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Thrombosis Research Oct 2022Piezo1 is an important mechanosensitive channel implicated in vascular remodeling. However, the role of Piezo1 in different types of vascular cells during the...
INTRODUCTION
Piezo1 is an important mechanosensitive channel implicated in vascular remodeling. However, the role of Piezo1 in different types of vascular cells during the development of pulmonary hypertension (PH) induced by high shear stress is largely unknown.
MATERIALS AND METHODS
We used a rat PH model established by left pulmonary artery ligation (LPAL, for 2-5 weeks), which mimics the high flow and hemodynamic stress, to study Piezo1 contribution to pulmonary vascular remodeling.
RESULTS
Right ventricular systolic pressure (RVSP), a surrogate measure for pulmonary arterial systolic pressure, and right ventricular wall thickness, a measure for right ventricular hypertrophy, were significantly increased in LPAL rats compared with Sham-control (SHAM) rats. Rats in LPAL-5w groups developed remarkable pulmonary vascular remodeling, while phenylephrine-induced contraction and acetylcholine-induced relaxation were both significantly inhibited in these rats. Upregulation of Piezo1, in association with increase in cytosolic Ca concentration ([Ca]), was observed in pulmonary arterial smooth muscle cells (PASMCs) from LPAL-2w and LPAL-5w rats in comparison to the SHAM controls. Piezo1 upregulation in PASMCs from LPAL rats was directly related to Yes-associated protein (YAP)/ TEA domain transcription factor 4 (TEAD4). Piezo1 expression was also upregulated in the whole-lung tissue of LPAL rats. The endothelial upregulation of Piezo1 was related to transcriptional regulation by RELA (p65) and lung inflammation.
CONCLUSION
The upregulation of Piezo1 in both PASMCs and ECs coordinates with each other via different cell signaling pathways to cause pulmonary vascular remodeling in LPAL-PH rats, providing novel insights into the cell-type specific pathogenic roles of Piezo1 in shear stress-associated experimental PH.
Topics: Animals; Rats; Acetylcholine; Cell Proliferation; Hypertension, Pulmonary; Membrane Proteins; Muscle, Smooth, Vascular; Phenylephrine; Pulmonary Artery; Transcription Factor 4; Up-Regulation; Vascular Remodeling; YAP-Signaling Proteins
PubMed: 35988445
DOI: 10.1016/j.thromres.2022.08.006 -
Veterinary Anaesthesia and Analgesia Nov 2022To determine whether dobutamine, norepinephrine or phenylephrine infusions alleviate hypotension in isoflurane-anaesthetized dogs administered dexmedetomidine with...
OBJECTIVE
To determine whether dobutamine, norepinephrine or phenylephrine infusions alleviate hypotension in isoflurane-anaesthetized dogs administered dexmedetomidine with vatinoxan.
STUDY DESIGN
Balanced, randomized crossover trial.
ANIMALS
A total of eight healthy Beagle dogs.
METHODS
Each dog was anaesthetized with isoflurane (end-tidal isoflurane 1.3%) and five treatments: dexmedetomidine hydrochloride (2.5 μg kg) bolus followed by 0.9% saline infusion (DEX-S); dexmedetomidine and vatinoxan hydrochloride (100 μg kg) bolus followed by an infusion of 0.9% saline (DEX-VAT-S), dobutamine (DEX-VAT-D), norepinephrine (DEX-VAT-N) or phenylephrine (DEX-VAT-P). The dexmedetomidine and vatinoxan boluses were administered at baseline (T0) and the treatment infusion was started after 15 minutes (T15) if mean arterial pressure (MAP) was < 90 mmHg. The treatment infusion rate was adjusted every 5 minutes as required. Systemic haemodynamics were recorded at T0 and 10 (T10) and 45 (T45) minutes. A repeated measures analysis of covariance model was used.
RESULTS
Most dogs had a MAP < 70 mmHg at T0 before treatment. Treatments DEX-S and DEX-VAT all significantly increased MAP at T10, but systemic vascular resistance index (SVRI) was significantly higher and cardiac index (CI) lower after DEX-S than after DEX-VAT. CI did not significantly differ between DEX-S and DEX-VAT-S at T45, while SVRI remained higher with DEX-S. Normotension was achieved by all vasoactive infusions in every dog, whereas MAP was below baseline with DEX-VAT-S, and higher than baseline with DEX-S at T45. Median infusion rates were 3.75, 0.25 and 0.5 μg kg minute for dobutamine, norepinephrine and phenylephrine, respectively. Dobutamine and norepinephrine increased CI (mean ± standard deviation, 3.35 ± 0.70 and 3.97 ± 1.24 L minute m, respectively) and decreased SVRI, whereas phenylephrine had the opposite effect (CI 2.13 ± 0.45 L minute m).
