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Journal of the American Heart... Sep 2023Background Pathological cardiac hypertrophy is a major cause of heart failure morbidity. The complex mechanism of intermolecular interactions underlying the pathogenesis...
Background Pathological cardiac hypertrophy is a major cause of heart failure morbidity. The complex mechanism of intermolecular interactions underlying the pathogenesis of cardiac hypertrophy has led to a lack of development and application of therapeutic methods. Methods and Results Our study provides the first evidence that TRAF4, a member of the tumor necrosis factor receptor-associated factor (TRAF) family, acts as a promoter of cardiac hypertrophy. Here, Western blotting assays demonstrated that TRAF4 is upregulated in cardiac hypertrophy. Additionally, TRAF4 deletion inhibits the development of cardiac hypertrophy in a mouse model after transverse aortic constriction surgery, whereas its overexpression promotes phenylephrine stimulation-induced cardiomyocyte hypertrophy in primary neonatal rat cardiomyocytes. Mechanistically, RNA-seq analysis revealed that TRAF4 promoted the activation of the protein kinase B pathway during cardiac hypertrophy. Moreover, we found that inhibition of protein kinase B phosphorylation rescued the aggravated cardiomyocyte hypertrophic phenotypes caused by TRAF4 overexpression in phenylephrine-treated neonatal rat cardiomyocytes, suggesting that TRAF4 may regulate cardiac hypertrophy in a protein kinase B-dependent manner. Conclusions Our results revealed the regulatory function of TRAF4 in cardiac hypertrophy, which may provide new insights into developing therapeutic and preventive targets for this disease.
Topics: Mice; Animals; Rats; Proto-Oncogene Proteins c-akt; TNF Receptor-Associated Factor 4; Heart Failure; Phenylephrine; Cardiomegaly
PubMed: 37642020
DOI: 10.1161/JAHA.122.028185 -
Optometry and Vision Science : Official... Mar 2020Pupillometry protocols evaluating rod/cone- and melanopsin-driven responses often use mydriatics to ensure maximal stimulus exposure; however, retinal effects of... (Comparative Study)
Comparative Study
SIGNIFICANCE
Pupillometry protocols evaluating rod/cone- and melanopsin-driven responses often use mydriatics to ensure maximal stimulus exposure; however, retinal effects of mydriatics are not fully understood. We demonstrate that dilation with either atropine or phenylephrine results in similar enhancements of rod/cone- and melanopsin-driven pupil responses.
PURPOSE
The purposes of this study were to compare the effects of atropine, a muscarinic antagonist, and phenylephrine, an adrenergic agonist, on consensual pupil responses and to assess the repeatability of pupil metrics without mydriasis.
METHODS
Right eye pupil responses of 20 adults aged 21 to 42 years were recorded before and 45 minutes after instillation of 0.5% atropine or 2.5% phenylephrine in the left eye. Stimuli were presented to the left eye and included six alternating 1-second 651-nm "red" and 456-nm "blue" flashes. Metrics included baseline pupil diameter, maximal constriction, 6- and 30-second post-illumination pupil responses, and early (0 to 10 seconds) and late (10 to 30 seconds) areas under the curve.
RESULTS
Dilation of the stimulated eye with either mydriatic significantly increased the 6-second post-illumination pupil response and early and late areas under the curve for blue stimuli, and early area under the curve for red stimuli (P < .05 for all). Melanopsin-driven post-illumination pupil responses, achieved with either phenylephrine or atropine, did not significantly differ from each other (P > .05 for all). Without mydriasis, intersession intraclass correlation coefficients for pupil metrics were 0.63 and 0.50 (6- and 30-second post-illumination pupil responses, respectively) and 0.78 and 0.44 (early and late areas under the curve, respectively) for blue stimuli, with no significant difference between sessions (P > .05 for all).
CONCLUSIONS
Dilation with phenylephrine or atropine resulted in similar enhancements of the rod/cone- and melanopsin-driven pupil responses, despite differing mechanisms. Early pupil metrics without mydriasis demonstrated moderate to good intersession repeatability.
