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The Journal of Pharmacology and... Jun 2024Streptolysin O (SLO), a bacterial toxin produced by common hemolytic streptococci, including and resident microbiota, may be associated with inflammation in the...
Streptolysin O (SLO), a bacterial toxin produced by common hemolytic streptococci, including and resident microbiota, may be associated with inflammation in the cardiovascular system. We previously reported that short-term treatment with SLO at relatively high concentrations (10-1000 ng/mL) diminished acetylcholine-induced, endothelial-dependent relaxation in a concentration-dependent manner. However, the vascular function effects of long-term exposure to SLO at lower concentrations are poorly understood. In this study, treatment of rat aorta with endothelium with SLO (0.1-10 ng/mL) for 72 h inhibited contractions in response to norepinephrine and phenylephrine in a concentration-dependent manner, and this effect was abolished by endothelium denudation. We also observed decreased endothelium-dependent relaxation in aorta treated with a lower concentration of SLO (10 ng/mL) for 72 h. Long-term treatment with SLO (10 ng/mL) increased the expression of iNOS in aorta with endothelium but not aorta without endothelium, and the SLO-induced decrease in contraction was restored by treatment with NOS inhibitors. Pharmacologic and gene-mutant analyses further indicated that SLO-induced vascular dysfunction and iNOS upregulation are mediated through the TLR4/NOX2/ROS/p38 MAPK pathways. SLO treatment (46.8 pg/kg/min) for 7 days also diminished vascular contraction and relaxation activity in aorta with endothelium. We concluded that long-term treatment with SLO inhibits vascular contractile responses, primarily due to increased iNOS expression in the endothelium through TLR4-mediated pathways. Our present results, together with those of our previous study, suggest that endothelial cells play a key role in the pathophysiologic changes in cardiovascular function associated with long-term exposure to SLO. In the present study, we showed that long-term exposure to streptococcal exotoxin SLO inhibits agonist-induced contraction in rat aorta with endothelium, driven primarily by elevated iNOS production via NOX2-mediated ROS production through TLR4 activation on endothelial cells. treatment with SLO for 7 days also diminished vascular contraction and relaxation, providing evidence of possible pathophysiologic roles of SLO in endothelium-dependent vascular homeostasis.
PubMed: 38858090
DOI: 10.1124/jpet.124.002121 -
Open Medicine (Warsaw, Poland) 2024Understanding the intricate relationship between cancer clinicopathological features and anesthetics dosage is crucial for optimizing patient outcomes and safety during...
Understanding the intricate relationship between cancer clinicopathological features and anesthetics dosage is crucial for optimizing patient outcomes and safety during surgery. This retrospective study investigates this relationship in patients with non-small cell lung cancer (NSCLC) undergoing video-assisted thoracic surgery (VATS). A comprehensive analysis of medical records was undertaken for NSCLC patients who underwent VATS with intravenous compound inhalation general anesthesia. Patients were categorized based on histological, chemotherapy, radiotherapy, and epidural anesthesia factors. Statistical analysis was performed to compare the differences between the groups. The results revealed compelling insights. Specifically, patients with lung adenocarcinoma (LUAD) undergoing VATS exhibited higher dosages of rocuronium bromide and midazolam during general anesthesia, coupled with a shorter post-anesthesia care unit (PACU) stay compared to those with squamous cell carcinoma (sqCL). Furthermore, chemotherapy patients undergoing VATS demonstrated diminished requirements for phenylephrine and remifentanil in contrast to their non-chemotherapy counterparts. Similarly, radiotherapy patients undergoing VATS demonstrated a decreased necessity for rocuronium bromide compared to non-radiotherapy patients. Notably, patients who received epidural anesthesia in combination with general anesthesia manifested reduced hydromorphone requirements and prolonged hospital stays compared to those subjected to general anesthesia alone. In conclusion, the findings from this study indicate several important observations in diverse patient groups undergoing VATS. The higher dosages of rocuronium bromide and midazolam in LUAD patients point to potential differences in drug requirements among varying lung cancer types. Additionally, the observed shorter PACU stay in LUAD patients suggests a potentially expedited recovery process. The reduced anesthetic requirements of phenylephrine and remifentanilin chemotherapy patients indicate distinct responses to anesthesia and pain management. Radiotherapy patients requiring lower doses of rocuronium bromide imply a potential impact of prior radiotherapy on muscle relaxation. Finally, the combination of epidural anesthesia with general anesthesia resulted in reduced hydromorphone requirements and longer hospital stays, suggesting the potential benefits of this combined approach in terms of pain management and postoperative recovery. These findings highlight the importance of tailoring anesthesia strategies for specific patient populations to optimize outcomes in VATS procedures.
