Pectin methylesterases (PMEs) catalyze pectin demethylation and facilitate the determination of the degree of methyl esterification of cell wall in higher plants. The regulation of PME activity through endogenous proteinaceous PME inhibitors (PMEIs) alters the status of pectin methylation and influences plant growth and development. In this study, we performed a PMEI screening assay using a chemical library and identified a strong inhibitor, phenylephrine (PE). PE, a small molecule, competitively inhibited plant PMEs, including orange PME and Arabidopsis PME. Physiologically, cultivation of Brassica campestris seedlings in the presence of PE showed root growth inhibition. Microscopic observation revealed that PE inhibits elongation and development of root hairs. Molecular studies demonstrated that Root Hair Specific 12 (RHS12) encoding a PME, which plays a role in root hair development, was inhibited by PE with a Ki value of 44.1 μM. The biochemical mechanism of PE-mediated PME inhibition as well as a molecular docking model between PE and RHS12 revealed that PE interacts within the catalytic cleft of RHS12 and interferes with PME catalytic activity. Taken together, these findings suggest that PE is a novel and non-proteinaceous PME inhibitor. Furthermore, PE could be a lead compound for developing a potent plant growth regulator in agriculture.

We have previously found that hyperkalemic cardioplegic arrest in the setting of cardiopulmonary bypass (CP/CPB) is associated with impairment of the coronary arteriolar response to phenylephrine in nondiabetic (ND) patients. We hypothesized that diabetes may alter coronary arteriolar response to alpha-1 adrenergic agonist in the setting of CP/CPB. In this study, we further investigated the effects of diabetes on the altered coronary arteriolar response to phenylephrine in patients undergoing cardiac surgery.

 Maternal hypotension is a common complication of spinal anesthesia in cesarean section and requires immediate intervention. Phenylephrine is most commonly used as a vasopressor agent for the treatment of hypotension due to subarachnoid block. Our aim was to compare the bolus dose of 50 µg of phenylephrine with a fixed infusion at 50 µg.min-1 of phenylephrine for maintaining arterial blood pressure during cesarean delivery.

Oxygen supply to the brain is of special importance during intracranial surgery because it may be compromised by intracranial pathology. A high arterial blood pressure (mean arterial pressure above 80 mmHg) and a high arterial oxygen tension (PaO2 above 12 kPa) is therefore often targeted in these patients, when for example intracranial pressure is increased or when a mass effect on brain tissue from a tumour is present, and it is pursued by administering vasopressors such as phenylephrine and by increasing inspiratory oxygen fraction (FiO2 ). However, whether these interventions increase cerebral oxygenation remains uncertain. We aimed to investigate the effect of hyperoxia and phenylephrine on brain tissue oxygen tension (PbtO2 ) in patients undergoing craniotomy.

Fentanyl was reported to inhibit the alpha(1)-adrenoceptor agonist-induced contraction. The goal of this in vitro study was to identify the alpha(1)-adrenoceptor subtype primarily involved in the fentanyl-induced attenuation of phenylephrine-induced contraction in isolated endothelium-denuded rat aorta.

Regulation of uterine contractility is an important aspect of women's health. Phenylephrine, a selective agonist of the α1-adrenoceptor and a potent smooth muscle constrictor, is widely used in women even during pregnancy to relieve cold-related symptoms, to treat postpartum haemorrhoid, and during routine eye exams. We performed isometric tension recordings to investigate the effect of phenylephrine on mouse uterine contractility. Phenylephrine decreased spontaneous and oxytocin-induced contractions in non-pregnant mouse uterine rings and strips with an IC50 of ~1 μM. Prazosin, an inhibitor of α1-adrenoceptor, did not prevent phenylephrine-mediated relaxations. Conversely, ICI118551, an antagonist of β2-adrenoceptors, inhibited phenylephrine relaxation. In the presence of ICI118551, high concentrations (>30 μM) of phenylephrine caused mouse uterine contractions, suggesting that β-adrenoceptor-mediated inhibition interferes with the phenylephrine contractile potential. Phenylephrine-dependent relaxation was reduced in the uterus of pregnant mice. We used primary mouse and human uterine smooth muscle cells (M/HUSMC) to establish the underlying mechanisms. Phenylephrine stimulated large increases in intracellular cAMP in M/HUSMCs. These cAMP transients were decreased when HUSMCs were cultured in the presence of oestrogen and progesterone to mimic the pregnancy milieu. Thus, phenylephrine is a strong relaxant in the non-pregnant mouse uterus, but exhibits diminished effect in the pregnant uterus.

