLRP3 inflammasome and the TLR4/NF-kB/iNOS signaling cascade. [ABSTRACT FROM AUTHOR]

Introduction: Isoproterenol (ISO) is regarded as an adrenergic non-selective β agonist. It regulates myocardial contractility and may cause damage to cardiac tissues. Alchemilla vulgaris (AV) is an herbal plant that has garnered considerable attention due to its anti-inflammatory and antioxidant bioactive components. The present investigation assessed the cardioprotective potential of AV towards ISOinduced myocardial damage. Methods: Four groups of mice were utilized: control that received saline, an ISO group (85 mg/kg, S.C.), ISO + AV100, and ISO + AV200 groups (mice received 100 or 200 mg/kg AV orally along with ISO). Results and discussion: ISO induced notable cardiac damage demonstrated by clear histopathological disruption and alterations in biochemical parameters. Intriguingly, AV treatment mitigates ISO provoked oxidative stress elucidated by a substantial enhancement in superoxide dismutase (SOD) and catalase (CAT) activities and reduced glutathione (GSH) content, as well as a considerable reduction in malondialdehyde (MDA) concentrations. In addition, notable downregulation of inflammatory biomarkers (IL-1β, TNF-α, and RAGE) and the NF-κB/p65 pathway was observed in ISO-exposed animals following AV treatment. Furthermore, the pro-apoptotic marker Bax was downregulated together with autophagy markers Beclin1 and LC3 with in ISO-exposed animals when treated with AV. Pre-treatment with AV significantly alleviated ISO-induced cardiac damage in a dose related manner, possibly due to their antioxidant and antiinflammatory properties. Interestingly, when AV was given at higher doses, a remarkable restoration of ISO-induced cardiac injury was revealed. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation contributes to the progression of isoproterenol (ISO)‐induced heart failure (HF). Caspase‐associated recruitment domain (CARD) families are crucial proteins for initiation of inflammation in innate immunity. Nonetheless, the relevance of CARDs in ISO‐driven cardiac remodelling is little explored. Methods: This study utilized Card9−/− mice and reconstituted C57BL/6 mice with either Card9−/− or Otud1−/− marrow‐derived cells. Mechanistic studies were conducted in primary macrophages, cardiomyocytes, fibroblasts and HEK‐293T cells. Results: Here, we demonstrated that CARD9 was substantially upregulated in murine hearts infused with ISO. Either whole‐body CARD9 knockout or myeloid‐specific CARD9 deletion inhibited ISO‐driven murine cardiac inflammation, remodelling and dysfunction. CARD9 deficiency in macrophages prevented ISO‐induced inflammation and alleviated remodelling changes in cardiomyocytes and fibroblasts. Mechanistically, we found that ISO enhances the activity of CARD9 by upregulating ovarian tumour deubiquitinase 1 (OTUD1) in macrophages. We further demonstrated that OTUD1 directly binds to the CARD9 and then removes the K33‐linked ubiquitin from CARD9 to promote the assembly of the CARD9‐BCL10‐MALT1 (CBM) complex, without affecting CARD9 stability. The ISO‐activated CBM complex results in NF‐κB activation and macrophage‐based inflammatory gene overproduction, which then enhances cardiomyocyte hypertrophy and fibroblast fibrosis, respectively. Myeloid‐specific OTUD1 deletion also attenuated ISO‐induced murine cardiac inflammation and remodelling. Conclusions: These results suggested that the OTUD1‐CARD9 axis is a new pro‐inflammatory signal in ISO‐challenged macrophages and targeting this axis has a protective effect against ISO‐induced HF. Key points: Macrophage CARD9 was elevated in heart tissues of mice under chronic ISO administration.Either whole‐body CARD9 knockout or myeloid‐specific CARD9 deficiency protected mice from ISO‐induced inflammatory heart remodeling.ISO promoted the assembly of CBM complex and then activated NF‐κB signaling in macrophages through OTUD1‐mediated deubiquitinating modification.OTUD1 deletion in myeloid cells protected hearts from ISO‐induced injuries in mice. [ABSTRACT FROM AUTHOR]