PubMed: 38841176
DOI: 10.1515/med-2024-0961 -
The Journal of Biological Chemistry Jun 2024During postnatal cardiac hypertrophy, cardiomyocytes undergo mitotic exit, relying on DNA replication-independent mechanisms of histone turnover to maintain chromatin...
During postnatal cardiac hypertrophy, cardiomyocytes undergo mitotic exit, relying on DNA replication-independent mechanisms of histone turnover to maintain chromatin organization and gene transcription. In other tissues, circadian oscillations in nucleosome occupancy influence clock-controlled gene expression, suggesting a role for the circadian clock in temporal control of histone turnover and coordinated cardiomyocyte gene expression. To elucidate roles for the master circadian transcription factor, Bmal1, in histone turnover, chromatin organization, and myocyte-specific gene expression and cell growth in the neonatal period. Bmal1 knockdown in neonatal rat ventricular myocytes (NRVM) decreased myocyte size, total cellular protein synthesis, and transcription of the fetal hypertrophic gene Nppb following treatment with serum or the α-adrenergic agonist phenylephrine (PE). Depletion of Bmal1 decreased expression of clock-controlled genes Per2 and Tcap, as well as Sik1, a Bmal1 target upregulated in adult versus embryonic hearts. Bmal1 knockdown impaired Per2 and Sik1 promoter accessibility as measured by MNase-qPCR and impaired histone turnover as measured by metabolic labeling of acid-soluble chromatin fractions. Sik1 knockdown in turn decreased myocyte size, while simultaneously inhibiting Nppb transcription and activating Per2 transcription. Linking these changes to chromatin remodeling, depletion of the replication-independent histone variant H3.3a inhibited myocyte hypertrophy and prevented PE-induced changes in clock-controlled gene transcription. Bmal1 is required for neonatal myocyte growth, replication-independent histone turnover, and chromatin organization at the Sik1 promoter. Sik1 represents a novel clock-controlled gene that coordinates myocyte growth with hypertrophic and clock-controlled gene transcription. Replication-independent histone turnover is required for transcriptional remodeling of clock-controlled genes in cardiac myocytes in response to growth stimuli.
PubMed: 38830405
DOI: 10.1016/j.jbc.2024.107434 -
Brazilian Journal of Medical and... 2024Arthritis has important cardiovascular repercussions. Phenylephrine-induced vasoconstriction is impaired in rat aortas in the early phase of the adjuvant-induced...
Arthritis has important cardiovascular repercussions. Phenylephrine-induced vasoconstriction is impaired in rat aortas in the early phase of the adjuvant-induced arthritis (AIA), around the 15th day post-induction. Therefore, the present study aimed to verify the effects of AIA on hyporesponsiveness to phenylephrine in rat aortas. AIA was induced by intradermal injection of Mycobacterium tuberculosis (3.8 mg/dL) in the right hind paw of male Wistar rats (n=27). Functional experiments in isolated aortas were carried out 15 days after AIA induction. Morphometric and stereological analyses of the aortas were also performed 36 days after the induction of AIA. AIA did not promote structural modifications in the aortas at any of the time points studied. AIA reduced phenylephrine-induced contraction in endothelium-intact aortas, but not in endothelium-denuded aortas. However, AIA did not change KCl-induced contraction in either endothelium-intact or denuded aortas. L-NAME (non-selective NOS inhibitor), 1400W (selective iNOS inhibitor), and ODQ (guanylyl cyclase inhibitor) reversed AIA-induced hyporesponsiveness to phenylephrine in intact aortas. 7-NI (selective nNOS inhibitor) increased the contraction induced by phenylephrine in aortas from AIA rats. In summary, the hyporesponsiveness to phenylephrine induced by AIA was endothelium-dependent and mediated by iNOS-derived NO through activation of the NO-guanylyl cyclase pathway.