Cardiac hypertrophy is determined by an increase of cell size in cardiomyocytes (CMCs). Among the cellular processes regulating the growth of cell size, the increase of protein synthesis rate represents a critical event. Most of translational factors promoting protein synthesis stimulate cardiac hypertrophy. In contrast, activity of translational repressor factors, in cardiac hypertrophy, is not fully determined yet. Here we report the effect of a translational modulator, eIF6/p27BBP in the hypertrophy of neonatal rat CMCs. The increase of eIF6 levels surprisingly prevent the growth of cell size induced by phenylephrine, through a block of protein synthesis without affecting skeletal rearrangement and ANF mRNA expression. Thus, this work uncovers a new translational cardiac regulator independent by other well-known factors such as mTOR signalling or eIF2β.

We have demonstrated that phenylephrine (PE) activates the capsaicin-sensitive nerves, and then activates capsaicin-sensitive nerves to release an unknown substance that facilitates the release of norepinephrine (NE) from adrenergic nerves. Subsequently, NE stimulates β-ARs in the detrusor muscle in mice, leading to neurogenic relaxation of the urinary bladder (UB).

Moderate and severe hypothermia with cardiopulmonary bypass during aortic surgery can cause some complications such as endothelial cell dysfunction or coagulation disorders. This study found out the difference of vascular reactivity by phenylephrine in moderate and severe hypothermia.

Induction of general anesthesia frequently induces arterial hypotension, which is often treated with a vasopressor, such as phenylephrine. As a pure α-agonist, phenylephrine is conventionally considered to solely induce arterial vasoconstriction and thus increase cardiac afterload but not cardiac preload. In specific circumstances, however, phenylephrine may also contribute to an increase in venous return and thus cardiac output (CO). The aim of this study is to describe the initial time course of the effects of phenylephrine on various hemodynamic variables and to evaluate the ability of advanced hemodynamic monitoring to quantify these changes through different hemodynamic variables. In 24 patients, after induction of anesthesia, during the period before surgical stimulus, phenylephrine 2 µg kg-1 was administered when the MAP dropped below 80% of the awake state baseline value for > 3 min. The mean arterial blood pressure (MAP), heart rate (HR), end-tidal CO2 (EtCO2), central venous pressure (CVP), stroke volume (SV), CO, pulse pressure variation (PPV), stroke volume variation (SVV) and systemic vascular resistance (SVR) were recorded continuously. The values at the moment before administration of phenylephrine and 5(T5) and 10(T10) min thereafter were compared. After phenylephrine, the mean(SD) MAP, SV, CO, CVP and EtCO2 increased by 34(13) mmHg, 11(9) mL, 1.02(0.74) L min-1, 3(2.6) mmHg and 4.0(1.6) mmHg at T5 respectively, while both dynamic preload variables decreased: PPV dropped from 20% at baseline to 9% at T5 and to 13% at T10 and SVV from 19 to 11 and 14%, respectively. Initially, the increase in MAP was perfectly aligned with the increase in SVR, until 150 s after the initial increase in MAP, when both curves started to dissociate. The dissociation of the evolution of MAP and SVR, together with the changes in PPV, CVP, EtCO2 and CO indicate that in patients with anesthesia-induced hypotension, phenylephrine increases the CO by virtue of an increase in cardiac preload.

Background: Phenylephrine and atropine can cause serious adverse effects when applied in combination. We investigated the effect of phenylephrine eye drops combined with intravenous atropine on the cardiovascular system in patients under general anesthesia undergoing intraocular surgery. Methods: The effects of the drugs were observed through clinical study. Thirteen patients undergoing intraocular surgery under general anesthesia were observed in this study; all were injected intravenously with atropine due to the oculocardiac reflex during surgery. To study the combination of drugs, an in vivo study was performed on rats. Seventy-two standard deviation rats that received phenylephrine eye drops and intravenous atropine treatment under general anesthesia were assessed, of which 18 treated with these drugs simultaneously were administered normal saline, neostigmine or esmolol. Blood pressure and heart rate were recorded and analyzed. Findings: The age of the patients ranged from seven to 14 years old with an average age of 10.7 years old, and 11 patients were male. In patients, 5% phenylephrine eye drops combined with intravenous atropine led to a significant heart rate increase and the increase lasted 20 min. The significant increase in diastolic blood pressure and systolic blood pressure lasted for 15 and 25 min, respectively. From five to 25 min after intravenous atropine treatment, the systolic blood pressure and diastolic blood pressure were both more than 20% higher than that at baseline. In rats, the changes in blood pressure and heart rate were independent of the phenylephrine and atropine administration sequence but were related to the administration time interval. The neostigmine group showed a significant decrease in blood pressure after the increase from the administration of phenylephrine and atropine. Interpretation: Phenylephrine eye drops combined with intravenous atropine have obvious cardiovascular effects that can be reversed by neostigmine. This drug combination should be used carefully for ophthalmic surgery, especially in patients with cardio-cerebrovascular diseases.

