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B G Hoebel

Publications and source records attributed to B G Hoebel.

At least 37 records · Page 2Linked to original sources
PubMed1998

Submaximal stimulation of porcine endothelial cells causes focal Ca2+ elevation beneath the cell membrane.

1. Endothelial cell activation is correlated with increased cytosolic Ca2+ concentration, often monitored with cytoplasmic Ca2+ dyes, such as fura-2 and Calcium Green-1. We tested the hypothesis that during weak stimulation of porcine coronary artery endothelial cells, focal, subplasmalemmal Ca2+ elevations occur which are controlled by cell membrane Na(+)-Ca2+ exchange near mitochondrial membrane and superficial endoplasmic reticulum (SER). 2. Bulk Ca2+ concentration ([Ca2+]b) was monitored using fura-2 or Calcium Green-1 and subplasmalemmal Ca2+ concentration ([Ca2+]sp) was determined with FFP-18. The distribution of the SER network was estimated using laser scanning and deconvolution microscopy. 3. Sodium fluoride (10 mmol l-1) and submaximal concentrations of bradykinin (Bk; 1 nmol l-1) stimulated Ca2+ entry with no increase in [Ca2+]b. Although inositol 1,4,5-trisphosphate formation and intracellular Ca2+ release in response to both stimuli were similar, Ca2+ entry in response to NaF exceeded that in response to 1 nmol l-1 BK by fourfold, suggesting additional effects of NaF on Ca+ entry pathways but stimulation via intracellular Ca2+ release. 4. Prevention of Na(+)-Ca2+ exchange activity by decreasing extracellular Na+ unmasked intracellular Ca2+ release in response to NaF and 1 nmol l-1 Bk, indicated by an increase in [Ca2+]b. Thereby, NaF depleted Bk-releasable Ca2+ pools, while mitochondrial Ca2+ content (released with FCCP or oligomycin) and the amount of Ca2+ stored within the cells (released with ionomycin) was increased compared with cells treated with NaF under normal Na+ conditions. The NaF-initiated increase in [Ca2+]b and depletion of Bk-releasable Ca2+ pool(s) in the low-Na+ condition was diminished by 25 mumol l-1 ryanodine, indicating the involvement of Ca(2+)-induced Ca2+ release (CICR). 5. In simultaneous recordings of [Ca2+]sp (with FFP-18) and [Ca2+]b (with Calcium Green-1), 1 nmol l-1 Bk or 10 mmol l-1 NaF yielded focal [Ca2+] elevation in the subplasmalemmal region with no increase in the perinuclear area. 6. Treatment with 10 mumol-1 nocodazole caused the SER to collapse and unmasked Ca2+ release in response to 1 nmol l-1 Bk and 10 mmol l-1 NaF, similar to low-Na+ conditions, while the effect of thapsigargin was not changed. 7. These data show that in endothelial cells, focal, subplasmalemmal Ca2+ elevations in response to small or slow IP3 formation occur due to vectorial Ca2+ release from the SER towards the plasmalemma followed by Ca2+ extrusion by Na(+)-Ca2+ exchange. While these local Ca2+ elevations are not detectable with Ca2+ dyes for the determination of [Ca2+]b, prevention of Ca2+ extrusion or SER disruption yields increases in [Ca2+]b partially due to CICR. 8. All of the data support our hypothesis that in weakly stimulated endothelial cells, intracellular Ca2+ release and [Ca2+] elevation are limited to the subplasmalemmal region. We propose that the SER co-operates with associated parts of the plasma membrane to control Ca2+ homeostasis, Ca2+ distribution and Ca2+ entry. The existence of such a subplasmalemmal Ca2+ control unit (SCCU) needs to be considered in discussions of Ca2+ signalling, especially when cytoplasmic Ca2+ dyes, such as fura-2 or Calcium Green-1, are used.

Animals↗
PubMed1998

Origin and function of epoxyeicosatrienoic acids in vascular endothelial cells: more than just endothelium-derived hyperpolarizing factor?