Topics: Animals; Male; Phenylephrine; Rats, Wistar; Arthritis, Experimental; Nitric Oxide; Vasoconstriction; Endothelium, Vascular; Vasoconstrictor Agents; Rats; Aorta
PubMed: 38775546
DOI: 10.1590/1414-431X2024e13304 -
Pharmaceutical Biology Dec 2024The mechanisms of Traditional Chinese Medicine (TCM) Guizhi-Gancao Decoction (GGD) remain unknown.
Network pharmacology integrated with experimental validation to elucidate the mechanisms of action of the Guizhi-Gancao Decoction in the treatment of phenylephrine-induced cardiac hypertrophy.
CONTEXT
The mechanisms of Traditional Chinese Medicine (TCM) Guizhi-Gancao Decoction (GGD) remain unknown.
OBJECTIVE
This study explores the mechanisms of GGD against cardiac hypertrophy.
MATERIALS AND METHODS
Network pharmacology analysis was carried out to identify the potential targets of GGD. experiments, C57BL/6J mice were divided into Con, phenylephrine (PE, 10 mg/kg/d), 2-chloroadenosine (CADO, the stable analogue of adenosine, 2 mg/kg/d), GGD (5.4 g/kg/d) and GGD (5.4 g/kg/d) + CGS15943 (a nonselective adenosine receptor antagonist, 4 mg/kg/d). experiments, primary neonatal rat cardiomyocytes (NRCM) were divided into Con, PE (100 µM), CADO (5 µM), GGD (10 g/mL) and GGD (10 g/mL) + CGS15943 (5 µM). Ultrasound, H&E and Masson staining, hypertrophic genes expression and cell surface area were conducted to verify the GGD efficacy. Adenosine receptors (ADORs) expression were tested real-time polymerase chain reaction (PCR), western blotting and immunofluorescence analysis.
RESULTS
Network pharmacology identified ADORs among those of the core targets of GGD. experiments demonstrated that GGD attenuated PE-induced increased surface area (with an EC of 5.484 × 10 g/mL). data shown that GGD attenuated PE-induced ventricular wall thickening. and data indicated that GGD alleviated PE-induced hypertrophic gene expression (e.g., ANP, BNP and MYH7/MYH6), A1AR over-expression and A2aAR down-expression. Moreover, CADO exerts effects similar to GGD, whereas CGS15943 eliminated most effects of GGD.
DISCUSSION AND CONCLUSIONS
Our findings suggest the mechanism by which GGD inhibits cardiac hypertrophy, highlighting regulation of ADORs as a potential therapeutic strategy for HF.
Topics: Animals; Drugs, Chinese Herbal; Phenylephrine; Cardiomegaly; Mice, Inbred C57BL; Mice; Male; Rats; Myocytes, Cardiac; Network Pharmacology; Rats, Sprague-Dawley; Cells, Cultured; Disease Models, Animal; Medicine, Chinese Traditional
PubMed: 38773737
DOI: 10.1080/13880209.2024.2354335 -
Investigative Ophthalmology & Visual... May 2024Earlier reports highlighted the predominant presence of aquaporin 4 (AQP4) in the duct cells of rabbit lacrimal glands (LGs). Whereas significant alterations in AQP4...