The present study evaluated the cardioprotective effect of astaxanthin (ASX) against isoproterenol (ISO) induced myocardial infarction in rats via the pathway of mitochondrial biogenesis as the possible molecular target of astaxanthin. The control group was injected with normal physiological saline subcutaneously for 2 days. The second group was injected with ISO at a dose of 85 mg/kg bwt subcutaneously for 2 days. The third, fourth and fifth groups were supplemented with ASX at doses of 10, 20, 30 mg/kg bwt, respectively daily by oral gavage for 21 days then injected with ISO dose of 85 mg/kg bwt subcutaneously for 2 successive days. Isoproterenol administration in rats elevated the activities of Creatine kinase‐MB (CK‐MB), aspartate transaminase (AST), lactate dehydrogenase (LDH), and other serum cardiac biomarkers Troponin‐I activities, oxidative stress biomarkers, malondialdehyde(MDA), Nuclear factor‐kappa B (NF‐KB), while it decreased Peroxisome proliferator‐activated receptor‐gamma coactivator (PGC‐1α), Nuclear factor erythroid‐2‐related factor 2 (Nfe212), mitochondrial transcriptional factor A (mt TFA), mitochondrial DNA copy number and glutathione system parameters. However, Astaxanthin decreased the activities of serum AST, LDH, CK‐MB, and Troponin I that elevated by ISO. In addition, it increased glutathione peroxidase and reductase activities, total glutathione and reduced GSH content, and GSH/GSSG ratio, mtDNA copy number, PGC‐1α expression and Tfam expression that improved mitochondrial biogenesis while it decreased GSSG and MDA contents and NF‐KB level in the cardiac tissues. This study indicated that astaxanthin relieved isoproterenol induced myocardial infarction via scavenging free radicals and reducing oxidative damage and apoptosis in cardiac tissue. [ABSTRACT FROM AUTHOR]

Despite considerable advances in interventions and treatment, there is a high mortality rate in patients with myocardial infarction (MI). This is the first study to investigate the protective effects of 3, 4‐dihydroxybenzoic acid against isoproterenol induced MI in rats. MI was induced by isoproterenol (100‐mg/kg body weight) in rats. Then, rats were treated with 3, 4‐dihydroxybenzoic acid (16‐mg/kg body weight) for 2 weeks. Serum creatine kinase‐MB, cardiac troponin‐T, cardiac troponin‐I, and heart thiobarbituric acid reactive substances were significantly (p < 0.05) increased and heart superoxide dismutase and catalase activities were significantly (p < 0.05) reduced in isoproterenol‐induced myocardial infarcted rats. Isoproterenol induction significantly (p < 0.05) elevated the plasma homocysteine and serum high sensitivity‐C‐reactive protein levels. Furthermore, an enzyme‐linked immunosorbent assay, reverse transcription polymerase chain study, and immunohistochemical (IHC) staining revealed significantly (p < 0.05) elevated levels and expression of serum/myocardial nuclear factor‐κB, tumor necrosis factor‐alpha, interleukin‐1 beta, and Interleukin‐6 and significantly (p < 0.05) reduced levels/expression of serum/myocardial interleukin‐10 in myocardial infarcted rats. Nevertheless, isoproterenol‐induced rats treated with 3, 4‐dihydroxybenzoic acid considerably (p < 0.05) attenuated all the biochemical, molecular, and IHC parameters investigated and inhibited oxidative stress and inflammation and protected the heart, through its antioxidant and anti‐inflammatory mechanisms. [ABSTRACT FROM AUTHOR]