1. In addition to their contribution to endothelium-derived hyperpolarization, our understanding of the physiological function of epoxyeicosatrienoic acids (EET) within the vascular wall and the actual enzymes involved in the formation of the EET in endothelial cells is very limited. In the present study, the expression of potential cytochrome P450 (CYP) mono/epoxygenases was assessed in endothelial cells isolated from porcine and bovine aortas as well as in the human umbilical vein-derived cell lines EA.hy926 and ECV304. 2. Expression of CYP2B1, CYP2E1 and CYP3A could be found. The latter were inducible by dexamethasone/clofibrate for 72 h, a procedure that also enhanced CYP epoxygenase activity in endothelial cells. 3. Enzyme induction yielded increases in capacitative Ca2+ entry and membrane hyperpolarization in response to autacoids, such as bradykinin and thapsigargin. Thiopentone sodium, an inhibitor of endothelial CYP mono/epoxygenase(s), diminished autacoid-induced capacitative Ca2+ entry and membrane hyperpolarization, while the effect of EET remained unchanged. 4. Epoxyeicosatrienoic acids activated endothelial tyrosine kinase activity in a concentration-dependent manner. Arachidonic acid, at 20-fold higher concentrations, also increased tyrosine kinase activity. Because only the effect of arachidonic acid was inhibited by thiopentone sodium, an inhibitor of CYP mono/epoxygenases, these data suggest that arachidonic acid needs to be converted to the EET in order to stimulate tyrosine kinase. 5. All these data provide clear evidence that the CYP epoxygenase-derived arachidonic acid metabolites (EET) not only serve as potential endothelium-derived hyperpolarizing factors but also constitute highly active intracellular messengers with a physiological role including the control of Ca2+ signalling, membrane potential and tyrosine kinase activity.

8,11,14-Eicosatrienoic Acid↗
PubMed1998

Effects of superoxide anions on endothelial Ca2+ signaling pathways.

Although the involvement of free radicals in the development of endothelial dysfunction under pathological conditions, like diabetes and hypercholesterolemia, has been proposed frequently, there is limited knowledge as to how superoxide anions (O2-) might affect endothelial signal transduction. In this study, we investigated the effects of preincubation with the O2(-)-generating system xanthine oxidase/hypoxanthine (XO/HX) on mechanisms for Ca2+ signaling in cultured porcine aortic endothelial cells. Incubation of cells with XO/HX yielded increased intracellular Ca2+ release and capacitative Ca2+ entry in response to bradykinin and ATP in a time- and concentration-dependent manner. This effect was prevented by superoxide dismutase but not by the tyrosine kinase inhibitor tyrphostin A48. In addition, capacitative Ca2+ entry induced by the receptor-independent stimulus 2,5-di-(tert-butyl)-1,4-benzohydroquinone or thapsigargin was enhanced in O2(-)-exposed cells (+38% and +32%, respectively). Increased Ca2+ release in response to bradykinin in XO/HX-pretreated cells might be due to enhanced formation of inositol-1,4,5-trisphosphate (+140%). Exposure to XO/HX also affected other signal transduction mechanisms involved in endothelial Ca2+ signaling, such as microsomal cytochrome P450 epoxygenase and membrane hyperpolarization to Ca2+ store depletion with thapsigargin (+103% and +48%, respectively) and tyrosine kinase activity (+97%). A comparison of bradykinin-initiated intracellular Ca2+ release and thapsigargin-induced hyperpolarization with membrane viscosity modulated by XO/HX (decrease in viscosity) or cholesterol (increase in viscosity) reflected a negative correlation between bradykinin-initiated Ca2+ release and membrane viscosity. Because intracellular Ca2+ is a main regulator of endothelial vascular function, our data suggest that O2- anions are involved in regulation of the vascular endothelium.

Adenosine Triphosphate↗
PubMed1997

Antioxidants prevent high-D-glucose-enhanced endothelial Ca2+/cGMP response by scavenging superoxide anions.

Very recently we proposed that hyperactivity of endothelial Ca2+/cGMP signaling under hyperglycemic conditions is due to superoxide anion (O2-) release. The present study was designed to investigate changes in endothelial glutathione (GSH) levels in response to high D-glucose and possible prevention of the high-D-glucose-initiated changes in Ca2+/cGMP signal by antioxidants. Under hyperglycemic conditions, GSH content increased by 29% within 4 h. Co-incubation with 10 mM GSH during high-D-glucose treatment normalized the Ca2+/cGMP response associated with an increase in GSH content by 222%. Vitamin C (250 microM) markedly diminished the high-D-glucose-mediated hyperreactivity of endothelial Ca2+ entry (by 40%) and Ca2+ release (by 52%). Similar to GSH, co-incubation with vitamin E (alpha-tocopherol; 50 micrograms/ml) and probucol (50 microM) completely prevented the high-D-glucose-initiated hyperreactivity of the endothelial Ca2+/cGMP response. Vitamin E, probucol, GSH and vitamin C diminished the high-D-glucose-mediated O2- release by 78, 65, 89 and 46%, respectively. These data suggest that antioxidants prevent high-D-glucose-initiated changes in endothelial Ca2+/cGMP response by scavenging the overshoot of O2-.