CONCLUSIONS AND CLINICAL RELEVANCE
Hypotension in isoflurane-anaesthetized dogs administered dexmedetomidine and vatinoxan can be treated with either dobutamine or norepinephrine.
Topics: Dogs; Animals; Isoflurane; Dexmedetomidine; Dobutamine; Anesthetics, Inhalation; Phenylephrine; Norepinephrine; Saline Solution; Blood Pressure; Hypotension; Dog Diseases
PubMed: 36058821
DOI: 10.1016/j.vaa.2022.07.007 -
Cell Death & Disease Jul 2023Pathological cardiac hypertrophy involves multiple regulators and several signal transduction pathways. Currently, the mechanisms of it are not well understood....
Pathological cardiac hypertrophy involves multiple regulators and several signal transduction pathways. Currently, the mechanisms of it are not well understood. Differentially expressed in FDCP 6 homolog (DEF6) was reported to participate in immunity, bone remodeling, and cancers. The effects of DEF6 on pathological cardiac hypertrophy, however, have not yet been fully characterized. We initially determined the expression profile of DEF6 and found that DEF6 was upregulated in hypertrophic hearts and cardiomyocytes. Our in vivo results revealed that DEF6 deficiency in mice alleviated transverse aortic constriction (TAC)-induced cardiac hypertrophy, fibrosis, dilation and dysfunction of left ventricle. Conversely, cardiomyocyte-specific DEF6-overexpression aggravated the hypertrophic phenotype in mice under chronic pressure overload. Similar to the animal experiments, the in vitro data showed that adenovirus-mediated knockdown of DEF6 remarkably inhibited phenylephrine (PE)-induced cardiomyocyte hypertrophy, whereas DEF6 overexpression exerted the opposite effects. Mechanistically, exploration of the signal pathways showed that the mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2)-extracellular signal-regulated kinase 1/2 (ERK1/2) cascade might be involved in the prohypertrophic effect of DEF6. Coimmunoprecipitation and GST (glutathione S-transferase) pulldown analyses demonstrated that DEF6 can directly interact with small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1), and the Rac1 activity assay revealed that the activity of Rac1 is altered with DEF6 expression in TAC-cardiac hypertrophy and PE-triggered cardiomyocyte hypertrophy. In the end, western blot and rescue experiments using Rac1 inhibitor NSC23766 and the constitutively active mutant Rac1(G12V) verified the requirement of Rac1 and MEK1/2-ERK1/2 activation for DEF6-mediated pathological cardiac hypertrophy. Our study substantiates that DEF6 acts as a deleterious regulator of cardiac hypertrophy by activating the Rac1 and MEK1/2-ERK1/2 signaling pathways, and suggests that DEF6 may be a potential treatment target for heart failure.
Topics: Mice; Animals; Mitogen-Activated Protein Kinase 3; Cardiomegaly; Heart Failure; Signal Transduction; Myocytes, Cardiac; Phenylephrine; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37524688
DOI: 10.1038/s41419-023-05948-0 -
Cardiovascular Research Mar 2023The carotid bodies (CBs) of spontaneously hypertensive (SH) rats exhibit hypertonicity and hyperreflexia contributing to heightened peripheral sympathetic outflow. We...
AIMS
The carotid bodies (CBs) of spontaneously hypertensive (SH) rats exhibit hypertonicity and hyperreflexia contributing to heightened peripheral sympathetic outflow. We hypothesized that CB hyperexcitability is driven by its own sympathetic innervation.
METHODS AND RESULTS
To test this, the chemoreflex was activated (NaCN 50-100 µL, 0.4 µg/µL) in SH and Wistar rats in situ before and after: (i) electrical stimulation (ES; 30 Hz, 2 ms, 10 V) of the superior cervical ganglion (SCG), which innervates the CB; (ii) unilateral resection of the SCG (SCGx); (iii) CB injections of an α1-adrenergic receptor agonist (phenylephrine, 50 µL, 1 mmol/L), and (iv) α1-adrenergic receptor antagonist prazosin (40 µL, 1 mmol/L) or tamsulosin (50 µL, 1 mmol/L). ES of the SCG enhanced CB-evoked sympathoexcitation by 40-50% (P < 0.05) with no difference between rat strains. Unilateral SCGx attenuated the CB-evoked sympathoexcitation in SH (62%; P < 0.01) but was without effect in Wistar rats; it also abolished the ongoing firing of chemoreceptive petrosal neurones of SH rats, which became hyperpolarized. In Wistar rats, CB injections of phenylephrine enhanced CB-evoked sympathoexcitation (33%; P < 0.05), which was prevented by prazosin (26%; P < 0.05) in SH rats. Tamsulosin alone reproduced the effects of prazosin in SH rats and prevented the sensitizing effect of the SCG following ES. Within the CB, α1A- and α1B-adrenoreceptors were co-localized on both glomus cells and blood vessels. In conscious SH rats instrumented for recording blood pressure (BP), the CB-evoked pressor response was attenuated after SCGx, and systolic BP fell by 16 ± 4.85 mmHg.