PURPOSE
Earlier reports highlighted the predominant presence of aquaporin 4 (AQP4) in the duct cells of rabbit lacrimal glands (LGs). Whereas significant alterations in AQP4 mRNA levels have been observed in experimental dry eye and during pregnancy, the impact of AQP4 in LG ductal fluid production remains unclear. In our recent work, the role of AQP4 in LG ductal fluid secretion was investigated utilizing wild type (WT) and AQP4 knock out (KO) mice.
METHODS
Tear production was assessed in both WT and KO animals. Immunostaining was used to identify AQP4 protein. Duct segments were harvested from LGs of WT and KO mice. Fluid secretion and filtration permeability (Pf) were quantified using video-microscopy. Ductal tear production, elicited by a cell-permeable cAMP analogue (8-bromo cAMP), carbachol, vasoactive intestinal peptide (VIP), and phenylephrine (PHE), were assessed in both WT and KO ducts.
RESULTS
A higher expression of AQP4 protein was noted in the duct cells from WT mice when compared to acinar cells. Pf did not show notable alterations between WT and AQP4 KO ducts. Carbachol elicited comparable secretory responses in ducts from both WT and KO animals. However, 8-bromo cAMP, VIP, and PHE stimulation resulted in decreased secretion in ducts from AQP4 KO LGs.
CONCLUSIONS
Our findings underscore the functional relevance of AQP4 in the fluid production of mouse LG ducts. AQP4 seems to play different roles in fluid secretions elicited by different secretagogues. Specifically, cAMP-mediated, and adrenergic agonist-related secretions were reduced in AQP4 KO ducts.
Topics: Animals; Mice; Lacrimal Apparatus; Tears; Mice, Knockout; Aquaporin 4; Mice, Inbred C57BL; Female
PubMed: 38771571
DOI: 10.1167/iovs.65.5.30 -
Medicine May 2024This study was aimed to analyze ocular biometric changes following cycloplegia in pediatric patients with strabismus and amblyopia. Cycloplegia is routinely used to... (Observational Study)
Observational Study
This study was aimed to analyze ocular biometric changes following cycloplegia in pediatric patients with strabismus and amblyopia. Cycloplegia is routinely used to measure refractive error accurately by paralyzing accommodation. However, effects on axial length (AL), anterior chamber depth (ACD), keratometry (Km), and white-to-white distance (WTW) are not well studied in this population. This retrospective study examined 797 patients (1566 eyes) undergoing cycloplegic refraction at a Samsung Kangbuk hospital pediatric ophthalmology clinic from 2010 to 2023. Ocular biometry was measured before and after instilling 1% cyclopentolate and 0.5% phenylephrine/0.5% tropicamide. Patients were categorized by strabismus diagnosis, age, refractive error and amblyopia status. Differences in AL, ACD, Km, WTW, and refractive error pre- and post-cycloplegia were analyzed using paired t tests. ACD (3.44 ± 0.33 vs 3.58 ± 0.29 mm, P < .05) and WTW (12.09 ± 0.42 vs 12.30 ± 0.60 mm, P < .05) increased significantly after cycloplegia in all groups except other strabismus subgroup (Cs) in both parameters and youngest subgroup (G1) in ACD. Refractive error demonstrated a hyperopic shift from -0.48 ± 3.00 D to -0.06 ± 3.32 D (P < .05) in overall and a myopic shift from -6.97 ± 4.27 to -8.10 ± 2.26 in high myopia (HM). Also, AL and Km did not change significantly. In conclusion, cycloplegia impacts ocular biometrics in children with strabismus and amblyopia, significantly increasing ACD and WTW. Refractive error shifts hyperopically in esotropia subgroup (ET) and myopically in high myopia subgroup (HM), eldest subgroup (G3) relating more to anterior segment changes than AL/Km. Understanding cycloplegic effects on biometry is important for optimizing refractive correction in these patients.
