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Drug Design, Development and Therapy 2024Ondansetron reduces the median effective dose (ED50) of prophylactic phenylephrine to prevent spinal-induced hypotension (SIH) during cesarean delivery. However, the... (Randomized Controlled Trial)
Randomized Controlled Trial
Dose-Response Study of Phenylephrine for Preventing Spinal-Induced Hypotension During Cesarean Delivery with Combined Spinal-Epidural Anesthesia Under the Effect of Prophylactic Intravenous Ondansetron.
BACKGROUND
Ondansetron reduces the median effective dose (ED50) of prophylactic phenylephrine to prevent spinal-induced hypotension (SIH) during cesarean delivery. However, the exact dose response of phenylephrine in combination with prophylactic ondansetron for preventing SIH is unknown. Therefore, this study aimed to determine the dose-response of phenylephrine to prevent SIH in cesarean delivery when 4 mg of ondansetron was used as a preventive method.
METHODS
A total of 80 parturients were enrolled and divided randomly into four groups (n = 20 in each group) who received either 0.2, 0.3, 0.4, or 0.5 μg/kg/min of prophylactic phenylephrine. Ten minutes before the initiation of spinal induction, 4 mg prophylactic ondansetron was administered. The effective dose of prophylactic phenylephrine was defined as the dose required to prevent hypotension after the period of intrathecal injection and up to neonatal delivery. The ED50 and ED90 of prophylactic phenylephrine and 95% confidence intervals (95% CI) were calculated using probit analysis.
RESULTS
The ED50 and ED90 for prophylactic phenylephrine to prevent SIH were 0.25 (95% CI, 0.15 to 0.30), and 0.45 (95% CI, 0.39 to 0.59) μg/kg/min, respectively. No significant differences were observed in the side effects and neonatal outcomes between the four groups.
CONCLUSION
The administration of 4 mg of prophylactic ondansetron was associated with an ED50 of 0.25 (95% CI, 0.15~0.30) and ED90 of 0.45 (95% CI, 0.39~0.59) μg/kg/min for phenylephrine to prevent SIH.
Topics: Adult; Female; Humans; Pregnancy; Anesthesia, Epidural; Anesthesia, Spinal; Cesarean Section; Dose-Response Relationship, Drug; Hypotension; Ondansetron; Phenylephrine
PubMed: 38707613
DOI: 10.2147/DDDT.S452983 -
Molecular Nutrition & Food Research May 2024Prenatal nutrition imbalance correlates with developmental origin of cardiovascular diseases; however whether maternal high-sucrose diet (HS) during pregnancy causes...
SCOPE
Prenatal nutrition imbalance correlates with developmental origin of cardiovascular diseases; however whether maternal high-sucrose diet (HS) during pregnancy causes vascular damage in renal interlobar arteries (RIA) from offspring still keeps unclear.
METHODS AND RESULTS
Pregnant rats are fed with normal drinking water or 20% high-sucrose solution during the whole gestational period. Swollen mitochondria and distributed myofilaments are observed in vascular smooth muscle cells of RIA exposed to prenatal HS. Maternal HS increases phenylephrine (PE)-induced vasoconstriction in the RIA from adult offspring. NG-Nitro-l-arginine (L-Name) causes obvious vascular tension in response to PE in offspring from control group, not in HS. RNA-Seq of RIA is performed to reveal that the gene retinoid X receptor g (RXRg) is significantly decreased in the HS group, which could affect vascular function via interacting with PPARγ pathway. By preincubation of RIA with apocynin (NADPH inhibitor) or capivasertib (Akt inhibitor), the results indicate that ROS and Akt are the vital important factors to affect the vascular function of RIA exposure to prenatal HS.
CONCLUSION
Maternal HS during the pregnancy increases PE-mediated vasoconstriction of RIA from adult offspring, which is mainly related to the enhanced Akt and ROS regulated by the weakened PPARγ-RXRg.
Topics: Animals; Pregnancy; Female; PPAR gamma; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Signal Transduction; Prenatal Exposure Delayed Effects; Vasoconstriction; Rats, Sprague-Dawley; Dietary Sucrose; Rats; Renal Artery; Male; Phenylephrine; Maternal Nutritional Physiological Phenomena
PubMed: 38704749
DOI: 10.1002/mnfr.202300871 -
Arquivos Brasileiros de Cardiologia Apr 2024Vascular dysfunction constitutes the etiology of many diseases, such as myocardial infarction and hypertension, with the disruption of redox homeostasis playing a role...