CONCLUSIONS
The sympathetic innervation of the CB is tonically activated and sensitizes the CB of SH but not Wistar rats. Furthermore, sensitization of CB-evoked reflex sympathoexcitation appears to be mediated by α1-adrenoceptors located either on the vasculature and/or glomus cells. The SCG is novel target for controlling CB pathophysiology in hypertension.
Topics: Rats; Animals; Carotid Body; Rats, Wistar; Tamsulosin; Hypertension; Sympathetic Nervous System; Blood Pressure; Rats, Inbred SHR; Phenylephrine; Prazosin
PubMed: 35048948
DOI: 10.1093/cvr/cvac008 -
Acta Anaesthesiologica Scandinavica Aug 2023Phenylephrine increases systemic- and pulmonary resistances and therefore may increase blood pressures at the expense of blood flow. Cardio-pulmonary bypass alters... (Clinical Trial)
Clinical Trial
BACKGROUND
Phenylephrine increases systemic- and pulmonary resistances and therefore may increase blood pressures at the expense of blood flow. Cardio-pulmonary bypass alters vasoreactivity and many patients exhibit chronotropic insufficiency after cardiac surgery. We aimed to describe the haemodynamic effects of phenylephrine infusion after cardiac surgery.
METHODS
Patients in steady state after low-risk cardiac surgery received incremental infusion rates of phenylephrine up to 1.0 μg/kg/min with the aim of increasing systemic mean arterial blood pressure 20 mmHg. Invasive haemodynamic parameters, including pulmonary wedge pressures, were captured along with echocardiographic measures of biventricular function before, during phenylephrine infusion at target systemic blood pressure, and 20 min after phenylephrine discontinuation.
RESULTS
Thirty patients were included. Phenylephrine increased mean arterial pressure increased from 78 (±9) mmHg to 98 (±10) mmHg with phenylephrine infusion. Also, pulmonary blood pressure as well as systemic- and pulmonary resistances increased. The ratio between systemic- and pulmonary artery resistances did not change statistically significantly (p = .59). Median cardiac output was 4.35 (interquartile range [IQR] 3.6-5.4) L/min at baseline and increased significantly with phenylephrine infusion (median Δcardiac output was 0.25 [IQR 0.1-0.6] L/min) (p = .012). Pulmonary artery wedge pressure increased from 10.2 (±3.0) mmHg to 11.9 (±3.4) mmHg (p < .001). This was accompanied by significant increases in central venous pressure. Phenylephrine infusion increased left ventricular end-diastolic volume from 105 (±46) mL to 119 (±44) mL (p < .001). All results of phenylephrine infusion were reversed with discontinuation.
CONCLUSION
In haemodynamically stable patients after cardiac surgery, phenylephrine increased PVR and SVR, but did not change the PVR/SVR ratio. Phenylephrine increased biventricular filling pressures and left ventricular end-diastolic area. Consequently, CO increased as ejection fraction was maintained. These findings do not discourage the use of phenylephrine after low-risk cardiac surgery.
REGISTRATION
clinicaltrial.gov (identifier NCT04419662).
