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Fundamental & Clinical Pharmacology Oct 2023Volatile anesthetics may cause vascular dysfunction; however, underlying effects are unclear. The aim of the present study was to investigate whether sevoflurane and...
Volatile anesthetics may cause vascular dysfunction; however, underlying effects are unclear. The aim of the present study was to investigate whether sevoflurane and isoflurane affect vascular function, nitric oxide (NO) bioavailability, and biomarkers of oxidative stress and inflammation. Wistar rats were divided into three experimental groups: Not anesthetized (control group) or submitted to anesthesia with isoflurane (Iso group) or sevoflurane (Sevo group). Hemodynamic parameters were monitored during anesthesia, and blood gas values and biochemical determinants were analyzed. Isometric contractions were recorded in aortic rings. Vasoconstriction induced by potassium chloride (KCl) and phenylephrine (Phe) were measured. No differences in hemodynamic parameters and blood gasses variables were observed. Impaired KCl and Phe-induced contractions were observed in endothelium-intact aorta of Sevo compared to Iso and Control groups. Redox imbalance was found in Sevo and Iso groups. Reduced NO bioavailability and increased activity of matrix metalloproteinase 2 (MMP-2) were observed in Sevo, but not in the Iso group. While reduced IL-10 and IL-1β were observed in Sevo, increases in IL-1β in the Iso group were found. Sevoflurane, but not isoflurane, anesthesia impairs vasocontraction, and reduced NO and cytokines and increased MMP-2 activity may be involved in vascular dysfunction after sevoflurane anesthesia.
Topics: Rats; Animals; Isoflurane; Sevoflurane; Matrix Metalloproteinase 2; Methyl Ethers; Anesthetics, Inhalation; Rats, Wistar; Anesthesia
PubMed: 37085979
DOI: 10.1111/fcp.12901 -
International Journal of Molecular... Jul 2023Patients with obstructive sleep apnea (OSA) exhibit a high prevalence of pulmonary hypertension and right ventricular (RV) hypertrophy. However, the exact molecule...
Patients with obstructive sleep apnea (OSA) exhibit a high prevalence of pulmonary hypertension and right ventricular (RV) hypertrophy. However, the exact molecule responsible for the pathogenesis remains unknown. Given the resistance to RV dilation observed in transient receptor potential canonical 3 mice during a pulmonary hypertension model induced by phenylephrine (PE), we hypothesized that TRPC3 also plays a role in chronic intermittent hypoxia (CIH) conditions, which lead to RV dilation and dysfunction. To test this, we established an OSA mouse model using 8- to 12-week-old 129/SvEv wild-type and mice in a customized breeding chamber that simulated sleep and oxygen cycles. Functional parameters of the RV were evaluated through analysis of cardiac cine magnetic resonance images, while histopathological examinations were conducted on cardiomyocytes and pulmonary vessels. Following exposure to 4 weeks of CIH, mice exhibited significant RV dysfunction, characterized by decreased ejection fraction, increased end-diastole RV wall thickness, and elevated expression of pathological cardiac markers. In addition, reactive oxygen species (ROS) signaling and the endothelin system were markedly increased solely in the hearts of CIH-exposed mice. Notably, no significant differences in pulmonary vessel thickness or the endothelin system were observed in the lungs of wild-type (WT) and mice subjected to 4 weeks of CIH. In conclusion, our findings suggest that TRPC3 serves as a regulator of RV resistance in response to pressure from the pulmonary vasculature, as evidenced by the high susceptibility to RV dilation in mice without notable changes in pulmonary vasculature under CIH conditions.
Topics: Animals; Mice; Chronic Disease; Endothelins; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Mice, 129 Strain; Sleep Apnea, Obstructive; Disease Models, Animal
PubMed: 37511045
DOI: 10.3390/ijms241411284 -
Cell Death & Disease Jun 2024Pathological cardiac hypertrophy is one of the major risk factors of heart failure and other cardiovascular diseases. However, the mechanisms underlying pathological...