Topics: Administration, Ophthalmic; Adrenergic alpha-1 Receptor Agonists; Adult; Atropine; Female; Humans; Male; Muscarinic Antagonists; Mydriatics; Ophthalmic Solutions; Phenylephrine; Photic Stimulation; Photoreceptor Cells, Vertebrate; Pupil; Reflex, Pupillary; Rod Opsins; Young Adult
PubMed: 32168243
DOI: 10.1097/OPX.0000000000001486 -
Anasthesiologie, Intensivmedizin,... Jun 2021Vasopressors are widely used in anaesthesiology and critical care medicine, to treat harmless (e.g. anaesthesia-induced hypotension) as well as life-threatening...
Vasopressors are widely used in anaesthesiology and critical care medicine, to treat harmless (e.g. anaesthesia-induced hypotension) as well as life-threatening conditions (e.g. septic shock). Some clinically used vasopressors resemble endogenous substances - such as norepinephrine - while others have been artificially synthesized (e.g. phenylephrine). Most of the substances used in different clinical scenarios have various effects except for vasoconstriction alone. Therefore, a thorough understanding of the pharmacology and clinical profile of every single substance is of highest importance prior to practical usage. Furthermore, the fundamentals of vascular physiology and vasotonic regulation are mandatory to safely provide vasopressor-based therapies. This article covers the essentials of physiology and pharmacology of vasopressors, and the clinical settings they are used in (e.g. septic shock, vasoplegic shock after cardiac surgery, trauma-induced hypotension).
Topics: Humans; Norepinephrine; Phenylephrine; Shock; Shock, Septic; Vasoconstrictor Agents
PubMed: 34187073
DOI: 10.1055/a-1214-4472 -
Journal of Basic and Clinical... Jun 2021Chemokine receptor antagonists are being explored for their therapeutic potential in various disease processes. As the chemokine (C-C motif) receptor 2 (CCR2) antagonist...
OBJECTIVES
Chemokine receptor antagonists are being explored for their therapeutic potential in various disease processes. As the chemokine (C-C motif) receptor 2 (CCR2) antagonist RS504393 is known to compete with ligand binding to α-adrenoceptors, we tested a panel of 10 CCR antagonists for interactions with α-adrenoceptors to evaluate potential cardiovascular activities and side-effect profiles.
METHODS
The PRESTO-Tango β-arrestin recruitment assay was utilized to test whether the CCR antagonists interfere with α-AR activation upon stimulation with phenylephrine. Pressure myography with isolated rat resistance arteries was employed to assess their effects on phenylephrine-induced vasoconstriction. The following antagonists were tested: CCR1-BX471, BX513, BI639667; CCR2-RS504393, INCB3284; CCR3-SB328437; and CCR4-AZD2098, and C021; CCR5-Maraviroc; CCR10-BI6901. The pan-α-adrenoceptor antagonist prazosin was used as control.
RESULTS
Among the CCR antagonists tested, RS504393, BX513, and C021 inhibited phenylephrine-induced β-arrestin recruitment to α-adrenoceptor and phenylephrine-induced vasoconstriction. While RS504393 functioned as a competitive α-adrenoceptor blocker, BX513 and C021 functioned as noncompetitive α-adrenoceptor antagonists in both assay systems. Furthermore, RS504393, BX513, and C021 dose-dependently dilated arteries that were fully preconstricted with phenylephrine.
CONCLUSIONS
Our data suggest that CCR antagonists should be screened for cross-reactivity with α-adrenoceptors to exclude potential adverse cardiovascular effects when used as anti inflammatory drugs.
Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Phenylephrine; Prazosin; Rats; Receptors, Adrenergic, alpha-1; Receptors, Chemokine; beta-Arrestins
PubMed: 34144642
DOI: 10.1515/jbcpp-2020-0523 -
International Ophthalmology Aug 2020To evaluate the effect of topical tropicamide 1% and phenylephrine 2.5% instillation on macular and peripapillary microvasculature measurements with optical coherence...
PURPOSE
To evaluate the effect of topical tropicamide 1% and phenylephrine 2.5% instillation on macular and peripapillary microvasculature measurements with optical coherence tomography angiography (OCTA).