Heart Failure (HF) continues to be a complex public health issue with increasing world population prevalence. Although overall mortality has decreased for HF and hypertrophic cardiomyopathy (HCM), a precursor for HF, their prevalence continues to increase annually. Because the etiology of HF and HCM is heterogeneous, it has been difficult to identify novel therapies to combat these diseases. Isoproterenol (ISP), a non-selective β-adrenoreceptor agonist, is commonly used to induce cardiotoxicity and cause acute and chronic HCM and HF in mice. However, the variability in dose and duration of ISP treatment used in studies has made it difficult to determine the optimal combination of ISP dose and delivery method to develop a reliable ISP-induced mouse model for disease. Here we examined cardiac effects induced by ISP via subcutaneous (SQ) and SQ-minipump (SMP) infusions across 3 doses (2, 4, and 10mg/kg/day) over 2 weeks to determine whether SQ and SMP ISP delivery induced comparable disease severity in C57BL/6J mice. To assess disease, we measured body and heart weight, surface electrocardiogram (ECG), and echocardiography recordings. We found all 3 ISP doses comparably increase heart weight, but these increases are more pronounced when ISP was administered via SMP. We also found that the combination of ISP treatment and delivery method induces contrasting heart rate, RR interval, and R and S amplitudes that may place SMP treated mice at higher risk for sustained disease burden. Mice treated via SMP also had increased heart wall thickness and LV Mass, but mice treated via SQ showed greater increase in gene markers for hypertrophy and fibrosis. Overall, these data suggest that at 2 weeks, mice treated with 2, 4, or 10mg/kg/day ISP via SQ and SMP routes cause similar pathological heart phenotypes but highlight the importance of drug delivery method to induce differing disease pathways. [ABSTRACT FROM AUTHOR]

Raspberry ketone (RK) is an active constituent obtained from Rubus idaeus (Rosaceae), which has been traditionally used against diabetes, hypertension, etc. The objective of this study was to assess the cardioprotective effect of RK against isoproterenol (ISO)-induced cardiac hypertrophy in Wistar rats. Rats were arbitrarily divided into six groups and were treated daily with raspberry ketone (100 and 200 mg/kg), fenofibrate (80 mg/kg) and propranolol (10 mg/kg) along with ISO (3 mg/kg, subcutaneously) for 28 days. Twenty-four hours after the last dose administration, serum and heart tissue samples from the animals were taken and their hemodynamic (blood pressure, heart rate], biochemical (CK-MB, LDH, troponin-T, PPAR-α, apolipoprotein C III, c-reactive protein, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, very-low-density lipoprotein, malondialdehyde, reduced glutathione, superoxide dismutase, catalase, Na+-K+-ATPase, total antioxidant capacity, and nitric oxide), histopathological, and immunohistochemical (caspase-3, nuclear factor-κB, tumor necrosis factor-α) analysis was performed along with gravimetric analysis. Administration of ISO significantly altered the cardiac integrity and physiology and these changes were significantly averted by the administration of RK (100 and 200 mg/kg). These results were also found to be comparable with those of the standard drugs, fenofibrate and propranolol. The assessment of cardiac morphology by histopathological and immunohistochemical analysis further validated these results. This study thus demonstrated that RK at doses of 100 and 200 mg/kg showed a dose-dependent decrease in inflammation, oxidative stress, and dyslipidemia against ISO-induced cardiac hypertrophy in Wistar rats, which could be due to agonistic action of RK at PPAR-α receptor subtype. [ABSTRACT FROM AUTHOR]