Pathological cardiac hypertrophy is one of the major risk factors of heart failure and other cardiovascular diseases. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. Here, we identified the first evidence that TNFAIP3 interacting protein 3 (TNIP3) was a negative regulator of pathological cardiac hypertrophy. We observed a significant upregulation of TNIP3 in mouse hearts subjected to transverse aortic constriction (TAC) surgery and in primary neonatal rat cardiomyocytes stimulated by phenylephrine (PE). In Tnip3-deficient mice, cardiac hypertrophy was aggravated after TAC surgery. Conversely, cardiac-specific Tnip3 transgenic (TG) mice showed a notable reversal of the same phenotype. Accordingly, TNIP3 alleviated PE-induced cardiomyocyte enlargement in vitro. Mechanistically, RNA-sequencing and interactome analysis were combined to identify the signal transducer and activator of transcription 1 (STAT1) as a potential target to clarify the molecular mechanism of TNIP3 in pathological cardiac hypertrophy. Via immunoprecipitation and Glutathione S-transferase assay, we found that TNIP3 could interact with STAT1 directly and suppress its degradation by suppressing K48-type ubiquitination in response to hypertrophic stimulation. Remarkably, preservation effect of TNIP3 on cardiac hypertrophy was blocked by STAT1 inhibitor Fludaradbine or STAT1 knockdown. Our study found that TNIP3 serves as a novel suppressor of pathological cardiac hypertrophy by promoting STAT1 stability, which suggests that TNIP3 could be a promising therapeutic target of pathological cardiac hypertrophy and heart failure.
Topics: Animals; Cardiomegaly; STAT1 Transcription Factor; Myocytes, Cardiac; Mice; Rats; Male; Mice, Inbred C57BL; Ubiquitination; Membrane Proteins; Mice, Transgenic; Humans; Phenylephrine; Protein Stability; Mice, Knockout
PubMed: 38926347
DOI: 10.1038/s41419-024-06805-4 -
Pain and Therapy Aug 2023This study aims to evaluate the efficacy of esketamine on postoperative recovery quality after laparoscopic bariatric surgery.
INTRODUCTION
This study aims to evaluate the efficacy of esketamine on postoperative recovery quality after laparoscopic bariatric surgery.
METHODS
Patients (n = 74) scheduled for laparoscopic bariatric surgery were randomly divided into two groups: the esketamine group (group E: 0.5 mg/kg/h infusion, i.e., 0.2 mL/kg/h) or the control group (group C: 0.2 mL/kg/h normal saline infusion). The infusions were stopped 20 min before the end of the procedure. The primary outcome was the Quality of Recovery-40 (QoR-40) score on postoperative day 1 (POD 1). The secondary outcomes included QoR-40 scores on PODs 2 and 7, Numeric Rating Scale (NRS) on PODs 1, 2, and 7, time to extubation, additional postoperative analgesic use, length of hospital stay, and time to first exhaust. Additonally, the safety indices were also recorded, including hemodynamic profile, perioperative anesthesia index (Ai), utilization of vasoactive drugs or urapidil, and side effects.
RESULTS
All in all, 70 of the 74 patients completed the study, 35 in each group. The difference of QoR-40 scores on POD 1 was both statistically and clinically significant [difference 7.21, 95% confidence interval (CI) 5.17, 9.25, p < 0.001]. The difference of QoR-40 on POD 2 was statistically significant but clinically insignificant (difference 4.81, 95% CI 2.69, 6.92, p < 0.001). The difference of NRS scores on POD 1 was statistically significant (difference -1.23, 95% CI -2.36, -0.10, p = 0.033). Compared with group C, group E had a lower utilization rate of phenylephrine and higher Ai values (p < 0.05). There was no statistical difference between the two groups on other measures.
CONCLUSION
Continuous ketamine infusion seems to be safe and well tolerated in laparoscopic bariatric surgery. It improved the quality of postoperative recovery and reduced pain on POD 1. In spite of the increased Ai value during the surgery, it also provided better hemodynamics with less usage of phenylephrine.