METHODS
Forty eyes of 40 consecutive healthy adults with no known systemic or ocular disease were recruited for this prospective consecutive case study. After complete ophthalmological examination, all patients underwent OCTA measurements (OptoVue Inc, Freemont, CA, USA) to assess foveal avascular zone (FAZ) area, FAZ perimeter, acircularity index of FAZ, foveal density, vessel density of superficial and deep capillary plexus and peripapillary capillary plexus. 6 × 6 mm macular and 4.5 × 4.5 mm peripapillary OCTA images were undertaken before and 30 min after instillation of tropicamide (20 eyes) or phenylephrine (20 eyes) instillation to the right eye, and these were compared to each other and to fellow control eye.
RESULTS
15 male and 25 female patients with a mean age of 43.3 (18-60) years were recruited for the study. Superficial, deep and peripapillary capillary plexus measurements of tropicamide 1% and phenylephrine 2.5% instilled right eyes and left control eyes were similar before and 30 min after instillation (P > 0.05 for all). FAZ assessment tool variables were also similar before and after instillation (P > 0.05 for all) for both eyes.
CONCLUSION
Topical pupillary dilatation with tropicamide 1% and phenylephrine 2.5% did not affect macular and peripapillary OCTA measurements. Follow-up OCTA images in retina and glaucoma patients can be captured with a dilated or undilated pupil which seems not to be affected by tropicamide or phenylephrine.
Topics: Adult; Female; Fluorescein Angiography; Humans; Male; Microvessels; Middle Aged; Phenylephrine; Prospective Studies; Retinal Vessels; Tomography, Optical Coherence; Tropicamide
PubMed: 32307622
DOI: 10.1007/s10792-020-01371-y -
Veterinary Ophthalmology Nov 2021Evaluate the effect of repeated doses of topical 1% cyclopentolate hydrochloride alone and in combination with topical 2.5% phenylephrine on pupil diameter (PD), tear...
OBJECTIVE
Evaluate the effect of repeated doses of topical 1% cyclopentolate hydrochloride alone and in combination with topical 2.5% phenylephrine on pupil diameter (PD), tear production (STT-1), intraocular pressure (IOP), digestive function (gut motility and feces production), and heart rate (HR).
ANIMAL STUDIED
Six healthy mares.
PROCEDURES
In a prospective, randomized, controlled, and crossover design study, the left eye of six healthy mares was administered 0.2 mL of cyclopentolate alone and in combination with 0.2 mL of phenylephrine. The drugs were administered 3 times a day for 1 day, twice a day for 1 day, and then once a day for 2 days, as commonly used in practice. Daily and two days after the last topical drug administration, HR, digestive auscultation, feces production, STT-1, IOP, and PD were recorded.
RESULTS
The cyclopentolate alone significantly increased the horizontal and vertical PD of the treated eye from day 2 to day 6 (p < .0001) compared with the baseline value. The combination with topical phenylephrine did not have any additional effect on mydriasis compare with the cyclopentolate alone. The other ocular and digestive parameters were not affected by repeated doses of cyclopentolate alone or combined.
CONCLUSIONS
Repeated administration of cyclopentolate alone or combined with phenylephrine induce a significant mydriasis for at least 48 h after the last administration in normal horses' eyes, and do not affect STT-1, IOP, digestive function, and HR. The phenylephrine combined with the cyclopentolate did not potentiate the pupil dilation when compared with cyclopentolate alone in healthy horses.
Topics: Administration, Topical; Animals; Cyclopentolate; Female; Horses; Mydriatics; Ophthalmic Solutions; Phenylephrine; Prospective Studies; Pupil
PubMed: 33982406
DOI: 10.1111/vop.12896 -
Clinical Science (London, England :... Nov 2022Cardiac hypertrophy is necessary for the heart to accommodate an increase in workload. Physiological, compensated hypertrophy (e.g. with exercise) is reversible and...