Topics: Humans; Amblyopia; Strabismus; Retrospective Studies; Male; Female; Child; Biometry; Mydriatics; Child, Preschool; Refraction, Ocular; Cyclopentolate; Refractive Errors; Adolescent; Anterior Chamber; Axial Length, Eye
PubMed: 38758890
DOI: 10.1097/MD.0000000000038143 -
Bioscience Reports Jun 2024Surgeries that require general anesthesia occur in 1.5-2% of gestations. Isoflurane is frequently used because of its lower possibility of affecting fetal growth....
Surgeries that require general anesthesia occur in 1.5-2% of gestations. Isoflurane is frequently used because of its lower possibility of affecting fetal growth. Therefore, we examined the isoflurane anesthesia-induced effects on maternal hemodynamic and vascular changes. We hypothesized that isoflurane would enhance endothelium-dependent vasodilation as a consequence of increased nitric oxide and decreased metalloproteinases (MMPs). Female rats (n=28) were randomized into 4 groups (7 rats/group): conscious (non-anesthetized) non-pregnant group, non-pregnant anesthetized group, conscious pregnant group, and pregnant anesthetized group. Anesthesia was performed on the 20th pregnancy day, and hemodynamic parameters were monitored. Nitric oxide metabolites, gelatinolytic activity of MMP-2 and MMP-9, and the vascular function were assessed. Isoflurane caused no significant hemodynamic changes in pregnant compared with non-pregnant anesthetized group. Impaired acetylcholine-induced relaxations were observed only in conscious non-pregnant group (by approximately 62%) versus 81% for other groups. Phenylephrine-induced contractions were greater in endothelium-removed aorta segments of both pregnant groups (with or without isoflurane) compared with non-pregnant groups. Higher nitric oxide metabolites were observed in anesthetized pregnant in comparison with the other groups. Reductions in the 75 kDa activity and concomitant increases in 64 kDa MMP-2 isoforms were observed in aortas of pregnant anesthetized (or not) groups compared with conscious non-pregnant group. Isoflurane anesthesia shows stable effects on hemodynamic parameters and normal MMP-2 activation in pregnancy. Furthermore, there were increases in nitric oxide bioavailability, suggesting that isoflurane provides protective actions to the endothelium in pregnancy.
Topics: Animals; Female; Pregnancy; Rats; Anesthetics, Inhalation; Endothelium, Vascular; Hemodynamics; Isoflurane; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Nitric Oxide; Vasodilation; Rats, Wistar
PubMed: 38757914
DOI: 10.1042/BSR20240192 -
MedRxiv : the Preprint Server For... May 2024Individuals with spinal cord injury (SCI) commonly have autonomic dysreflexia (AD) with increased sympathetic activity. After SCI, individuals have decreased baroreflex...
Why do different people with Spinal Cord Injury have differing severity of symptoms with Autonomic Dysreflexia? Exploring relationships of vascular alpha-1 adrenoreceptor and baroreflex sensitivity after SCI.
INTRODUCTION
Individuals with spinal cord injury (SCI) commonly have autonomic dysreflexia (AD) with increased sympathetic activity. After SCI, individuals have decreased baroreflex sensitivity and increased vascular responsiveness.
OBJECTIVE
To evalate relationship between baroreflex and blood vessel sensitivity with autonomic dysreflexia symptoms.
DESIGN
Case control.
SETTING
Tertiary academic center.
PATIENTS
14 individuals with SCI, 17 matched uninjured controls.
INTERVENTIONS
All participants quantified AD symptoms using the Autonomic Dysfunction Following SCI (ADFSCI)-AD survey. Participants received three intravenous phenylephrine boluses, reproducibly increasing systolic blood pressure (SBP) 15-40 mmHg. Continuous heart rate (R-R interval, ECG), beat-to-beat blood pressures (finapres), and popliteal artery flow velocity were recorded. Vascular responsiveness (α1 adrenoreceptor sensitivity) and heart rate responsiveness to increased SBP (baroreflex sensitivity) were calculated.