PubMed: 37171754
DOI: 10.1007/s40122-023-00519-9 -
Biochemical and Biophysical Research... Oct 2023Cardiotoxicity caused by adrenergic receptor agonists overdosing or stress-induced catecholamine release promotes cardiomyopathy, resembling Takotsubo cardiomyopathy...
Cardiotoxicity caused by adrenergic receptor agonists overdosing or stress-induced catecholamine release promotes cardiomyopathy, resembling Takotsubo cardiomyopathy (TC). TC is characterized by transient regional systolic dysfunction of the left ventricle. The animal models of TC and modalities for assessing regional wall motion abnormalities in animal models are lacking. We previously reported the protective role of a small noncoding microRNA-204-5p (miR-204) in cardiomyopathies, but its role in TC remains unknown. Here we compared the impact of miR-204 absence on phenylephrine (PE)-induced and transaortic constriction (TAC)-induced changes in cardiac muscle motion in the posterior and anterior apical, mid, and basal segments of the left ventricle using 2-dimensional speckle-tracking echocardiography (2-STE). Wildtype and miR-204 mice were subjected to cardiac stress in the form of PE for four weeks or TAC-induced pressure overload for five weeks. PE treatment increased longitudinal and radial motion in the apex of the left ventricle and shortened the peak motion time of all left ventricle segments. The TAC led to decreased longitudinal and radial motion in the left ventricle segments, and there was no difference in the peak motion time. Compared to wildtype mice, PE-induced peak cardiac muscle motion time in the anterior base of the left ventricle was significantly earlier in the miR-204 mice. There was no difference in TAC-induced peak cardiac muscle motion time between wildtype and miR-204 mice. Our findings demonstrate that PE and TAC induce regional wall motion abnormalities that 2-STE can detect. It also highlights the role of miR-204 in regulating cardiac muscle motion during catecholamine-induced cardiotoxicity.
Topics: Animals; Mice; Phenylephrine; Cardiotoxicity; Echocardiography; Takotsubo Cardiomyopathy; Cardiomyopathies; MicroRNAs
PubMed: 37454401
DOI: 10.1016/j.bbrc.2023.07.011 -
Cell Death & Disease Nov 2023Phenotypic and functional changes in vascular smooth muscle cells (VSMCs) contribute significantly to cardiovascular diseases (CVD) but factors driving early adverse...
Phenotypic and functional changes in vascular smooth muscle cells (VSMCs) contribute significantly to cardiovascular diseases (CVD) but factors driving early adverse vascular changes are poorly understood. We report on novel and important roles for the Brn-3b/POU4F2 (Brn-3b) transcription factor (TF) in controlling VSMC integrity and function. Brn-3b protein is expressed in mouse aorta with localisation to VSMCs. Male Brn-3b knock-out (KO) aortas displayed extensive remodelling with increased extracellular matrix (ECM) deposition, elastin fibre disruption and small but consistent narrowing/coarctation in the descending aortas. RNA sequencing analysis showed that these effects were linked to deregulation of genes required for calcium (Ca) signalling, vascular contractility, sarco-endoplasmic reticulum (S/ER) stress responses and immune function in Brn-3b KO aortas and validation studies confirmed changes in Ca signalling genes linked to increased intracellular Ca and S/ER Ca depletion [e.g. increased, Cacna1d Ca channels; ryanodine receptor 2, (RyR2) and phospholamban (PLN) but reduced ATP2a1, encoding SERCA1 pump] and chaperone proteins, Hspb1, HspA8, DnaJa1 linked to increased S/ER stress, which also contributes to contractile dysfunction. Accordingly, vascular rings from Brn-3b KO aortas displayed attenuated contractility in response to KCl or phenylephrine (PE) while Brn-3b KO-derived VSMC displayed abnormal Ca signalling following ATP stimulation. This data suggests that Brn-3b target genes are necessary to maintain vascular integrity /contractile function and deregulation upon loss of Brn-3b will contribute to contractile dysfunction linked to CVD.
