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Circulation Mar 2022Recent studies have established that CCR2 (C-C chemokine receptor type 2) marks proinflammatory subsets of monocytes, macrophages, and dendritic cells that contribute to...
BACKGROUND
Recent studies have established that CCR2 (C-C chemokine receptor type 2) marks proinflammatory subsets of monocytes, macrophages, and dendritic cells that contribute to adverse left ventricle (LV) remodeling and heart failure progression. Elucidation of the effector mechanisms that mediate adverse effects of CCR2 monocytes, macrophages, and dendritic cells will yield important insights into therapeutic strategies to suppress myocardial inflammation.
METHODS
We used mouse models of reperfused myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation to investigate CCL17 (C-C chemokine ligand 17). We used knockout mice, flow cytometry, RNA sequencing, biochemical assays, cell trafficking studies, and in vivo cell depletion to identify the cell types that generate CCL17, define signaling pathways that controlled its expression, delineate the functional importance of CCL17 in adverse LV remodeling and heart failure progression, and determine the mechanistic basis by which CCL17 exerts its effects.
RESULTS
We demonstrated that CCL17 is expressed in CCR2 macrophages and cluster of differentiation 11b conventional dendritic cells after myocardial infarction, angiotensin II and phenylephrine infusion, and diphtheria toxin cardiomyocyte ablation. We clarified the transcriptional signature of CCL17 macrophages and dendritic cells and identified granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling as a key regulator of CCL17 expression through cooperative activation of STAT5 (signal transducer and activator of transcription 5) and canonical NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) signaling. deletion resulted in reduced LV remodeling, decreased myocardial fibrosis and cardiomyocyte hypertrophy, and improved LV systolic function after myocardial infarction and angiotensin II and phenylephrine infusion. We observed increased abundance of regulatory T cells (Tregs) in the myocardium of injured knockout mice. CCL17 inhibited Treg recruitment through biased activation of CCR4. CCL17 activated Gq signaling and CCL22 (C-C chemokine ligand 22) activated both Gq and ARRB (β-arrestin) signaling downstream of CCR4. CCL17 competitively inhibited CCL22 stimulated ARRB signaling and Treg migration. We provide evidence that Tregs mediated the protective effects of deletion on myocardial inflammation and adverse LV remodeling.
CONCLUSIONS
These findings identify CCL17 as a proinflammatory mediator of CCR2 macrophages and dendritic cells and suggest that inhibition of CCL17 may serve as an effective strategy to promote Treg recruitment and suppress myocardial inflammation.
Topics: Angiotensin II; Animals; Chemokine CCL17; Diphtheria Toxin; Heart Failure; Humans; Inflammation; Ligands; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Phenylephrine; T-Lymphocytes, Regulatory; Ventricular Remodeling
PubMed: 35113652
DOI: 10.1161/CIRCULATIONAHA.121.055888 -
Anaesthesia Jan 2018
Topics: Adult; Anesthesia, Obstetrical; Anesthesia, Spinal; Cesarean Section; Consensus; Ephedrine; Female; Humans; Hypotension; Phenylephrine; Practice Guidelines as Topic; Pregnancy; Vasoconstrictor Agents
PubMed: 29090733
DOI: 10.1111/anae.14080 -
British Journal of Anaesthesia May 2022
Randomized Controlled Trial
Prophylactic norepinephrine or phenylephrine infusion for bradycardia and post-spinal anaesthesia hypotension in patients with preeclampsia during Caesarean delivery: a randomised controlled trial.
Topics: Anesthesia, Obstetrical; Anesthesia, Spinal; Bradycardia; Cesarean Section; Female; Humans; Hypotension; Norepinephrine; Phenylephrine; Pre-Eclampsia; Pregnancy; Vasoconstrictor Agents
PubMed: 35190176
DOI: 10.1016/j.bja.2022.01.027 -
The British Journal of Ophthalmology Apr 1981Guttae phenylephrine 10% produced a significant decrease in intraocular pressure and increase in facility of outflow in eyes with untreated ocular hypertension. If at...