Right ventricular failure (RVF) is a major cause of early mortality after heart transplantation (HT). Isoproterenol (Iso) has chronotropic, inotropic, and vasodilatory properties, which might improve right ventricle function in this setting. We aimed to investigate the hemodynamic effects of isoproterenol on patients with post-HT RVF. We conducted a 1-yr retrospective observational study including patients receiving isoproterenol (Iso) and dobutamine for early RVF after HT. A comprehensive multiparametric hemodynamic evaluation was performed successively three times: no isoproterenol, low doses: 0.025 µg/kg/min, and high doses: 0.05 µg/kg/min (henceforth, respectively, called no Iso, low Iso, and high Iso). From June 2022 to June 2023, 25 patients, median [interquartile range (IQR) 25–75] age 54 [38–61] yr, were included. Before isoproterenol was introduced, all patients received dobutamine, and 15 (60%) were on venoarterial extracorporeal membrane oxygenation (VA-ECMO). Isoproterenol significantly increased heart rate from 84 [77–99] (no Iso) to 91 [88–106] (low Iso) and 102 [90–122] beats/min (high Iso, P < 0.001). Similarly, cardiac index rose from 2.3 [1.4–3.1] to 2.7 [1.8–3.4] and 3 [1.9–3.7] L/min/m2 (P < 0.001) with a concomitant increase in indexed stroke volume (28 [17–34] to 31 [20–34] and 33 [23–35] mL/m2, P < 0.05). Effective pulmonary arterial elastance and pressures were not modified by isoproterenol. Pulmonary vascular resistance (PVR) tended to decrease from 2.9 [1.4–3.6] to 2.3 [1.3–3.5] wood units (WU), P = 0.06. Right ventricular ejection fraction/systolic pulmonary artery pressure (sPAP) evaluating right ventricle-pulmonary artery (RV-PA) coupling increased after isoproterenol from 0.8 to 0.9 and 1%·mmHg−1 (P = 0.001). In conclusion, in post-HT RVF, isoproterenol exhibits chronotropic and inotropic effects, thereby improving RV-PA coupling and resulting in a clinically relevant increase in the cardiac index. NEW & NOTEWORTHY: This study offers a detailed and comprehensive hemodynamic investigation at the bedside, illustrating the favorable impact of isoproterenol on right ventricular-pulmonary arterial coupling and global hemodynamics. It elucidates the physiological effects of an underused inotropic strategy in a critical clinical scenario. By enhancing cardiac hemodynamics, isoproterenol has the potential to expedite right ventricular recovery and mitigate primary graft dysfunction, thereby reducing the duration of mechanical support and intensive care unit stay posttransplantation. [ABSTRACT FROM AUTHOR]

Background: Isoproterenol is a drug used for the treatment of bradycardia that has many side effects due to its non-selective β-adrenoceptor agonist properties. Aim: In this study, we evaluated an in vivo experimental model for isoproterenol (ISO) cardiac injury using BALB/c mice and protective treatment with a combined optimized dose of Arctiin (AR) and Lactobacillus plantarum (LP) (ARLP; 30 mg/kg b.w. AR and viable 106 CFU/mL LP p.o.) together. Introduction: Isoproterenol causes cardiac injury in many instances. Arctiin is a naturally occurring lignin glycoside present in many herbal medicinal plants that has many beneficial effects for humans. Lactobacillus plantarum is yet another beneficial probiotic that benefits largely to humans. Materials and Methods: Male BALB/c mice in appropriate groups (6 animals each) were treated with ARLP for 7 days with ISO administration (100 mg/kg i.p.) on days 5 and 6. On the 8th day, animals were sacrificed. Serum and heart samples were collected for further processing. CK-MB, cardiac troponin, AST, ALT, LDH, GST, GPx, CAT, SOD, GSH, GSSG, MDA, nuclear factor kappa B (NFκB), TNF-α, and IL-6 by ELISA and gene expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) were estimated in samples. Results: Mice administered with ISO showed a prominent rise in the serum marker enzyme activities and tissue oxidative stress markers (MDA and GSSG). Furthermore, marked reductions in body weight and enzymatic and non-enzymatic antioxidant levels were noticed in ISO toxicity. Alterations in proinflammatory cytokines (TNF-α and IL-6) and Nrf2 levels by RT-PCR were analyzed. Histopathology of the heart also indicated cardiac injury in ISO-intoxicated mice. ARLP pretreatment prevented all these cardiac injuries and exerted significant (p ≤ 0.05) prophylactic protection toward cardiac tissue. Further, we analyzed the possible interactions between AR and LP in vitro, to understand the influence of ARonLP, which showed no significant suppressive/antibacterial activity on LP. Conclusion: In conclusion, ARLP exerts a strong cardioprotective and anti-inflammatory activity in cardiovascular injury. [ABSTRACT FROM AUTHOR]