BACKGROUND
Vascular dysfunction constitutes the etiology of many diseases, such as myocardial infarction and hypertension, with the disruption of redox homeostasis playing a role in the imbalance of the vasomotor control mechanism. Our group previously has shown that thyroid hormones exert protective effects on the aortic tissue of infarcted rats by improving angiogenesis signaling.
OBJECTIVE
Investigate the role of triiodothyronine (T3) on vascular response, exploring its effects on isolated aortas and whether there is an involvement of vascular redox mechanisms.
METHODS
Isolated aortic rings (intact- and denuded-endothelium) precontracted with phenylephrine were incubated with T3 (10-8, 10-7, 10-6, 10-5, and 10-4 M), and tension was recorded using a force-displacement transducer coupled with an acquisition system. To assess the involvement of oxidative stress, aortic rings were preincubated with T3 and subsequently submitted to an in vitro reactive oxygen species (ROS) generation system. The level of significance adopted in the statistical analysis was 5%.
RESULTS
T3 (10-4 M) promoted vasorelaxation of phenylephrine precontracted aortic rings in both intact- and denuded-endothelium conditions. Aortic rings preincubated in the presence of T3 (10-4 M) also showed decreased vasoconstriction elicited by phenylephrine (1 µM) in intact-endothelium preparations. Moreover, T3 (10-4 M) vasorelaxation effect persisted in aortic rings preincubated with NG-nitro-L-arginine methylester (L-NAME, 10 µM), a nonspecific NO synthase (NOS) inhibitor. Finally, T3 (10-4 M) exhibited, in vitro, an antioxidant role by reducing NADPH oxidase activity and increasing SOD activity in the aorta's homogenates.
CONCLUSION
T3 exerts dependent- and independent-endothelium vasodilation effects, which may be related to its role in maintaining redox homeostasis.
Topics: Animals; Vasodilation; Male; Triiodothyronine; Rats, Wistar; Oxidation-Reduction; Reactive Oxygen Species; Oxidative Stress; Phenylephrine; Endothelium, Vascular; Rats; Reproducibility of Results; Vasoconstrictor Agents; Aorta, Thoracic; In Vitro Techniques; Vasoconstriction
PubMed: 38695407
DOI: 10.36660/abc.20230236 -
Heliyon May 2024Hypotension is one of the most common and dangerous complications following combined spinal epidural anesthesia during elective cesarean delivery. Many methods are used...
BACKGROUD
Hypotension is one of the most common and dangerous complications following combined spinal epidural anesthesia during elective cesarean delivery. Many methods are used to prevent or treat the hypotension with pharmacological or non-pharmacological measures. Our aim was to assess left-lateral position and phenylephrine prophylactic treatment for the prevention or treatment of maternal hypotension.
METHODS
A total of 127 pregnant women were enrolled to be analyzed. The primary outcome measure was the incidence of maternal hypotension and secondary outcome measures included maternal demographic characteristics, anesthesia-to-incision time interval, birthweight and Apgar scores.
RESULTS
The incidence of hypotension was 65.4 % in sequential reactive treatment and only 11.3 % achieved complete anesis after left-lateral position, significantly higher than 17.4 % in left-lateral position combined phenylephrine prophylactic treatment ( < 0.001). The increasing in gestational age may decrease the hypotension risk ( < 0.001). There were no significantly differences with maternal age, gravidity, parity, BMI before pregnancy, BMI before cesarean section, anesthesia-to-incision time interval, birthweight and Apgar scores ( > 0.05). The univariate logistic regression analysis revealed a significant association between treatment and hypotension (OR 0.11, 95 % CI 0.05-0.27). After adjusting for confounding variables, the risk of hypotension was decreased in subjects with treatment (OR 0.1, 95 % CI 0.04-0.25; OR 0.15, 95 % CI 0.05-0.43; OR 0.16, 95 % CI 0.05-0.46). The results of stratified and interaction analyses of the association between treatment revealed no interactive role from maternal age, gravidity and BMI before cesarean section ( > 0.05).
CONCLUSIONS
Single use of left-lateral position had limited effective and left-lateral position combined prophylactic phenylephrine used may be much better to prevent or treat hypetension, but larger studies with more robust data are needed to confirm these findings.
PubMed: 38694024
DOI: 10.1016/j.heliyon.2024.e30019 -
Circulation Apr 2024Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce....