Guttae phenylephrine 10% produced a significant decrease in intraocular pressure and increase in facility of outflow in eyes with untreated ocular hypertension. If at the same time pigment was released into the aqueous, the pressure and outflow effect was nullified. Guttae pilocarpine 2% also reduced pressure and increased outflow, but if phenylephrine was added to the pilocarpine 2 responses appeared. If no pigment was released, pressure decreased and outflow increased; if pigment was released, there was no significant change in either. An identical response was shown by eyes with treated open-angle glaucoma. In eyes with treated exfoliation glaucoma pilocarpine and phenylephrine combined produced a significant increase in pressure and decrease in outflow because of pigment release. Finally, 18 eyes are described in which pigment release produced a mean increase in intraocular pressure of 14 mmHg. An acute release of pigment has an outflow-blocking effect that can be readily demonstrated. It provides an explanation for some of the paradoxical responses that occur after the instillation of autonomic drugs. It also provides a sufficient explanation for glaucoma associated with pigment dispersion.
Topics: Drug Combinations; Glaucoma; Humans; Intraocular Pressure; Phenylephrine; Pigment Epithelium of Eye; Pilocarpine; Pupil
PubMed: 7236570
DOI: 10.1136/bjo.65.4.258 -
Journal of the American College of... Jun 2014
Topics: Female; Humans; Hypotension; Kidney Transplantation; Male; Phenylephrine; Postoperative Complications; Vasoconstrictor Agents
PubMed: 24840692
DOI: 10.1016/j.jamcollsurg.2014.03.017 -
Minerva Anestesiologica Oct 2020
Topics: Humans; Phenylephrine; Vasoconstrictor Agents
PubMed: 32613813
DOI: 10.23736/S0375-9393.20.14716-3 -
Anesthesiology Sep 2009
Topics: Adult; Anesthesia, Obstetrical; Anesthesia, Spinal; Cesarean Section; Ephedrine; Female; Humans; Hypotension; Infant, Newborn; Phenylephrine; Pregnancy; Vasoconstrictor Agents
PubMed: 19672174
DOI: 10.1097/ALN.0b013e3181b16466 -
BMC Pulmonary Medicine Jun 2021Different from current cognition, our study demonstrated that adrenergic receptors agonist phenylephrine significantly relaxed isolated pulmonary artery but constricted...
BACKGROUND
Different from current cognition, our study demonstrated that adrenergic receptors agonist phenylephrine significantly relaxed isolated pulmonary artery but constricted pulmonary veins. Through comparing differences in the effects of commonly used vasoactive drugs on pulmonary artery and veins, the study aimed to improve efficiency and accuracy of isolated pulmonary vascular experiments, and to provide experimental basis for clinical drug use.
METHODS
The contractile responses of pulmonary arteries and veins from twelve-week-old Male Sprague-Dawley rats to phenylephrine, arginine vasopressin (AVP), U46619, endothelin-1, and potassium chloride (KCl) were recorded, as well as the relaxation in response to phenylephrine, AVP, acetylcholine. To further explore the mechanism, some vessels was also pre-incubated with adrenergic receptors antagonists propranolol, prazosin and nitric oxide synthesis inhibitor N[gamma]-nitro-L-arginine methyl ester (L-NAME) before addition of the experimental drugs.
RESULTS
Phenylephrine constricted pulmonary veins directly, but constricted pulmonary artery only after incubation with propranolol or/and L-NAME. The pulmonary artery exhibited significant relaxation to AVP with or without L-NAME incubation. AVP more clearly constricted the veins after incubation with L-NAME. Changes in vascular tension also varied from pulmonary artery to veins for KCl stimulation. Different from phenomena presented in veins, acetylcholine did not relax pulmonary artery preconstricted by KCl, U46619, and endothelin-1.
CONCLUSIONS
According to the results, phenylephrine, KCl, AVP, and acetylcholine could be used to distinguish pulmonary arteries and pulmonary veins in vitro. This also suggested that the pulmonary arteries and pulmonary veins have great differences in physiology and drug reactivity.
Topics: Acetylcholine; Animals; Arginine Vasopressin; Male; Phenylephrine; Potassium Chloride; Pulmonary Artery; Pulmonary Veins; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents
PubMed: 34090386
DOI: 10.1186/s12890-021-01558-8 -
Journal of Cataract and Refractive... May 2017To evaluate the study drug OMS302 (Omidria [phenylephrine and ketorolac injection 1.0%/0.3%]) compared with a balanced salt solution (vehicle), ketorolac, and... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To evaluate the study drug OMS302 (Omidria [phenylephrine and ketorolac injection 1.0%/0.3%]) compared with a balanced salt solution (vehicle), ketorolac, and phenylephrine on pupil diameter during cataract surgery and early postoperative ocular pain.