Animals↗
PubMed1997

Neuroscience and appetitive behavior research: 25 years.

Neuroscience techniques have made major contributions to the understanding of appetitive behavior. Highlights in six areas are summarized to illustrate progress during the 25 years of the Columbia Appetitive Behavior Seminar: (1) discovery of angiotensin and aldosterone in the control of thirst and salt appetite; (2) electrophysiological decoding of chemoreceptive information in the brain; (3) a new foundation in the hypothalamus built on peptides, such as neuropeptide Y and galanin, interacting with monoamines and steroids in the control of appetite for macronutrients; (4) discovery of numerous peptides that mediate and integrate satiety, such as cholecystokinin, insulin, leptin and enterostatin, and other systems that suppress eating during illness; (5) better understanding of appetite suppressant drugs, and (6) exploration of a circuit that translates hypothalamic signals into behavioral action through connections to brainstem reflex arcs and forebrain instrumental response systems.

Appetite↗
PubMed1997

Activation of microsomal cytochrome P450 mono-oxygenase by Ca2+ store depletion and its contribution to Ca2+ entry in porcine aortic endothelial cells.

1. We investigated how microsomal cytochrome P450 mono-oxygenase (Cyp450 MO) is regulated in cultured porcine aortic endothelial cells. The hypothesis that a Cyp450 MO-derived metabolite links Ca2+ store depletion and Ca2+ entry was studied further. 2. Microsomal Cyp450 MO was monitored fluorometrically by dealkylation of 1-ethoxypyrene-3,6,8-tris-(dimethyl-sulphonamide; EPSA) in saponin permeabilized cells or in subcellular compartments. Endothelial Ca2+ signalling was measured by a standard fura-2 technique, membrane potential was determined with the potential-sensitive fluorescence dye, bis-(1,3-dibutylbarbituric acid) pentamethine oxonol (DiBAC4(5)) and tyrosine kinase was quantified by measuring the phosphorylation of a immobilized substrate with a horseradish peroxidase labelled phosphotyrosine specific antibody. 3. Depletion of cellular Ca2+ pools with inositol 1,4,5-trisphosphate (IP3), thapsigargin or cyclopiazonic acid activated microsomal Cyp450 MO. Similar to direct Ca2+ store depletion, chelating of intramicrosomal Ca2+ with oxalate stimulated Cyp450 MO activity, while changing cytosolic free Ca2+ failed to influence Cyp450 MO activity. These data indicate that microsomal Cyp450 MO is activated by depletion of IP3-sensitive stores. 4. Besides the common cytochrome P450 inhibitors, econazole, proadifen and miconazole, thiopentone sodium and methohexitone inhibited Cyp450 MO in a concentration-dependent manner. The physiological substrate of Cyp450 MO, arachidonic acid, inhibited EPSA dealkylation. In contrast to most other cytochrome P450 inhibitors used in this study, thiopentone sodium did not directly interfere with Ca2+ entry pathways, membrane hyperpolarization due to K+ channel activation or tyrosine kinase activity. 5. Inhibition of Cyp450 MO by thiopentone sodium diminished Ca2+/Mn2+ entry to Ca2+ store depletion by 43%, while it did not interfere with intracellular Ca2+ release by IP3 or thapsigargin. 6. Cyp450 MO inhibition with thiopentone sodium diminished autacoid-induced membrane hyperpolarization. 7. Induction of Cyp450 MO with dexamethasone/clofibrate for 72 h yielded increases in thapsigargin-induced Cyp450 MO activity (by 35%), Ca2+/Mn2+ entry (by 105%) and membrane hyperpolarization (by 40%). 8. The Cyp450 MO-derived compounds, 11,12 and 5,6-epoxyeicosatrienoic acids (EETs) yielded membrane hyperpolarization, insensitive to thiopentone sodium. 9. These data demonstrate that endothelial Cyp450 MO is activated by Ca2+ store depletion and Cyp450 MO produced compounds that hyperpolarize endothelial cells. 10. The data presented and our previous findings indicate that Cyp450 MO plays a crucial role in the regulation of store-operated Ca2+ influx. We propose that Cyp450 MO-derived EETs constitute a signal for Ca2+ entry activation and increase the driving force for Ca2+ entry by membrane hyperpolarization in porcine aortic endothelial cells.