Introduction: Myocardial infarction (MI) is a global burden that implies on quality of life. Platelet-rich plasma (PRP) is an autologous source of growth factors that is recently suggested due to its healing properties. Isoproterenol (ISO) is a β-agonist drug used as experimental model of myocardial injury through cardiac hyperactivity and production of reactive oxygen species. Aim of Work: To investigate the role of PRP in preservation of cardiac tissue and enhancing healing in isoproterenol (ISO) induced myocardial injury. Materials and Methods: 48 adult male albino rats were used as follows; Control group (N=18), Myocardial injury group (N=18) and Myocardial injury with PRP group (N=12). ISO was administered as a single subcutaneous dose (67 mg/kg) and PRP was injected intracardiac after 12 h from ISO injection. Hearts were harvested at 7 days and 21 days and left ventricular sections were stained for histological and immunohistochemical study. Results: Isoproterenol treated sections showed necrosis and apoptosis of myocardial fibers with loss of striations. Interstiuim showed mononuclear cellular infiltration and significant increase in collagen deposition. Moreover, blood vessels showed congestion and hemorrhage. Examination of PRP treated sections showed restoration of normal architecture of myocardial fibers. There was a statistically significant decrease in apoptosis and necrosis of myocardial cells. Also, interstitium showed an apparent decrease in mononuclear cellular infiltration and hemorrhage. These findings were observed after one week of PRP administration and became more evident after three weeks. Meanwhile, collagen deposition showed highly significant decrease in PRP treated group only after three weeks in comparison to ISO only treated group. Conclusion: PRP was found to decrease myocardial death and accelerate healing. PRP can be considered a simple, economically feasible and favorable strategy in management of myocardial injury. [ABSTRACT FROM AUTHOR]

Targeting non-pulmonary vein triggers (NPVTs) after pulmonary vein isolation may reduce atrial fibrillation (AF) recurrence. Isoproterenol infusion and cardioversion of spontaneous or induced AF can provoke NPVTs but typically require vasopressor support and increased procedural time. The purpose of this study was to identify risk factors for the presence of NPVTs and create a risk score to identify higher-risk subgroups. Using the AF ablation registry at the Hospital of the University of Pennsylvania, we included consecutive patients who underwent AF ablation between January 2021 and December 2022. We excluded patients who did not receive NPVT provocation testing after failing to demonstrate spontaneous NPVTs. NPVTs were defined as non-pulmonary vein ectopic beats triggering AF or focal atrial tachycardia. We used risk factors associated with NPVTs with P <.1 in multivariable logistic regression model to create a risk score in a randomly split derivation set (80%) and tested its predictive accuracy in the validation set (20%). In 1530 AF ablations included, NPVTs were observed in 235 (15.4%). In the derivation set, female sex (odds ratio [OR] 1.40; 95% confidence interval [CI] 0.96–2.03; P =.080), sinus node dysfunction (OR 1.67; 95% CI 0.98–2.87; P =.060), previous AF ablation (OR 2.50; 95% CI 1.70–3.65; P <.001), and left atrial scar (OR 2.90; 95% CI 1.94–4.36; P <.001) were risk factors associated with NPVTs. The risk score created from these risk factors (PRE 2 SSS 2 score; [PRE]vious ablation: 2 points, female [S]ex: 1 point, [S]inus node dysfunction: 1 point, left atrial [S]car: 2 points) had good predictive accuracy in the validation cohort (area under the receiver operating characteristic curve 0.728; 95% CI 0.648–0.807). A risk score incorporating predictors for NPVTs may allow provocation of triggers to be performed in patients with greatest expected yield. [ABSTRACT FROM AUTHOR]

Objective: To investigate the cardioprotective potential of betulin in isoproterenol (ISO)-induced myocardial injury in rats. Methods: Wistar rats were divided into five groups (n=10): normal, ISO, nebivolol 5 mg/kg, and betulin (20 & 40 mg/kg). Nebivolol and betulin were administered orally for 29 days. ISO (85 mg/kg) was administered subcutaneously on day 27 and day 28 to induce myocardial injury. On day 29, blood was collected for determination of cardiac markers, and hemodynamic parameters were investigated. The levels of oxidative stress markers and the gene expressions of apoptotic markers and inflammatory mediators were evaluated. Moreover, 2,3,5-triphenyltetrazolium chloride staining and histopathological analysis were also performed. Results: Betulin reduced the size of myocardial infarction, decreased elevated levels of cardiac enzymes, and maintained hemodynamic functions. It also inhibited ISO-induced upregulation of Bax, caspase-3, NF-κB, and IL-6, enhanced endogenous antioxidant enzymes, and reduced lipid peroxidation. Additionally, pretreatment with betulin alleviated myocardial ischemic damage, as reflected by reduced myonecrosis, edema, and inflammatory changes. Conclusions: Betulin exhibits strong cardioprotective activity against ISO-induced myocardial injury by anti-inflammatory, antiapoptotic, and antioxidant activities. [ABSTRACT FROM AUTHOR]