Topics: Humans; Blood Pressure; Cardiac Output; Cardiac Surgical Procedures; Hemodynamics; Phenylephrine; Pulmonary Wedge Pressure
PubMed: 37186094
DOI: 10.1111/aas.14256 -
Anaesthesia Jan 2024We conducted a systematic review of the literature reporting phenylephrine-induced changes in blood pressure, cardiac output, cerebral blood flow and cerebral tissue... (Review)
Review
We conducted a systematic review of the literature reporting phenylephrine-induced changes in blood pressure, cardiac output, cerebral blood flow and cerebral tissue oxygen saturation as measured by near-infrared spectroscopy in humans. We used the proportion change of the group mean values reported by the original studies in our analysis. Phenylephrine elevates blood pressure whilst concurrently inducing a reduction in cardiac output. Furthermore, despite increasing cerebral blood flow, it decreases cerebral tissue oxygen saturation. The extent of phenylephrine's influence on cardiac output (r = -0.54 and p = 0.09 in awake humans; r = -0.55 and p = 0.007 in anaesthetised humans), cerebral blood flow (r = 0.65 and p = 0.002 in awake humans; r = 0.80 and p = 0.003 in anaesthetised humans) and cerebral tissue oxygen saturation (r = -0.72 and p = 0.03 in awake humans; r = -0.24 and p = 0.48 in anaesthetised humans) appears closely linked to the magnitude of phenylephrine-induced blood pressure changes. When comparing the effects of phenylephrine in awake and anaesthetised humans, we found no evidence of a significant difference in cardiac output, cerebral blood flow or cerebral tissue oxygen saturation. There was also no evidence of a significant difference in effect on systemic and cerebral circulations whether phenylephrine was given by bolus or infusion. We explore the underlying mechanisms driving the phenylephrine-induced cardiac output reduction, cerebral blood flow increase and cerebral tissue oxygen saturation decrease. Individualised treatment approaches, close monitoring and consideration of potential risks and benefits remain vital to the safe and effective use of phenylephrine in acute care.
Topics: Humans; Phenylephrine; Vasoconstrictor Agents; Oxygen; Blood Pressure; Cerebrovascular Circulation
PubMed: 37948131
DOI: 10.1111/anae.16172 -
The Journal of Surgical Research Oct 2022The study aims to investigate the effect of parabiosis method on endothelial dysfunction in naturally aging mice and determine the time projections for predicted...
INTRODUCTION
The study aims to investigate the effect of parabiosis method on endothelial dysfunction in naturally aging mice and determine the time projections for predicted improvement in the mentioned target group.
METHODS
The balb/c mice were separated into six groups, these being; isochronic old, heterochronic old (HP-O), isochronic young, heterochronic young, young control, and old control. After parabiosis protocol, animals were sacrificed at the third, fifth, seventh, and ninth weeks, and their thoracic aortas were isolated. The vasodilatation and vasoconstriction responses of the vessels were detected using potassium chloride and phenylephrine, acetylcholine (ACh), and sodium nitroprusside.
RESULTS
Aging had a significant decreasing effect on maximum ACh relaxation responses (P < 0.01). However, in the HP-O group, the maximum ACh relaxation response in the third week was significantly lower (P < 0.05), but this effect disappeared in the ninth week. Maximum phenylephrine contraction responses were lower in the heterochronic parabiosis group (P < 0.05).
CONCLUSIONS
ACh responses increased at the end of the ninth week in the HP-O group, therefore, the parabiosis model may have an improving effect on endothelial dysfunction seen in aging.
Topics: Acetylcholine; Animals; Endothelium, Vascular; Female; Mice; Nitroprusside; Parabiosis; Phenylephrine; Vasoconstriction; Vasodilation
PubMed: 35598495
DOI: 10.1016/j.jss.2022.04.054 -
Annals of Anatomy = Anatomischer... Jun 2024A reliable estimation of time since death can be important for the law enforcement authorities. The compound method encompassing supravital reactions such as the...
BACKGROUND
A reliable estimation of time since death can be important for the law enforcement authorities. The compound method encompassing supravital reactions such as the chemical excitability of the iris can be used to further narrow intervals estimated by temperature-based methods. Postmortem iris excitability was mostly assessed by parasympatholytic or parasympathomimetic substances. Little is known regarding sympathomimetic agents. The present study aims to describe the postmortem iris excitability using the sympathomimetic drug phenylephrine.
METHODS
Cadavers were included after body donors gave written informed consent during lifetime. Exclusion criteria were known eye disease, or a postmortem interval exceeding 26 hours. A pupillometer with a minimum measurement range of 0.5 mm was used to determine the horizontal pupil diameter before and 20 minutes after the application of phenylephrine. Increase in pupil diameter was labeled as positive reaction, unchanged pupil diameter was labeled as negative reaction, and decrease in pupil diameter was labeled as paradox reaction.
RESULTS
30 eyes from 16 cadavers (median age = 80.0; 9 males, 7 females) were examined. Initial pupil size was in median 3.5 mm (interquartile range [IQR]: 3.0-4.5 mm) and progressed to 4.0 mm (IQR: 3.5-5.0 mm) 20 minutes after drug instillation. The achieved pupil diameter difference comprised in median 0.5 mm (IQR: 0.0-1.0 mm). A positive reaction was observed in 21 cases. Negative reactions were observed in 5 cases and paradox reactions in 4 cases. Overall, there was a statistically significant difference in diameter between the initial and the reactive pupil (P = 0.0002).