Topics: Animals; Male; Mice; Aorta; Calcium; Cardiovascular Diseases; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Transcription Factor Brn-3B
PubMed: 38007517
DOI: 10.1038/s41419-023-06306-w -
Journal of the American Heart... Dec 2023Cardiac hypertrophy (CH) is a well-established risk factor for many cardiovascular diseases and a primary cause of mortality and morbidity among older adults. Currently,...
BACKGROUND
Cardiac hypertrophy (CH) is a well-established risk factor for many cardiovascular diseases and a primary cause of mortality and morbidity among older adults. Currently, no pharmacological interventions have been specifically tailored to treat CH. OTUD7B (ovarian tumor domain-containing 7B) is a member of the ovarian tumor-related protease (OTU) family that regulates many important cell signaling pathways. However, the role of OTUD7B in the development of CH is unclear. Therefore, we investigated the role of OTUD7B in CH.
METHODS AND RESULTS
OTUD7B knockout mice were used to assay the role of OTUD7B in CH after transverse aortic coarctation surgery. We further assayed the specific functions of OTUD7B in isolated neonatal rat cardiomyocytes. We found that OTUD7B expression decreased in hypertrophic mice hearts and phenylephrine-stimulated neonatal rat cardiomyocytes. Furthermore, OTUD7B deficiency exacerbated transverse aortic coarctation surgery-induced myocardial hypertrophy, abnormal cardiac function, and fibrosis. In cardiac myocytes, OTUD7B knockdown promoted phenylephrine stimulation-induced myocardial hypertrophy, whereas OTUD7B overexpression had the opposite effect. An immunoprecipitation-mass spectrometry analysis showed that OTUD7B directly binds to KLF4 (Krüppel-like factor 4). Additional molecular experiments showed that OTUD7B impedes KLF4 degradation by inhibiting lysine residue at 48 site-linked ubiquitination and suppressing myocardial hypertrophy by activating the serine/threonine kinase pathway.
CONCLUSIONS
These results demonstrate that the OTUD7B-KLF4 axis is a novel molecular target for CH treatment.
Topics: Mice; Rats; Animals; Kruppel-Like Factor 4; Aortic Coarctation; Cardiomegaly; Phenylephrine; Mice, Knockout; Ubiquitination; Myocytes, Cardiac; Mice, Inbred C57BL; Endopeptidases
PubMed: 38084712
DOI: 10.1161/JAHA.123.029745 -
Analytica Chimica Acta Oct 2023An electrochemical sensor with high sensitivity was designed and used to measure several drugs, including acetaminophen (AC), diphenhydramine (DPH), and phenylephrine...
An electrochemical sensor with high sensitivity was designed and used to measure several drugs, including acetaminophen (AC), diphenhydramine (DPH), and phenylephrine (PHE). This sensor was created using a carbon paste electrode (CPE) that has been modified with a GdZnMnO/ZnO nanocomposite. In order to analyze the developed sensor, scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM), X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FT-IR) techniques were used. The electrochemical behavior of the modified electrode was investigated by cyclic voltammetry, chronoamperometry, and apparent resistance spectroscopy methods. Also, the compound's diffusion coefficient (D) was calculated. By using the differential pulse voltammetry, AC, DPH, and PA were determined with detection limits of 2.5 × 10, 3.3 × 10, and 1.4 × 10 M in the linear concentration ranges of 0.09-900 μM. Finally, the designed sensor was utilized to measure the drug in real samples, and acceptable results were obtained.
Topics: Acetaminophen; Zinc Oxide; Spectroscopy, Fourier Transform Infrared; Phenylephrine; Diphenhydramine; Carbon; Electrochemical Techniques; Electrodes
PubMed: 37827630
DOI: 10.1016/j.aca.2023.341766 -
Ophthalmic Plastic and Reconstructive...To assess the predictability of phenylephrine testing for congenital ptosis and review outcomes of Müller's Muscle-conjunctival resection (MMCR) for congenital ptosis...
PURPOSE
To assess the predictability of phenylephrine testing for congenital ptosis and review outcomes of Müller's Muscle-conjunctival resection (MMCR) for congenital ptosis across ten years of follow-up.