Long-term β-adrenoceptor (β-AR) stimulation is a pathological mechanism associated with cardiovascular diseases resulting in endothelial and perivascular adipose tissue (PVAT) dysfunction. In this study, we aimed to identify whether β-adrenergic signaling has a direct effect on PVAT. Thoracic aorta PVAT was obtained from male Wistar rats and cultured ex vivo with the β-AR agonist isoproterenol (Iso; 1 µM) or vehicle for 24 hours. Conditioned culture medium (CCM) from Iso-treated PVAT induced a marked increase in aorta contractile response, induced oxidative stress, and reduced nitric oxide production in PVAT compared to vehicle. In addition, Iso-treated PVAT and PVAT-derived differentiated adipocytes exhibited higher corticosterone release and protein expression of 11β–hydroxysteroid dehydrogenase type 1 (11β-HSD1), an enzyme responsible for de novo synthesis of corticosterone. Macrophages exposed to Iso also exhibited increased corticosterone release in response to β-AR stimulation. Incubation of Iso-treated PVAT and PVAT-derived differentiated adipocytes with β3-AR antagonist restored aorta contractile function modulated by Iso-CCM and normalized 11β-HSD1 protein expression. These results show that β3-AR signaling leads to upregulation of 11β-HSD1 in PVAT, thus increasing corticosterone release and contributing to impair the anticontractile function of this tissue. [ABSTRACT FROM AUTHOR]

BackgroundHigh-dose isoproterenol infusion is a useful provocative maneuver to elicit triggers of atrial fibrillation (AF) during ablation. We evaluated whether the use of isoproterenol infusion to elicit triggers of AF after ablation is associated with differential outcomes.MethodsWe performed a retrospective study of all patients who underwent de novo radiofrequency catheter ablation of AF enrolled in the University of California, San Diego AF Ablation Registry. The primary outcome was freedom from atrial arrhythmias on or off antiarrhythmic drugs (AAD).ResultsOf 314 patients undergoing AF ablation, 235 (74.8%) received isoproterenol while 79 (25.2%) did not. Among those who received isoproterenol, 11 (4.7%) had additional triggers identified. There were no statistically significant differences in procedure time (p = 0.432), antiarrhythmic drug use (p = 0.289), procedural complications (p = 0.279), recurrences of atrial arrhythmias on or off AAD [adjusted hazard ratio (AHR) 0.92 (95% CI 0.58-1.46); p = 0.714], all-cause hospitalizations [AHR 1.00 (95% CI 0.60-1.67); p = 0.986], or all-cause mortality [AHR 0.14 (95% CI 0.01-3.52); p = 0.229] between groups.ConclusionsIn this registry analysis, use of isoproterenol is safe but was not associated with a reduction in recurrence of atrial arrhythmias.

Connexin-43 (Cx43) is the most abundant protein forming gap junction channels (GJCs) in cardiac ventricles. In multiple cardiac pathologies, including hypertrophy and heart failure, Cx43 is found remodeled at the lateral side of the intercalated discs of ventricular cardiomyocytes. Remodeling of Cx43 has been long linked to spontaneous ventricular arrhythmia, yet the mechanisms by which arrhythmias develop are still debated. Using a model of dystrophic cardiomyopathy, we previously showed that remodeled Cx43 function as aberrant hemichannels (non-forming GJCs) that alter cardiomyocyte excitability and, consequently, promote arrhythmias. Here, we aim to evaluate if opening of remodeled Cx43 can serve as a general mechanism to alter cardiac excitability independent of cellular dysfunction associated with a particular cardiomyopathy. To address this issue, we used a genetically modified Cx43 knock-in mouse (S3A) that promotes cardiac remodeling of Cx43 protein without apparent cardiac dysfunction. Importantly, when S3A mice were subjected to cardiac stress using the β-adrenergic agonist isoproterenol (Iso), they displayed acute and severe arrhythmias, which were not observed in WT mice. Pretreatment of S3A mice with the Cx43 hemichannel blocker, Gap19, prevented Iso-induced abnormal electrocardiographic behavior. At the cellular level, when compared with WT, Iso-treated S3A cardiomyocytes showed increased membrane permeability, greater plasma membrane depolarization, and Ca2+ overload, which likely caused prolonged action potentials, delayed after depolarizations, and triggered activity. All these cellular dysfunctions were also prevented by Cx43 hemichannel blockers. Our results support the notion that opening of remodeled Cx43 hemichannels, regardless of the type of cardiomyopathy, is sufficient to mediate cardiac-stress-induced arrhythmogenicity.