Cardiac hypertrophy is necessary for the heart to accommodate an increase in workload. Physiological, compensated hypertrophy (e.g. with exercise) is reversible and largely due to cardiomyocyte hypertrophy. Pathological hypertrophy (e.g. with hypertension) is associated with additional features including increased fibrosis and can lead to heart failure. RAF kinases (ARAF/BRAF/RAF1) integrate signals into the extracellular signal-regulated kinase 1/2 cascade, a pathway implicated in cardiac hypertrophy, and activation of BRAF in cardiomyocytes promotes compensated hypertrophy. Here, we used mice with tamoxifen-inducible cardiomyocyte-specific BRAF knockout (CM-BRAFKO) to assess the role of BRAF in hypertension-associated cardiac hypertrophy induced by angiotensin II (AngII; 0.8 mg/kg/d, 7 d) and physiological hypertrophy induced by phenylephrine (40 mg/kg/d, 7 d). Cardiac dimensions/functions were measured by echocardiography with histological assessment of cellular changes. AngII promoted cardiomyocyte hypertrophy and increased fibrosis within the myocardium (interstitial) and around the arterioles (perivascular) in male mice; cardiomyocyte hypertrophy and interstitial (but not perivascular) fibrosis were inhibited in mice with CM-BRAFKO. Phenylephrine had a limited effect on fibrosis but promoted cardiomyocyte hypertrophy and increased contractility in male mice; cardiomyocyte hypertrophy was unaffected in mice with CM-BRAFKO, but the increase in contractility was suppressed and fibrosis increased. Phenylephrine induced a modest hypertrophic response in female mice and, in contrast with the males, tamoxifen-induced loss of cardiomyocyte BRAF reduced cardiomyocyte size, had no effect on fibrosis and increased contractility. The data identify BRAF as a key signalling intermediate in both physiological and pathological hypertrophy in male mice, and highlight the need for independent assessment of gene function in females.
Topics: Female; Male; Mice; Animals; Myocytes, Cardiac; Proto-Oncogene Proteins B-raf; Phenylephrine; Hypertension; Tamoxifen; Cardiomegaly; Fibrosis
PubMed: 36331065
DOI: 10.1042/CS20220607 -
The American Journal of Emergency... Dec 2023Hypotension is a common problem in the emergency department (ED) and intensive care unit (ICU) and can increase risk for poor outcomes. Many EDs/ICUs utilize epinephrine...
BACKGROUND
Hypotension is a common problem in the emergency department (ED) and intensive care unit (ICU) and can increase risk for poor outcomes. Many EDs/ICUs utilize epinephrine and phenylephrine to treat hypotension and these medications are most often administered as a continuous infusion (CI). Push-dose (PD) is the administration of small medication doses as intermittent intravenous pushes (IVPs). There is limited information comparing the time required to prepare and administer PD versus CI and errors have been reported when preparing and administering these medications at bedside. This simulation study sought to estimate preparation and administration times and preparation and errors with PD and CI epinephrine and phenylephrine when prepared by an ED/ICU pharmacist.
METHODS
This crossover simulation study took place in a simulation center at an academic medical center and utilized a multi-venous intravenous training arm kit equip with an 18-gauge intravenous line, an extension tubing set, and a luer-lock adapter. The primary outcome was total preparation and administration time in seconds. The secondary outcome was major preparation and administration errors, defined as errors causing a five-fold or greater overdose.
RESULTS
In total, 16 pharmacists participated, including nine ED and seven ICU pharmacists. PD had faster total preparation and administration time and administration time, but not preparation time; PD showed an approximate 70 s decrease in total preparation and administration time versus CI. PD had more major preparation and administration errors and six PD preparations (18.8%, 6/32) had at least one major preparation and administration error. CI, on the other hand, had no major preparation and administration errors.
DISCUSSION
This simulation found faster total preparation and administration time with PD versus CI epinephrine and phenylephrine, but also found that PD had more major preparation and administration errors. Dilutional errors during medication preparation were the cause of 83.3% (5/6) of our overdoses.
CONCLUSION
This simulation study showed that ED/ICU pharmacists had faster median total preparation and administration times for PD epinephrine and phenylephrine versus CI, but PD also had more preparation and administration errors.
Topics: Humans; Phenylephrine; Medication Errors; Epinephrine; Infusions, Intravenous; Hypotension
PubMed: 37832396
DOI: 10.1016/j.ajem.2023.10.002 -
BMC Complementary Medicine and Therapies Apr 2022Trans-cinnamaldehyde (TCA) is one of the main pharmaceutical ingredients of Cinnamomum cassia Presl, which has been shown to have therapeutic effects on a variety of...
BACKGROUND
Trans-cinnamaldehyde (TCA) is one of the main pharmaceutical ingredients of Cinnamomum cassia Presl, which has been shown to have therapeutic effects on a variety of cardiovascular diseases. This study was carried out to characterize and reveal the underlying mechanisms of the protective effects of TCA against cardiac hypertrophy.