MAIN OUTCOME MEASURES
Baroreflex sensitivity after increased SBP; Vascular responsiveness through quantified mean arterial pressure (MAP) 2-minute area under the curve and change in vascular resistance.
RESULTS
SCI and control cohorts were well-matched with mean age 31.9 and 29.6 years (p=0.41), 21.4% and 17.6% female respectively. Baseline MAP (p=0.83) and R-R interval (p=0.39) were similar. ADFSCI-AD scores were higher following SCI (27.9+/-22.9 vs 4.2+/-2.9 in controls, p=0.002).To quantify SBP response, MAP area under the curve was normalized to dose/bodyweight. Individuals with SCI had significantly larger responses (0.26+/-0.19 mmHg*s/kg*ug) than controls (0.06+/-0.06 mmHg*s/kg*ug, p=0.002). Similarly, leg vascular resistance increased after SCI (24% vs 6% to a normalized dose, p=0.007). Baroreflex sensitivity was significantly lower after SCI (15.0+/-8.3 vs 23.7+/-9.3 ms/mmHg, p=0.01). ADFSCI-AD subscore had no meaningful correlation with vascular responsiveness (R=0.008) or baroreflex sensitivity (R=0.092) after SCI.
CONCLUSIONS
While this confirms smaller previous studies suggesting increased α1 adrenoreceptor sensitivity and lower baroreflex sensitivity in individuals with SCI, these differences lacked correlation to increased symptoms of AD. Further research into physiologic mechanisms to explain why some individuals with SCI develop symptoms is needed.
PubMed: 38746296
DOI: 10.1101/2024.05.02.24306772 -
Intensive Care Medicine Experimental May 2024Catecholamines are commonly used as therapeutic drugs in intensive care medicine to maintain sufficient organ perfusion during shock. However, excessive or sustained...
BACKGROUND
Catecholamines are commonly used as therapeutic drugs in intensive care medicine to maintain sufficient organ perfusion during shock. However, excessive or sustained adrenergic activation drives detrimental cardiac remodeling and may lead to heart failure. Whether catecholamine treatment in absence of heart failure causes persistent cardiac injury, is uncertain. In this experimental study, we assessed the course of cardiac remodeling and recovery during and after prolonged catecholamine treatment and investigated the molecular mechanisms involved.
RESULTS
C57BL/6N wild-type mice were assigned to 14 days catecholamine treatment with isoprenaline and phenylephrine (IsoPE), treatment with IsoPE and subsequent recovery, or healthy control groups. IsoPE improved left ventricular contractility but caused substantial cardiac fibrosis and hypertrophy. However, after discontinuation of catecholamine treatment, these alterations were largely reversible. To uncover the molecular mechanisms involved, we performed RNA sequencing from isolated cardiomyocyte nuclei. IsoPE treatment resulted in a transient upregulation of genes related to extracellular matrix formation and transforming growth factor signaling. While components of adrenergic receptor signaling were downregulated during catecholamine treatment, we observed an upregulation of endothelin-1 and its receptors in cardiomyocytes, indicating crosstalk between both signaling pathways. To follow this finding, we treated mice with endothelin-1. Compared to IsoPE, treatment with endothelin-1 induced minor but longer lasting changes in cardiomyocyte gene expression. DNA methylation-guided analysis of enhancer regions identified immediate early transcription factors such as AP-1 family members Jun and Fos as key drivers of pathological gene expression following catecholamine treatment.
CONCLUSIONS
The results from this study show that prolonged catecholamine exposure induces adverse cardiac remodeling and gene expression before the onset of left ventricular dysfunction which has implications for clinical practice. The observed changes depend on the type of stimulus and are largely reversible after discontinuation of catecholamine treatment. Crosstalk with endothelin signaling and the downstream transcription factors identified in this study provide new opportunities for more targeted therapeutic approaches that may help to separate desired from undesired effects of catecholamine treatment.
PubMed: 38733526
DOI: 10.1186/s40635-024-00632-9