SETTING
Twenty-three centers in the United States.
DESIGN
Randomized clinical trial.
METHODS
Patients were randomized (1:1:1:1) to receive vehicle, phenylephrine, ketorolac, or the study drug containing phenylephrine and ketorolac administered intracamerally during surgery. Intraoperative pupil diameter was determined each minute by video capture. Postoperative ocular pain was evaluated for up to 12 hours.
RESULTS
The study evaluated 223 patients. The study drug was significantly better than the vehicle and ketorolac in maintaining mydriasis (least-squares mean differences 0.9 ± 0.1 [SEM] and 0.7 ± 0.1 for the study drug versus vehicle and ketorolac, respectively; P < .0001 each). Ocular pain assessed using the Visual Analog Scale was significantly reduced for the study drug compared with the vehicle or phenylephrine (least-squares mean difference -4.6 ± 2.2 and P = .042 and 5.9 ± 2.2 and P = .009, respectively). Significantly fewer patients treated with the study drug (3 [6.1%]) had an intraoperative pupil diameter smaller than 6.0 mm compared with those treated with the vehicle (25 [47.2%]; P < .0001), ketorolac (18 [34.6%]; P = .0004), or phenylephrine (11 [22.4%]; P = .0216).
CONCLUSIONS
The study drug was safe and efficacious in maintaining mydriasis and reducing postoperative ocular pain. Both ketorolac and phenylephrine contributed to the therapeutic effects, with the combination showing superiority to either agent alone in maintaining an intraoperative pupil diameter of 6.0 mm or larger.
Topics: Cataract Extraction; Eye Pain; Humans; Ketorolac; Mydriasis; Mydriatics; Pain, Postoperative; Phenylephrine; Pupil
PubMed: 28602319
DOI: 10.1016/j.jcrs.2017.02.030 -
Anesthesiology Jan 1999Hypoperfusion and necrosis in free flaps used to correct tissue defects remain important clinical problems. The authors studied the effects of two vasoactive drugs,...
BACKGROUND
Hypoperfusion and necrosis in free flaps used to correct tissue defects remain important clinical problems. The authors studied the effects of two vasoactive drugs, sodium nitroprusside and phenylephrine, which are used frequently in anesthetic practice, on total blood flow and microcirculatory flow in free musculocutaneous flaps during general anesthesia.
METHODS
In a porcine model (n = 9) in which clinical conditions for anesthesia and microvascular surgery were simulated, latissimus dorsi free flaps were transferred to the lower extremity. Total blood flow in the flaps was measured using ultrasound flowmetry and microcirculatory flow was measured using laser Doppler flowmetry. The effects of sodium nitroprusside and phenylephrine were studied during local infusion through the feeding artery of the flap and during systemic administration.
RESULTS
Systemic sodium nitroprusside caused a 30% decrease in mean arterial pressure, but cardiac output did not change. The total flow in the flap decreased by 40% (P < 0.01), and microcirculatory flow decreased by 23% in the skin (P < 0.01) and by 30% in the muscle (P < 0.01) of the flap. Sodium nitroprusside infused locally into the flap artery increased the total flap flow by 20% (P < 0.01). Systemic phenylephrine caused a 30% increase in mean arterial pressure, whereas heart rate, cardiac output, and flap blood flow did not change. Local phenylephrine caused a 30% decrease (P < 0.01) in the total flap flow.
CONCLUSIONS
Systemic phenylephrine in a dose increasing the systemic vascular resistance and arterial pressure by 30% appears to have no adverse effects on blood flow in free musculocutaneous flaps. Sodium nitroprusside, however, in a dose causing a 30% decrease in systemic vascular resistance and arterial pressure, causes a severe reduction in free flap blood flow despite maintaining cardiac output.
Topics: Anesthesia, General; Animals; Hemodynamics; Microcirculation; Nitroprusside; Phenylephrine; Regional Blood Flow; Respiration; Surgical Flaps; Swine; Vasoconstrictor Agents; Vasodilator Agents
PubMed: 9915323
DOI: 10.1097/00000542-199901000-00020