8,11,14-Eicosatrienoic Acid↗
PubMed1997

Norepinephrine microinjections in the hypothalamic paraventricular nucleus increase extracellular dopamine and decrease acetylcholine in the nucleus accumbens: relevance to feeding reinforcement.

Norepinephrine (NE) was microinjected into the paraventricular nucleus (PVN), while microdialysis was used to monitor extracellular dopamine (DA) and acetylcholine (ACh) in the nucleus accumbens (NAc). The PVN is a site where exogenously administered NE can act through alpha 2 receptors to elicit eating behavior and preference for carbohydrates. It was hypothesized that NE in the PVN acts on a behavior reinforcement system by altering the DA/ACh balance in the NAc. NE microinjections (80 nmol in 0.3 microliter), which effectively elicited feeding in satiated rats in a separate test, caused a significant increase in extracellular DA (109%) and decrease in ACh (-27%) when the same animals were tested in the absence of food. In contrast when the food was available and ingested, ACh increased (51%) instead of decreasing. These results support the hypothesis that a functional link exists between the PVN and the NAc in which DA helps initiate and ACh helps stop appetitive behavior involved in the reinforcement of eating.

Acetylcholine↗
PubMed1996

Morphine and naloxone, i.p. or locally, affect extracellular acetylcholine in the accumbens and prefrontal cortex.

In rats with microdialysis probes in the nucleus accumbens (NAc) or prefrontal cortex (PFC), intraperitoneally (IP) delivered morphine on the 8th day of escalating doses decreased extracellular ACh in the NAc. On day 9, naloxone (5 mg/kg) precipitated withdrawal and increased the release of ACh. When morphine and methylnaloxonium were given locally into the NAc by reverse dialysis, the opiate again decreased extracellular ACh, and the opiate antagonist increased it. These effects were proportional to the dose of local infusions. Local morphine had the same ACh-lowering effect in morphine-dependent and nondependent rats, whereas local methylnaloxonium increased extracellular ACh significantly more in morphine-dependent animals. Systemic and local effects on ACh systems in the PFC were more complicated and showed some relation to locomotor activity. The results suggest that intrinsic ACh neurons in the NAc have a special relationship to opiate reinforcement such that extracellular ACh is low in response to morphine and high during withdrawal. Thus, low ACh may correlate with opiate reward, and high ACh with aversion.

Acetylcholine↗
PubMed1996

Systemic and local cocaine increase extracellular serotonin in the nucleus accumbens.

The effect of systemic or intra-accumbens injections of cocaine on serotonin (5-HT) overflow was studied by nucleus accumbens microdialysis in freely moving rats. In Experiment 1, cocaine was injected intraperitoneally at 0, 10, 20, and 30 mg/kg. In Experiment 2, cocaine (3.6, 7.2, and 14.4 mM), lidocaine (7.2 mM), or saline was infused through the probe by reverse microdialysis. Extracellular serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured by high-pressure liquid chromatography and electrochemical detection. Systemic administration of cocaine induced a dose-related increase in 5-HT overflow and a decrease of 5-HIAA. Intra-accumbens cocaine infusion also caused a dose-related increase in 5-HT, but no effect on 5-HIAA. As a control for local anesthesia, equimolar lidocaine did not increase 5-HT. The difference between lidocaine and cocaine was not due to unequal diffusion out of the probe, because previous in vivo calibration of the probe showed that more lidocaine than cocaine diffused out of the probe when equimolar solutions were infused. These experiments suggest that systemic cocaine acts on the nucleus accumbens to increase synaptic 5-HT.

Animals↗
PubMed1996

Mechanisms of L-NG nitroarginine/indomethacin-resistant relaxation in bovine and porcine coronary arteries.