Angiopoietin-like protein 4 (ANGPTL4) is a multifunctional secreted protein that can be induced by fasting, hypoxia and glucocorticoids. ANGPTL4 has been associated with a variety of diseases; however, the role of ANGPTL4 in cardiac hypertrophy remains poorly understood. In our study, we aimed to explore the effect of ANGPTL4 on phenylephrine-induced cardiomyocyte hypertrophy. Our results showed that knockdown of ANGPTL4 expression significantly exacerbated cardiomyocyte hypertrophy, as demonstrated by increased hypertrophic marker expression, including ANP and cell surface area. Moreover, significantly reduced fatty acid oxidation, as featured by decreased CPT-1 levels, was observed in hypertrophic cardiomyocytes following ANGPTL4 down-regulation. Furthermore, knockdown of ANGPLT4 led to down-regulated expression of peroxisome proliferator-activated receptor α (PPARα), which is the key regulator of cardiac fatty acid oxidation. In addition, ANGPTL4 silencing promoted the activation of JNK1/2, and JNK1/2 signaling blockade could restore the level of PPARα and significantly ameliorate the ANGPTL4 knockdown-induced cardiomyocyte hypertrophy. Therefore, our study demonstrated that ANGPTL4 regulates PPARα through JNK1/2 signaling and is required for the inhibition of cardiomyocyte hypertrophy.

Alpha adrenergic stimulation is known to produce vasoconstriction. We have earlier shown that, in spiral strips of small arteries Phenylephrine (PE) caused vasorelaxation under high nitric oxide (NO) environment. However, on further experimentation it was realized that the PE-induced vasorelaxant response occurred only with longitudinal strips of small arteries even under normal NO environment while circular strips showed contraction with PE even under high NO environment. Such PE-induced vasorelaxation of longitudinal strips was blocked by Phentolamine, an alpha-adrenergic receptor blocker. On delineation of specific receptor subtype, PE-induced relaxation was found to be mediated through alpha 1D receptor. However, this phenomenon is specific to small artery, as longitudinal smooth muscle of aorta showed only contractile response to adrenergic stimulation. There is no prior report of longitudinal smooth muscle in small artery up to our knowledge. The results of this study and histological examination of vessel sections suggest the presence of longitudinal smooth muscle in small artery and their relaxant response to alpha adrenergic stimulation is a novel phenomenon.

Ginsenoside Rg3 (Rg3) isolated from Panax ginseng relaxes vessels and exerts a cytoprotective effect. In view of the fact that nitric oxide (NO) is involved in vascular hyporeactivity and immunostimulation, the effects of total ginsenosides (GS) and Rg3 on the vascular responses and the expression of inducible nitric oxide synthase (iNOS) were investigated. Vasocontraction of endothelium-denuded aortic ring was induced by phenylephrine with or without GS or Rg3. The expression of iNOS was assessed by Western blot and RT-PCR analyses. NF-kappaB activation was monitored by gel shift, immunoblot and immunocytochemical analyses. Incubation of the endothelium-denuded aortic ring with GS or Rg3 inhibited phenylephrine-induced vasocontraction, which was abrogated by NOS inhibition. GS or Rg3 increased NO production in aortic rings, but Rb1, Rc, Re and Rg1 had no effect. Aortic rings obtained from rats treated with GS or Rg3 responded to phenylnephrine to a lesser extent, while producing NO to a larger extent, than those from control animals. GS or Rg3 induced iNOS in vascular smooth muscle. Rg3 induced iNOS with increase in NO production in Raw264.7 cells. Rg3 increased NF-kappaB DNA binding, whose band was supershifted with anti-p65 and anti-p50 antibodies, and elicited p65 nuclear translocation, which was accompanied by phosphorylation and degradation of I-kappaBalpha. PKC regulated iNOS induction by Rg3. In conclusion, Rg3 relaxes vessels as a consequence of NO production, to which iNOS induction contributes, and iNOS induction by Rg3 accompanied NF-kappaB activation, which involves phosphorylation and degradation of I-kappaBalpha and nuclear translocation of p65.

Catecholamine-induced vascular smooth muscle cell (VSMC) proliferation is one of the major events in the pathogenesis of atherosclerosis and vascular remodeling. The calcineurin-NFAT pathway plays a role in regulating growth and differentiation in various cell types. We investigated whether the calcineurin-NFAT pathway was involved in the regulation of phenylephrine-induced VSMC proliferation.