CONCLUSION
Although relatively rarely used, sympathomimetic drugs seem to be eligible for chemical postmortem iris excitability. Currently, assessment of postmortem iris excitability usually only involves parasympatholytic and parasympathomimetic agents. The findings of the present study give a hint that the application of a third agent with a sympathomimetic mechanism of action could provide additional information. Further studies assessing such a triple approach in the compound method in comparison with the current gold standard for estimation of time since death are mandatory to ensure reliable results.
Topics: Humans; Male; Female; Iris; Phenylephrine; Postmortem Changes; Pupil; Aged, 80 and over; Cadaver; Aged; Sympathomimetics
PubMed: 38460860
DOI: 10.1016/j.aanat.2024.152240 -
The American Journal of Emergency... Feb 2022There is limited evidence to support the efficacy and safety of push-dose vasopressor (PDP) use outside of the operating room (OR). Specifically, there are few... (Comparative Study)
Comparative Study
BACKGROUND
There is limited evidence to support the efficacy and safety of push-dose vasopressor (PDP) use outside of the operating room (OR). Specifically, there are few head-to-head comparisons of different PDP in these settings. The purpose of this study was to compare the efficacy and safety of push-dose phenylephrine (PDP-PE) and epinephrine (PDP-E) in the Emergency Department (ED).
METHODS
This retrospective, single-center study evaluated adults given PDP-PE or PDP-E in the ED from May 2017 to November 2020. The primary outcome was a change in heart rate (HR). Secondary outcomes included changes in blood pressure, adverse effects, dosing errors, fluid and vasopressor requirements, ICU and hospital lengths of stay (LOS), and in-hospital mortality.
RESULTS
Ninety-six patients were included in the PDP-PE group and 39 patients in the PDP-E group. Median changes in HR were 0 [-7, 6] and - 2 [-15, 5] beats per minute (BPM) for PDP-PE and PDP-E, respectively (p = 0.138). PDP-E patients had a greater median increase in systolic blood pressure (SBP) (33 [24, 53] vs. 26 [8, 51] mmHg; p = 0.049). Dosing errors occurred more frequently in patients that received PDP-E (5/39 [12.8%] vs. 2/96 [2.1%]; p = 0.021). PDP-E patients more frequently received continuous epinephrine infusions before and after receiving PDP-E. There were no differences in adverse effects, fluid requirements, LOS, or mortality.
CONCLUSION
PDP-E provided a greater increase in SBP compared to PDP-PE. However, dosing errors occurred more frequently in those receiving PDP-E. Larger head-to-head studies are necessary to further evaluate the efficacy and safety of PDP-E and PDP-PE.
Topics: Aged; Blood Pressure; Emergency Service, Hospital; Epinephrine; Female; Heart Rate; Humans; Male; Middle Aged; Phenylephrine; Retrospective Studies; Vasoconstrictor Agents
PubMed: 34864289
DOI: 10.1016/j.ajem.2021.11.033 -
Urology Aug 2021To establish predictive factors of patients who failed intra-cavernosal injection therapy and ultimately required corporoglandular shunting during first-time ischemic...
OBJECTIVE
To establish predictive factors of patients who failed intra-cavernosal injection therapy and ultimately required corporoglandular shunting during first-time ischemic priapism episodes.
METHODS
A retrospective review was performed of all patients over the age of 18 who presented to our institution with first-time episode of ischemic priapism from 2009 to 2019. Variables assessed included: body mass index, diabetes, hypertension, race, insurance-type, hypertension, etiology, age, duration of erection prior to evaluation, total amount of phenylephrine injected, and use of corporal irrigation. A receiver operating characteristic (ROC) curve was performed utilizing duration of erection and amount of phenylephrine.
RESULTS
One-hundred and forty-seven patients met inclusion criteria of which 24 patients required surgical intervention. There were differences associated with mean total phenylephrine used, duration of erection between shunted patients and non-shunted patients with regards to age (P = .38) or etiology (P = .81). Multivariable analysis revealed differences between duration of erection and BMI greater than 25 kg/m. ROC curve analyses revealed total amount of phenylephrine injected and duration of erection were acceptable and excellent predictors of need for shunt procedures with area under the curves of 0.72 and 0.90, respectively. Optimal cut-off values for each were found to be 950 mcg and 15.5 hours.
CONCLUSION
Our study suggests that patients who require greater than 950 mcg of total phenylephrine or present with erections lasting greater than 15.5 hours are significantly more likely to require corporoglandular shunting and should be counseled appropriately as such.
Topics: Adult; Erectile Dysfunction; Humans; Ischemia; Male; Penile Erection; Penis; Phenylephrine; Priapism; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Vascular Surgical Procedures
PubMed: 33823171
DOI: 10.1016/j.urology.2021.03.030