1. Coronary arteries from bovines (BCA) and pigs (PCA) were used for measuring endothelium-dependent relaxation in the presence of L-NG nitroarginine and indomethacin. As some compounds tested have been found to have an inhibitory effect on autacoid-activated endothelial Ca2+ signalling, endothelium-dependent relaxation was initiated with the Ca2+ ionophore A23187. 2. The common compounds for modulating arachidonic acid release/pathway, mepacrine and econazole only inhibited L-NG nitroarginine-resistant relaxation in BCA not in PCA. In contrast, proadifen (SKF 525A) diminished relaxation in BCA and PCA. Mepacrine and proadifen inhibited Hoe-234-initiated relaxation in BCA and PCA, while econazole only inhibited Hoe 234-induced relaxation in PCA. Due to the multiple effects of these compounds, caution is necessary in the interpretation of results obtained with these compounds. 3. The inhibitor of Ca(2+)-activated K+ channels, apamin, strongly attenuated A23187-induced L-NG nitroarginine-resistant relaxation in BCA while apamin did not affect L-NG nitroarginine-resistant relaxation in PCA. 4. Pertussis toxin blunted L-NG nitroarginine-resistant relaxation in BCA, while relaxation of PCA was not affected by pertussis toxin. 5. Thiopentone sodium inhibited endothelial cytochrome P450 epoxygenase (EPO) in PCA but not in BCA, while L-NG nitroarginine-resistant relaxation of BCA and PCA were unchanged. Protoporphyrine IX inhibited EPO in BCA and PCA and abolished L-NG nitroarginine-resistant relaxation of BCA not PCA. 6. An EPO-derived compound, 11,12-epoxy-eicosatrienoic acid (11,12-EET) yielded significant relaxation in BCA and PCA in three out of six experiments. 7. These findings suggest that L-NG nitroarginine-resistant relaxation in BCA and PCA constitutes two distinct pathways. In BCA, activation of Ca(2+)-activated K+ channels via a pertussis-toxin-sensitive G protein and EPO-derived compounds might be involved. In PCA, no selective inhibition of L-NG nitroarginine-resistant relaxation was found.

8,11,14-Eicosatrienoic Acid↗
PubMed1995

Maternal hormonal manipulations in rats cause obesity and increase medial hypothalamic norepinephrine release in male offspring.

In previous work it has been shown that adult male, but not female, offspring of rats that have either been injected with Protamine Zinc Insulin on days 15-20 gestation, or undernourished during the first 2 weeks of gestation, develop significant obesity commencing at about 50 days of age. The present experiment examines the question of whether rats with these two forms of obesity display neurochemical abnormalities in areas of the brain known to influence food intake and body weight. Twenty-one gauge stainless steel guide shafts were surgically implanted using standard stereotaxic procedures. One week later 26 ga microdialysis probes were lowered into the medial hypothalamus. Dialysates collected from male offspring in the two experimental conditions contain significantly higher norepinephrine (NE) levels than did controls. It would appear that in addition to sharing a similar time course of onset and a sex dependent expression of obesity, both of these models are also characterized by elevated medial hypothalamic NE. Since this obesity appears only in males, and at a time when testosterone levels are rapidly rising in males, and since testosterone has been shown to elevate food intake and body weights in rats, we also investigated whether gonadal weights or circulating testosterone levels were differentially elevated by our manipulations.

Animals↗
PubMed1995

Extracellular acetylcholine is increased in the nucleus accumbens following the presentation of an aversively conditioned taste stimulus.

To determine if acetylcholine (ACh) is released in the nucleus accumbens in response to a conditioned stimulus (CS) that reminds the animal of an aversive event, in vivo microdialysis was used to monitor extracellular ACh during conditioned taste aversion. Saccharin flavored water (2.5 mM saccharin) was paired twice with nausea induced by i.p. lithium chloride (100 mg/kg). This is normally sufficient to create an aversion to the taste of saccharin, but instead of a preference test, the saccharin solution was squirted directly into the rat's mouth via a cheek catheter during nucleus accumbens microdialysis. The result was a 40% increase in extracellular ACh. We reported earlier that dopamine changes in the opposite direction; it decreases. This suggests that high synaptic ACh and low DA are correlated with an aversive state and cessation of behavior.