METHODS
In this retrospective case series, all patients who underwent MMCR for congenital ptosis at a single institution between 2010 and 2020 were identified. Exclusion criteria included patients who had not undergone preoperative testing with 2.5% phenylephrine in the superior fornix; patients who underwent revision surgery; and patients who had a broken suture in the early postoperative period. Demographics, margin-reflex distance 1 (MRD1) values pre- and postphenylephrine, millimeters of tissue resected intraoperatively, and final postoperative MRD1 were recorded.
RESULTS
A total of 28 patients were included; 19 patients received MMCR and 9 patients received a combined MMCR plus tarsectomy. The amount of tissue resected ranged from 5 to 11 mm. There was no significant difference between median postphenylephrine MRD1 and median final postoperative MRD1 in either surgical group. Neither patient age nor levator function was significantly associated with a change in MRD1 in either group. The addition of a tarsectomy had no bearing on the final MRD1 value.
CONCLUSIONS
MMCR is a viable option for patients with congenital ptosis and moderate levator function with a response to phenylephrine. In these patients, MRD1 after 2.5% phenylephrine testing correlates to the final postoperative MRD1 outcome within 0.5 mm.
Topics: Humans; Phenylephrine; Blepharoplasty; Retrospective Studies; Blepharoptosis; Eyelids; Oculomotor Muscles; Treatment Outcome
PubMed: 36893062
DOI: 10.1097/IOP.0000000000002365 -
Immunity, Inflammation and Disease Aug 2023Cardiac hypertrophy is an initiating link to Heart failure (HF) which still seriously endangers human health. Transferrin receptor (TFRC), which promotes iron uptake...
TFRC in cardiomyocytes promotes macrophage infiltration and activation during the process of heart failure through regulating Ccl2 expression mediated by hypoxia inducible factor-1α.
BACKGROUND
Cardiac hypertrophy is an initiating link to Heart failure (HF) which still seriously endangers human health. Transferrin receptor (TFRC), which promotes iron uptake through the transferrin cycle, is essential for cardiac function. However, whether TFRC is involved in the process of pathological cardiac hypertrophy is not clear.
METHODS
Transverse aortic constriction (TAC) mouse model and mice primary cardiomyocytes treated with isoproterenol (ISO) or phenylephrine (PHE) were used to mimic cardiac hypertrophy in vivo and in vitro. Single cell RNA sequence data from heart tissues of TAC-model mice was obtained from the Gene Expression Omnibus (GEO) database, and was analyzed with R package Seurat. TFRC expression and macrophage infiltration in the heart tissue were tested by immunofluorescent staining. Macrophage polarization was detected by Flow Cytometry. TFRC expressions were detected by qRT-PCR, Western blot, and ELISA.
RESULTS
TFRC expression is increased in the pathological cardiac hypertrophy of mice model and positively associated with macrophage infiltration. Furthermore, TFRC in cardiomyocytes recruits and activates macrophages by secreting C-C motif ligand 2 (Ccl2) in the mice heart tissue with TAC surgery or in the primary cardiomyocytes stimulated with ISO or PHE to induce myocardial hypertrophy in vitro. Moreover, we find that TFRC promotes Ccl2 expression in cardiomyocytes via regulating signal transducer and activator of transcription 3 (STAT3). In addition, we find that increased TFRC expression in the HF tissue is regulated by hypoxia-inducible factor-1α (HIF-1α).
CONCLUSION
This in-depth study shows that TFRC in cardiomyocytes promotes HF development through inducing macrophage infiltration and activation via the STAT3-Ccl2 signaling, and TFRC expression in cardiomyocytes is regulated by HIF-1α during HF. This study first uncovers the role of TFRC in cardiomyocytes on macrophage infiltration and activation during HF.
Topics: Humans; Animals; Mice; Myocytes, Cardiac; Hypoxia-Inducible Factor 1, alpha Subunit; Heart Failure; Receptors, Transferrin; Disease Models, Animal; Cardiomegaly; Hypoxia
PubMed: 37647427
DOI: 10.1002/iid3.835