METHODS
We used phenylephrine (PE) to induce cardiac hypertrophy and treated with TCA in vivo and in vitro. In neonatal rat cardiomyocytes (NRCMs), RNA sequencing and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out to identify potential pathways of TCA. Then, the phosphorylation and nuclear localization of calcium/calmodulin-dependent protein kinase II (CaMKII) and extracellular signal-related kinase (ERK) were detected. In adult mouse cardiomyocytes (AMCMs), calcium transients, calcium sparks, sarcomere shortening and the phosphorylation of several key proteins for calcium handling were evaluated. For mouse in vivo experiments, cardiac hypertrophy was evaluated by assessing morphological changes, echocardiographic parameters, and the expression of hypertrophic genes and proteins.
RESULTS
TCA suppressed PE-induced cardiac hypertrophy and the phosphorylation and nuclear localization of CaMKII and ERK in NRCMs. Our data also demonstrate that TCA blocked the hyperphosphorylation of ryanodine receptor type 2 (RyR2) and phospholamban (PLN) and restored Ca handling and sarcomere shortening in AMCMs. Moreover, our data revealed that TCA alleviated PE-induced cardiac hypertrophy in adult mice and downregulated the phosphorylation of CaMKII and ERK.
CONCLUSION
TCA has a protective effect against PE-induced cardiac hypertrophy that may be associated with the inhibition of the CaMKII/ERK pathway.
Topics: Acrolein; Animals; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiomegaly; MAP Kinase Signaling System; Mice; Myocytes, Cardiac; Phenylephrine; Rats; Ryanodine Receptor Calcium Release Channel
PubMed: 35468773
DOI: 10.1186/s12906-022-03594-1 -
Drug Design, Development and Therapy 2022A direct comparison of phenylephrine, metaraminol, and norepinephrine in preventing hypotension during spinal anaesthesia for elective caesarean section has never been... (Comparative Study)
Comparative Study Randomized Controlled Trial
Comparison of Metaraminol, Phenylephrine, and Norepinephrine Infusion for Prevention of Hypotension During Combined Spinal-Epidural Anaesthesia for Elective Caesarean Section: A Three-Arm, Randomized, Double-Blind, Non-Inferiority Trial.
BACKGROUND
A direct comparison of phenylephrine, metaraminol, and norepinephrine in preventing hypotension during spinal anaesthesia for elective caesarean section has never been made.
PATIENTS AND METHODS
Seventy-five parturients scheduled for elective caesarean section were randomly assigned into the three groups. After spinal anaesthesia induction, patients received a bonus dose of vasopressor (norepinephrine 4ug, phenylephrine 50ug, or metaraminol 250ug) combined with continuous infusion (norepinephrine 8ug/mL, phenylephrine 100ug/mL, or metaraminol 500ug/mL) at a rate of 30 mL/h to prevent hypotension. The primary outcome was umbilical arterial (UA) pH and other intraoperative data were also recorded.
RESULTS
The UA pH was 7.32±0.03 for metaraminol, 7.31±0.03 for phenylephrine, and 7.31±0.03 for norepinephrine. The 95% CI of MD was -0.011 to 0.026 comparing metaraminol with norepinephrine and 0.0181 to 0.0182 comparing phenylephrine with norepinephrine. Both lower bounds of the 95% CI of MD were above the predetermined lower boundary of clinical non-inferiority of -0.03, indicating both metaraminol and phenylephrine were non-inferior to norepinephrine. Moreover, the incidence of hypotension was lower in metaraminol compared with norepinephrine ( = 0.01). However, the incidence of hypertension was significantly lower in both phenylephrine and metaraminol compared with norepinephrine.
CONCLUSION
Both metaraminol and phenylephrine were non-inferior to norepinephrine with respect to neonatal UA pH when used as a bolus and continuous infusion to prevent hypotension during combined spinal-epidural anaesthesia for elective caesarean section.
Topics: Adult; Anesthesia, Epidural; Anesthesia, Spinal; Cesarean Section; Double-Blind Method; Female; Humans; Hypotension; Infusions, Intravenous; Metaraminol; Norepinephrine; Phenylephrine; Pregnancy; Prospective Studies; Sympathomimetics
PubMed: 35027821
DOI: 10.2147/DDDT.S331177