BACKGROUND
Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce. Epigenetic modifications of mitochondrial DNA (mtDNA), such as methylation, play a pivotal role in modulating mitochondrial homeostasis. However, their involvement in HF remains unclear.
METHODS
Experimental HF models were established through continuous angiotensin II and phenylephrine (AngII/PE) infusion or prolonged myocardial ischemia/reperfusion injury. The landscape of N-methyladenine (6mA) methylation within failing cardiomyocyte mtDNA was characterized using high-resolution mass spectrometry and methylated DNA immunoprecipitation sequencing. A tamoxifen-inducible cardiomyocyte-specific knockout mouse model and adeno-associated virus vectors designed for cardiomyocyte-targeted manipulation of METTL4 (methyltransferase-like protein 4) expression were used to ascertain the role of mtDNA 6mA and its methyltransferase METTL4 in HF.
RESULTS
METTL4 was predominantly localized within adult cardiomyocyte mitochondria. 6mA modifications were significantly more abundant in mtDNA than in nuclear DNA. Postnatal cardiomyocyte maturation presented with a reduction in 6mA levels within mtDNA, coinciding with a decrease in METTL4 expression. However, an increase in both mtDNA 6mA level and METTL4 expression was observed in failing adult cardiomyocytes, suggesting a shift toward a neonatal-like state. METTL4 preferentially targeted mtDNA promoter regions, which resulted in interference with transcription initiation complex assembly, mtDNA transcriptional stalling, and ultimately mitochondrial dysfunction. Amplifying cardiomyocyte mtDNA 6mA through METTL4 overexpression led to spontaneous mitochondrial dysfunction and HF phenotypes. The transcription factor p53 was identified as a direct regulator of METTL4 transcription in response to HF-provoking stress, thereby revealing a stress-responsive mechanism that controls METTL4 expression and mtDNA 6mA. Cardiomyocyte-specific deletion of the gene eliminated mtDNA 6mA excess, preserved mitochondrial function, and mitigated the development of HF upon continuous infusion of AngII/PE. In addition, specific silencing of METTL4 in cardiomyocytes restored mitochondrial function and offered therapeutic relief in mice with preexisting HF, irrespective of whether the condition was induced by AngII/PE infusion or myocardial ischemia/reperfusion injury.
CONCLUSIONS
Our findings identify a pivotal role of cardiomyocyte mtDNA 6mA and the corresponding methyltransferase, METTL4, in the pathogenesis of mitochondrial dysfunction and HF. Targeted suppression of METTL4 to rectify mtDNA 6mA excess emerges as a promising strategy for developing mitochondria-focused HF interventions.
PubMed: 38686562
DOI: 10.1161/CIRCULATIONAHA.123.068358 -
American Journal of Physiology.... Jun 2024Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neurocognitive deficits perhaps related to upright...
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neurocognitive deficits perhaps related to upright hypocapnia and loss of cerebral autoregulation (CA). We performed N-back neurocognition testing and calculated the phase synchronization index (PhSI) between arterial pressure (AP) and cerebral blood velocity (CB) as a time-dependent measurement of cerebral autoregulation in 11 control (mean age = 24.1 yr) and 15 patients with ME/CFS (mean age = 21.8 yr). All patients with ME/CFS had postural tachycardia syndrome (POTS). A 10-min 60° head-up tilt (HUT) significantly increased heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, < 0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, < 0.05) and decreased end-tidal CO (ETCO; 33.9 ± 1.1 vs. 42.8 ± 1.2 Torr, < 0.05) in ME/CFS versus control. In ME/CFS, HUT significantly decreased CB compared with control (-22.5% vs. -8.7%, < 0.005). To mitigate the orthostatic CB reduction, we administered supplemental CO, phenylephrine, and acetazolamide and performed N-back testing supine and during HUT. Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct = 4 N-back during HUT in ME/CFS similar to control (ME/CFS = 38.5 ± 5.5 vs. ME/CFS + PE= 65.6 ± 5.7 vs. Control 56.9 ± 7.5). HUT in ME/CFS resulted in increased PhSI values indicating decreased CA. Although CO and acetazolamide had no effect on PhSI in ME/CFS, phenylephrine caused a significant reduction in PhSI (ME/CFS = 0.80 ± 0.03 vs. ME/CFS + PE= 0.69 ± 0.04, < 0.05) and improved cerebral autoregulation. Thus, PE improved neurocognitive function in patients with ME/CFS, perhaps related to improved neurovascular coupling, cerebral autoregulation, and maintenance of CB. We evaluated cognitive function before and after CO, acetazolamide, and phenylephrine, which mitigate orthostatic reductions in cerebral blood velocity. Neither CO nor acetazolamide affected N-back testing (% correct answers) during an orthostatic challenge. Only phenylephrine improved upright N-back performance in ME/CFS, as it both blocked hyperventilation and increased CO significantly compared with those untreated. And only phenylephrine resulted in improved PSI values in both ME/CFS and control while upright, suggesting improved cerebral autoregulation.