Background Increased left atrial pressure (LAP) contributes to dyspnea and heart failure with preserved ejection fraction in patients with atrial fibrillation (AF). The purpose of this study was to investigate the differences in baseline LAP and LAP response to rapid pacing between paroxysmal and persistent AF. Methods and Results This observational study prospectively enrolled 1369 participants who underwent AF catheter ablation, excluding those with reduced left ventricular ejection fraction. H2FPEF score was calculated by echocardiography and baseline characteristics. Patients underwent LAP measurements during AF, sinus rhythm, and heart rates of 90, 100, 110, and 120 beats per minute (bpm), induced by right atrial pacing and isoproterenol. The baseline LAP‐peak in the persistent AF group consistently exceeded that in the paroxysmal AF (PAF) group across each H2FPEF score subgroup (all P

Activation of β-adrenergic receptors (β-ARs) not only enhances learning and memory but also facilitates the induction of long-term potentiation (LTP), a form of synaptic plasticity involved in memory formation. To identify the mechanisms underlying β-AR-dependent forms of LTP we examined the effects of the β-AR agonist isoproterenol on LTP induction at excitatory synapses onto CA1 pyramidal cells in the ventral hippocampus. LTP induction at these synapses is inhibited by activation of SK-type K+ channels, suggesting that β-AR activation might facilitate LTP induction by inhibiting SK channels. However, although the SK channel blocker apamin enhanced LTP induction, it did not fully mimic the effects of isoproterenol. We therefore searched for potential alternative mechanisms using liquid chromatography-tandem mass spectrometry to determine how β-AR activation regulates phosphorylation of postsynaptic density (PSD) proteins. Strikingly, β-AR activation regulated hundreds of phosphorylation sites in PSD proteins that have diverse roles in dendritic spine structure and function. Moreover, within the core scaffold machinery of the PSD, β-AR activation increased phosphorylation at several sites previously shown to be phosphorylated after LTP induction. Together, our results suggest that β-AR activation recruits a diverse set of signaling pathways that likely act in a concerted fashion to regulate LTP induction.

Panax japonicus has long been utilized as an herbal remedy in Chinese traditional medicine for treating various diseases. In this investigation, we present the environmentally friendly silver nanoparticle (AgNP) synthesis by the aqueous extract of P. japonicas to follow its cardioprotective effects. Through various analytical methods, we identified the nanoparticles (NPs). Our XRD findings revealed the formation of Ag@P. japonicus, while FE-SEM imagery indicated a spherical shape, with NPs measuring less than 40 nm. The UV–Vis and FT-IR spectroscopy confirm the green synthesis of Ag@P. japonicus. In the medicinal section, 45 Wistar rats were utilized. These groups consisted of a normal group, a group that was solely treated with isoproterenol for inducing myocardial infarction, and two groups that were pretreated with AgNPs at different doses for 14 days. These pretreated groups were then challenged with isoproterenol. The expression of PI3K/Akt/mTOR and other downstream inflammatory and apoptotic mediators were followed. Additionally, the expression of Keap1, Nrf2, ECG, cardiac markers, and other downstream antioxidant enzymes were assessed. Treatment with AgNPs ameliorated the apoptosis, inflammation, and myocardial autophagy, regulated the PI3K/Akt/mTOR pathway, increased the antioxidant enzyme efficacies, and activated the Keap1/Nrf2/HO-1 pathway. The findings suggest that AgNPs may have a cardioprotective efficacy on myocardial infarction by mitigating the Keap1/Nrf2 pathway, GST, GPx, GSH, SOD, IL-1β, IL-6, TNF-α, NF-κB, Bax, Bcl2, caspase-9, caspase-3, and PI3K/Akt/mTOR pathway. Furthermore, the treatment decreased the infarct region size, attenuated the cardiac indicators levels, and mitigated immune cell infiltration and myocardial necrosis.