This study examined the effect of linolenic acid on the contraction of isolated endothelium-intact and -denuded rat aorta induced by phenylephrine and its underlying mechanism. This was conducted in the presence or absence of NW-nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), methylene blue, and calmidazolium. The effects of linolenic acid on contraction induced by calcium chloride in calcium-free Krebs solution containing 60 mM potassium chloride were also examined. Moreover, the effect of linolenic acid on the association between intracellular calcium level ([Ca2+]i) and tension induced by phenylephrine was examined. Finally, we examined the effects of linolenic acid on cGMP formation and endothelial nitric oxide synthase (eNOS) phosphorylation induced by phenylephrine. Linolenic acid (5 × 10-5 M) increased phenylephrine-induced contraction in endothelium-intact aorta (standardized mean difference [SMD] of log ED50: 2.23), whereas it decreased this contraction in endothelium-denuded aorta (SMD: 1.96). L-NAME, ODQ, methylene blue, and calmidazolium increased phenylephrine-induced contraction in endothelium-intact aorta. Linolenic acid decreased contraction induced by calcium chloride in calcium-free Krebs solution containing 60 mM potassium chloride in endothelium-denuded aorta. Linolenic acid caused an increase in [Ca2+]i (SMD at 3 × 10-7 M phenylephrine: 1.63) and calcium sensitivity induced by phenylephrine in endothelium-intact aorta. Conversely, linolenic acid decreased [Ca2+]i (SMD: 0.99) induced by phenylephrine in endothelium-denuded aorta. Linolenic acid decreased cGMP formation and eNOS phosphorylation induced by phenylephrine. These results suggest that linolenic acid increases phenylephrine-induced contraction, which is attributed to linolenic acid inhibition of endothelial NO release rather than its decrease of [Ca2+]i in vascular smooth muscle.

Ephedrine, unlike phenylephrine, has a dose-related propensity to depress fetal pH during spinal anesthesia during cesarean section. A low arterial umbilical cord pH has a strong association with neonatal mortality and morbidity. The purpose of this retrospective study was to investigate influences of vasopressor change on Apgar scores and adverse neonatal outcomes in cesarean section.

Cardiac hypertrophy is the main response of the heart to various extrinsic and intrinsic stimuli, and it is characterized by specific molecular and phenotypic changes. Recent in vitro and in vivo studies indicate the involvement of reactive oxygen species in the hypertrophic response. In this study, silibinin, a plant flavonolignan extracted from milk thistle with potent antioxidant activity, was evaluated for its effects in (a) preventing hydrogen peroxide (H2O2)-induced cellular damage and (b) blocking the phenylephrine-induced hypertrophic response. Using the in vitro model of embryonic rat heart-derived H9c2 cells, we showed that silibinin has a rather safe profile as concentrations up to 200μM did not affect cell viability. Pretreatment of H9c2 cells with silibinin resulted in better protection of H9c2 cells under conditions of H2O2-induced cellular stress compared to untreated cells as indicated by cell viability and DNA fragmentation assays. Furthermore, silibinin attenuated the phenylephrine-induced hypertrophic response as evidenced by the measurement of cell surface, up-regulation of atrial natriuretic peptide and increase of cellular protein levels. Moreover, silibinin repressed the phenylephrine-induced phosphorylation of ERK1/2 kinases, while it appeared to inhibit the weakly activated by phenylephrine phosphorylation of Akt. Based on our results, silibinin may attenuate the phenylephrine-induced hypertrophic response of H9c2 cells via antioxidant mechanisms involving mainly the inhibition of the intracellular signaling pathways mediated by ERK1/2 MAPKs and Akt.

The intravenous administration of indigo carmine has been reported to produce transiently increased blood pressure in patients. The goal of this in vitro study was to examine the effect of indigo carmine on phenylephrine-induced contractions in an isolated rat aorta and to determine the associated cellular mechanism with particular focus on the endothelium-derived vasodilators.

Phenylephrine (PE) is a canonical α1-adrenoceptor-selective agonist. However, unexpected effects of PE have been observed in preclinical and clinical studies, that cannot be easily explained by its actions on α1-adrenoceptors. The probability of the involvement of α2- and β-adrenoceptors in the effect of PE has been raised. In addition, our earlier study observed that PE released noradrenaline (NA) in a [Ca2+]o-independent manner. To elucidate this issue, we have investigated the effects of PE on [3H]NA release and α1-mediated smooth muscle contractions in the mouse vas deferens (MVD) as ex vivo preparation. The release experiments were designed to assess the effects of PE at the presynaptic terminal, whereas smooth muscle isometric contractions in response to electrical field stimulation were used to measure PE effect postsynaptically. Our results show that PE at concentrations between 0.3 and 30 µM significantly enhanced the resting release of [3H]NA in a [Ca2+]o-independent manner. In addition, prazosin did not affect the release of NA evoked by PE. On the contrary, PE-evoked smooth muscle contractions were inhibited by prazosin administration indicating the α1-adrenoceptor-mediated effect. When the function of the NA transporter (NAT) was attenuated with nisoxetine, PE failed to release NA and the contractions were reduced by approximately 88%. The remaining part proved to be prazosin-sensitive. The present work supports the substantial indirect effect of PE which relays on the cytoplasmic release of NA, which might explain the reported side effects for PE.