Topics: Humans; Cerebrovascular Circulation; Phenylephrine; Female; Male; Orthostatic Intolerance; Adult; Young Adult; Blood Flow Velocity; Blood Pressure; Fatigue Syndrome, Chronic; Tilt-Table Test; Cognition; Homeostasis; Case-Control Studies; Heart Rate; Arterial Pressure; Postural Orthostatic Tachycardia Syndrome
PubMed: 38682242
DOI: 10.1152/ajpregu.00071.2024 -
The Spine Journal : Official Journal of... Apr 2024Cervical spinal cord injury usually results in cardiorespiratory dysfunctions due to interruptions of the bulbospinal pathways innervating the cervical phrenic...
BACKGROUND
Cervical spinal cord injury usually results in cardiorespiratory dysfunctions due to interruptions of the bulbospinal pathways innervating the cervical phrenic motoneurons and thoracic sympathetic preganglionic neurons.
PURPOSE
The present study aimed to evaluate the therapeutic effects of adrenergic agents on systemic and spinal hemodynamics during acute cervical spinal cord injury.
STUDY DESIGN
In vivo animal study.
METHODS
The cardiorespiratory function and spinal cord blood flow and oxygenation level were monitored in response to cervical spinal cord contusion and intravenous infusion of three types of adrenergic agents (phenylephrine, dobutamine, and norepinephrine).
RESULTS
Cervical spinal cord contusion resulted in immediate reduction of respiratory airflow, arterial blood pressure, and spinal cord blood flow. The arterial blood pressure and spinal cord blood flow remained lower than the pre-injury value in contused animals infused with saline at 60 min post-injury. Infusion of phenylephrine (500, 1000, and 2000 μg/kg) and norepinephrine (125, 250, and 500 μg/kg) significantly increased the arterial blood pressure, while only norepinephrine augmented the spinal cord blood flow. Conversely, dobutamine (1000 and 2000 μg/kg) reduced both arterial blood pressure and spinal cord blood flow. Notably, administration of adrenergic agents tended to increase spinal cord hemorrhage in contused animals.
CONCLUSIONS
Infusion of norepinephrine can effectively maintain the blood pressure and improve spinal cord blood flow during acute spinal cord injury.
CLINICAL SIGNIFICANCE
Norepinephrine may be a superior medicine for hemodynamic management; however, the potential hemorrhage should be considered when utilizing the vasopressor to regulate systemic and spinal hemodynamics at the acute injured stage.
PubMed: 38679076
DOI: 10.1016/j.spinee.2024.04.023 -
International Journal of Molecular... Apr 2024(L.) Cusson, a member of the family, is rich in coumarins, such as imperatorin and osthole. fruit (CM) has a broad range of therapeutic potential that can be used in...
(L.) Cusson, a member of the family, is rich in coumarins, such as imperatorin and osthole. fruit (CM) has a broad range of therapeutic potential that can be used in anti-bacterial, anti-cancer, and sexual dysfunction treatments. However, its efficacy in lowering blood pressure through vasodilation remains unknown. This study aimed to assess the potential therapeutic effect of CM 50% ethanol extract (CME) on hypertension and the mechanism of its vasorelaxant effect. CME (1-30 µg/mL) showed a concentration-dependent vasorelaxation on constricted aortic rings in Sprague Dawley rats induced by phenylephrine via an endothelium-independent mechanism. The vasorelaxant effect of CME was inhibited by blockers of voltage-dependent and Ca-activated K channels. Additionally, CME inhibited the vascular contraction induced by angiotensin II and CaCl. The main active compounds of CM, i.e., imperatorin (3-300 µM) and osthole (1-100 µM), showed a concentration-dependent vasorelaxation effect, with half-maximal effective concentration values of 9.14 ± 0.06 and 5.98 ± 0.06 µM, respectively. Orally administered CME significantly reduced the blood pressure of spontaneously hypertensive rats. Our research shows that CME is a promising treatment option for hypertension. However, further studies are required to fully elucidate its therapeutic potential.