Acetylcholine↗
PubMed1995

Chronic food deprivation decreases extracellular dopamine in the nucleus accumbens: implications for a possible neurochemical link between weight loss and drug abuse.

In rats reduced to 80% of normal body weight (n = 9), the basal levels of extracellular dopamine (DA) in the nucleus accumbens (NAC), as determined by microdialysis, decreased significantly to 33% (mean +/- SEM) of their normal baseline (p < 01). Basal extracellular DA did not change significantly over a matching 3-week period in controls (n = 7). No changes were observed in NAC serotonin after weight reduction. These results indicate that parts of the mesolimbic DA system are depressed in underweight rats. The observed decrease in basal DA may be responsible for a variety of behavioral changes observed in undernourished humans and animals including the tendency to eat and gain weight when food becomes available. Given that DA can be released in the NAC when rats self-inject drugs of abuse, the present findings may help explain why animals increase drug intake when they are underweight.

Animals↗
PubMed1995

d-fenfluramine, but not d-norfenfluramine, uses calcium to increase extracellular serotonin.

Microdialysis in the hippocampus of freely moving rats was used to assess extracellular serotonin (5-HT) in response to local infusion of d-fenfluramine and its metabolite d-norfenfluramine with and without local calcium depletion. Verapamil (1 mM) in calcium-free Ringer infused via the microdialysis probe increased extracellular 5-HT and prevented the full increase in extracellular 5-HT normally caused by 1 mM d-fenfluramine. The results suggest d-fenfluramine might act in part as a calcium channel agonist favoring a calcium influx that in turn would trigger the exocytotic process in 5-HT terminals. d-norfenfluramine, on the other hand, was capable of releasing 5-HT, in vivo, in spite of depleted Ca levels.

Animals↗
PubMed1995

Rats self-inject a dopamine antagonist in the lateral hypothalamus where it acts to increase extracellular dopamine in the nucleus accumbens.

Local injection of sulpiride to block dopamine (primarily D2-type) receptors in the perifornical lateral hypothalamus (pf-LH) can induce locomotion, feeding, and drinking, and in the present study, local sulpiride induced reward and dopamine (DA) release in the nucleus accumbens. Sulpiride injected bilaterally (4, 8, and 16 micrograms/0.3 microliters), ipsilaterally, or contralaterally (8 micrograms) in the pf-LH increased extracellular levels of DA and its metabolites in the accumbens. Bilateral sulpiride injected posterior and medial to the pf-LH controlled for diffusion to the ventricle or ventral midbrain. Rats self-injected sulpiride (210 ng/21 nl/2 s) in the pf-LH (111 resp/2 h on drug lever vs. 20 resp on a blank lever). Thus, cells in the pf-LH establish connections with mesolimbic DA neurons involved in the behavior reinforcement process. Evidently hypothalamic cells with DA receptors normally inhibit aspects of behavior reinforcement. Disinhibition with hypothalamic sulpiride is reward for self-injection and cause of overeating that can lead to obesity.

Animals↗
PubMed1995

Chronic clozapine selectively decreases prefrontal cortex dopamine as shown by simultaneous cortical, accumbens, and striatal microdialysis in freely moving rats.

We used microdialysis to study the acute and chronic effects of clozapine on the metabolism of dopamine (DA) in terminal areas of the mesocortical, mesolimbic, and nigrostriatal systems simultaneously. In the acute experiment, groups of four rats received the following doses: 0 (vehicle), 10, 20, and 40 mg/kg of clozapine subcutaneously, which resulted in a dose-related increase in extracellular DA, 3,4-dihydroxyphenalacetic acid (DOPAC), and homovanillic acid (HVA) in the prefrontal cortex (PFC). In the nucleus accumbens (NAC) and striatum (STR), no significant changes were observed at any dose. In the chronic experiment, six rats received 20 mg/kg of clozapine and a control group received vehicle daily for 30 days. After 30 days of treatment, DA, DOPAC, and HVA were significantly lower in the PFC, and unchanged in the NAC or STR. The 30th clozapine injection failed to increase DA, DOPAC, or HVA in any of the three regions. We conclude that clozapine acted selectively on the mesocortical system, and that this may underlie clozapine's therapeutic, antipsychotic effect.

3,4-Dihydroxyphenylacetic Acid↗