Objective(s): Neurological disorders are the world’s most distressing problem. The adverse effects of current medications continue to compel scientists to seek safer, more effective, and economically affordable alternatives. In this vein, we explored the effect of D-Pinitol on isoproterenol-induced neurotoxicity in mice.Materials and Methods: Forty-two mice were randomly distributed into 7 groups each having 6 animals. Group I; received saline. Group II; received isoproterenol (ISO) 15 mg/kg/day, s.c. for 20 days. Group III, IV; received 50 and 100 mg/kg/day/oral of D-Pinitol, respectively along with ISO for 20 days. Group V; received D-Pinitol 100 mg/kg/day/oral for 20 days. Group VI; received propranolol 20 mg/kg/day/oral and ISO for 20 days. Group VII; received propranolol 20 mg/kg/day/oral for 20 days. On the 21st day after behavioral tests, blood was collected and mice were sacrificed for various biochemical, histopathological, and immunohistochemical analyses.Results: Chronic administration of isoproterenol caused neurotoxicity, cognitive dysfunction, and histopathological changes in the brain as evidenced by increase in GFAP, oxidative stress (via SOD, CAT, TBARS, and GSH), neuroinflammation (NF-kB, TNF-α, IL-6, and IL-10), and decrease in AchE and BDNF. Co-administration of D-Pinitol (100 mg/kg) significantly prevented these pathological alterations. The cognitive improvement was also observed through the forced swim test, elevated plus maze test, and rotarod test.Conclusion: Our findings on D-Pinitol thus clearly established its neuroprotective role in ISO-induced neurodegeneration in Swiss albino mice.

Cardiac maturation represents the last phase of heart development and is characterized by morphofunctional alterations that optimize the heart for efficient pumping. Its understanding provides important insights into cardiac regeneration therapies. Recent evidence implies that adrenergic signals are involved in the regulation of cardiac maturation, but the mechanistic underpinnings involved in this process are poorly understood. Herein, we explored the role of β-adrenergic receptor (β-AR) activation in determining structural and functional components of cardiomyocyte maturation. Temporal characterization of tyrosine hydroxylase and norepinephrine levels in the mouse heart revealed that sympathetic innervation develops during the first 3 wk of life, concurrent with the rise in β-AR expression. To assess the impact of adrenergic inhibition on maturation, we treated mice with propranolol, isolated cardiomyocytes, and evaluated morphofunctional parameters. Propranolol treatment reduced heart weight, cardiomyocyte size, and cellular shortening, while it increased the pool of mononucleated myocytes, resulting in impaired maturation. No changes in t-tubules were observed in cells from propranolol mice. To establish a causal link between β-AR signaling and cardiomyocyte maturation, mice were subjected to sympathectomy, followed or not by restoration with isoproterenol treatment. Cardiomyocytes from sympathectomyzed mice recapitulated the salient immaturity features of propranolol-treated mice, with the additional loss of t-tubules. Isoproterenol rescued the maturation deficits induced by sympathectomy, except for the t-tubule alterations. Our study identifies the β-AR stimuli as a maturation promoting signal and implies that this pathway can be modulated to improve cardiac regeneration therapies. NEW & NOTEWORTHY: Maturation involves a series of morphofunctional alterations vital to heart development. Its regulatory mechanisms are only now being unveiled. Evidence implies that adrenergic signaling regulates cardiac maturation, but the mechanisms are poorly understood. To address this point, we blocked β-ARs or performed sympathectomy followed by rescue experiments with isoproterenol in neonatal mice. Our study identifies the β-AR stimuli as a maturation signal for cardiomyocytes and highlights the importance of this pathway in cardiac regeneration therapies. [ABSTRACT FROM AUTHOR]