Topics: Animals; Cnidium; Plant Extracts; Blood Pressure; Rats, Sprague-Dawley; Rats; Fruit; Vasodilator Agents; Male; Rats, Inbred SHR; Antihypertensive Agents; Ethanol; Furocoumarins; Hypertension; Vasodilation; Coumarins
PubMed: 38673809
DOI: 10.3390/ijms25084223 -
Journal of Clinical Medicine Apr 2024: Sulodexide (SDX) is a drug known for restoring the glycocalyx, thereby offering endothelial protection and regulating permeability. Additionally, it has antithrombotic...
: Sulodexide (SDX) is a drug known for restoring the glycocalyx, thereby offering endothelial protection and regulating permeability. Additionally, it has antithrombotic and anti-inflammatory properties and has shown arterial vasodilatory effects. Endothelial cells play a crucial role in maintaining homeostasis, with their dysfunction being a key contributor to loss in vasodilatory response, especially in arterial pathologies. The aim of this study was to investigate the effects of SDX on stimulated vascular tonus in human arterial samples and to assess the function of the endothelial layer as a source of nitric oxide (NO). : A total of 16 internal mammary artery remnants from coronary artery bypass graft surgeries were dissected into endothelium-intact and endothelium-denuded groups (n = 8 each). The arterial rings were equilibrated under tension, with their basal tonus recorded before and after phenylephrine stimulation. SDX's impact on arterial contraction was assessed through cumulative dose-response curves. NO synthase inhibitor (Nω-nitro-L-arginine methyl ester) was used to assess SDX's vasodilatory effect over the NO pathway. : SDX application resulted in concentration-dependent vasorelaxation in both endothelium-intact and endothelium-denuded groups at certain doses. However, the inhibitory effect of SDX was more pronounced in endothelium-intact rings at higher doses compared to endothelium-denuded rings ( < 0.05). Similar inhibition of contraction curves was achieved for both endothelium-intact and endothelium-denuded rings after L-NAME pre-incubation, suggesting a necessity for NO-related endothelial pathways. : SDX exerts a concentration-dependent inhibition on arterial contraction, emphasizing the critical role of an intact endothelium and NO-mediated pathways in this process. This underscores SDX's potential in treating endothelial dysfunction-related pathologies.
PubMed: 38673605
DOI: 10.3390/jcm13082332 -
Biomolecules Apr 2024TRPC5 is a non-selective cation channel that is expressed in cardiomyocytes, but there is a lack of knowledge of its (patho)physiological role in vivo. Here, we examine...
TRPC5 is a non-selective cation channel that is expressed in cardiomyocytes, but there is a lack of knowledge of its (patho)physiological role in vivo. Here, we examine the role of TRPC5 on cardiac function under basal conditions and during cardiac hypertrophy. Cardiovascular parameters were assessed in wild-type (WT) and global TRPC5 knockout (KO) mice. Despite no difference in blood pressure or activity, heart rate was significantly reduced in TRPC5 KO mice. Echocardiography imaging revealed an increase in stroke volume, but cardiac contractility was unaffected. The reduced heart rate persisted in isolated TRPC5 KO hearts, suggesting changes in basal cardiac pacing. Heart rate was further investigated by evaluating the reflex change following drug-induced pressure changes. The reflex bradycardic response following phenylephrine was greater in TRPC5 KO mice but the tachycardic response to SNP was unchanged, indicating an enhancement in the parasympathetic control of the heart rate. Moreover, the reduction in heart rate to carbachol was greater in isolated TRPC5 KO hearts. To evaluate the role of TRPC5 in cardiac pathology, mice were subjected to abdominal aortic banding (AAB). An exaggerated cardiac hypertrophy response to AAB was observed in TRPC5 KO mice, with an increased expression of hypertrophy markers, fibrosis, reactive oxygen species, and angiogenesis. This study provides novel evidence for a direct effect of TRPC5 on cardiac function. We propose that (1) TRPC5 is required for maintaining heart rate by regulating basal cardiac pacing and in response to pressure lowering, and (2) TRPC5 protects against pathological cardiac hypertrophy.
Topics: Animals; TRPC Cation Channels; Cardiomegaly; Mice, Knockout; Mice; Heart Rate; Male; Myocytes, Cardiac; Mice, Inbred C57BL; Blood Pressure
PubMed: 38672459
DOI: 10.3390/biom14040442