OBJECTIVES: Nerve growth factor (NGF) induces neuron transdifferentiation of adrenal medulla chromaffin cells (AMCCs) and consequently downregulates the secretion of epinephrine (EPI), which may be involved in the pathogenesis of bronchial asthma. Mammalian achaete scute-homologous 1 (MASH1), a key regulator of neurogenesis in the nervous system, has been proved to be elevated in AMCCs with neuron transdifferentiation in vivo. This study aims to explore the role of MASH1 in the process of neuron transdifferentiation of AMCCs and the mechanisms. METHODS: Rat AMCCs were isolated and cultured. AMCCs were transfected with siMASH1 or MASH1 overexpression plasmid, then were stimulated with NGF and/or dexamethasone, PD98059 (a MAPK kinase-1 inhibitor) for 48 hours. Morphological changes were observed using light and electron microscope. Phenylethanolamine-N-methyltransferase (PNMT, the key enzyme for epinephrine synthesis) and tyrosine hydroxylase were detected by immunofluorescence. Western blotting was used to test the protein levels of PNMT, MASH1, peripherin (neuronal markers), extracellular regulated protein kinases (ERK), phosphorylated extracellular regulated protein kinases (pERK), and JMJD3. Real-time RT-PCR was applied to analyze the mRNA levels of MASH1 and JMJD3. EPI levels in the cellular supernatant were measured using ELISA. RESULTS: Cells with both tyrosine hydroxylase and PNMT positive by immunofluorescence were proved to be AMCCs. Exposure to NGF, AMCCs exhibited neurite-like processes concomitant with increases in pERK/ERK, peripherin, and MASH1 levels (all P<0.05). Additionally, impairment of endocrine phenotype was proved by a signifcant decrease in the PNMT level and the secretion of EPI from AMCCs (all P<0.01). MASH1 interference reversed the effect of NGF, causing increases in the levels of PNMT and EPI, conversely reduced the peripherin level and cell processes (all P<0.01). MASH1 overexpression significantly increased the number of cell processes and peripherin level, while decreased the levels of PNMT and EPI (all P<0.01). Compared with the NGF group, the levels of MASH1, JMJD3 protein and mRNA in AMCCs in the NGF+PD98059 group were decreased (all P<0.05). After treatment with PD98059 and dexamethasone, the effect of NGF on promoting the transdifferentiation of AMCCs was inhibited, and the number of cell processes and EPI levels were decreased (both P<0.05). In addition, the activity of the pERK/MASH1 pathway activated by NGF was also inhibited. CONCLUSIONS MASH1 is the key factor in neuron transdifferentiation of AMCCs. NGF-induced neuron transdifferentiation is probably mediated via pERK/MASH1 signaling.
Animals ; Rats ; Adrenal Medulla ; Cell Transdifferentiation ; Chromaffin Cells ; Dexamethasone ; Epinephrine/pharmacology* ; Mammals ; Nerve Growth Factor ; Neurons ; Peripherins ; Protein Kinases ; Tyrosine 3-Monooxygenase

Melatonin is a neurotransmitter that modulates various physiological phenomena including regulation and maintenance of the circadian rhythm. Nicotinic acetylcholine receptors (nAChRs) play an important role in oral functions including orofacial muscle contraction, salivary secretion, and tooth development. However, knowledge regarding physiological crosstalk between melatonin and nAChRs is limited. In the present study, the melatonin-mediated modulation of nAChR functions using bovine adrenal chromaffin cells, a representative model for the study of nAChRs, was investigated. Melatonin inhibited the nicotinic agonist dimethylphenylpiperazinium (DMPP) iodide-induced cytosolic free Ca²⁺ concentration ([Ca²⁺](i)) increase and norepinephrine secretion in a concentration-dependent manner. The inhibitory effect of melatonin on the DMPP-induced [Ca²⁺](i) increase was observed when the melatonin treatment was performed simultaneously with DMPP. The results indicate that melatonin inhibits nAChR functions in both peripheral and central nervous systems.
Calcium Signaling ; Central Nervous System ; Chromaffin Cells ; Circadian Rhythm ; Cytosol ; Dimethylphenylpiperazinium Iodide ; Melatonin ; Muscle Contraction ; Neurotransmitter Agents ; Nicotinic Agonists ; Norepinephrine ; Physiological Phenomena ; Receptors, Nicotinic ; Tooth

Pheochromocytomas are neoplasms of the adrenal gland that are derived from chromaffin cells. One of the most important features of this tumor is that it can synthesize and release catecholamines such as norepinephrine and epinephrine. Due to this, arterial hypertension is one of the most common manifestations of the tumor. Although arterial hypertension is a substantial risk factor for aortic dissection, aortic dissection is actually a rare manifestation of pheochromocytoma. Here, we report a patient with pheochromocytoma who presented with acute type B aortic dissection.
Adrenal Glands ; Catecholamines ; Chromaffin Cells ; Epinephrine ; Humans ; Hypertension ; Norepinephrine ; Pheochromocytoma* ; Risk Factors

Pheochromocytomas are rare catecholamine-secreting neuroendocrine tumors arising from chromaffin cells in the adrenal medulla. Typical classic triad are consisted of headaches, palpitations, and profuse diaphoresis. But some patients with pheochromocytomas have other cardiovascular manifestations such as left ventricular hypertrophy, congestive heart failure, and cardiac arrhythmia. Rarely, pheochromocytomas manifest as acute myocardial infarction leading to delayed diagnosis and treatment. We experienced one case of pheochromocytoma initially manifesting as acute myocardial infarction which showed normal coronary artery on coronary angiography. Pheochromocytoma should be suspected and evaluated in patients with acute myocardial infarction whose coronary angiography shows normal coronary without definite thrombosis.
Adrenal Medulla ; Arrhythmias, Cardiac ; Chromaffin Cells ; Coronary Angiography ; Coronary Vessels ; Delayed Diagnosis ; Headache ; Heart Failure ; Humans ; Hypertrophy, Left Ventricular ; Myocardial Infarction* ; Neuroendocrine Tumors ; Pheochromocytoma* ; Thrombosis

Paragangliomas are relatively rare chromaffin cell tumors which may be cured through resection. Patients with paragangliomas may develop metastatic diseases. There is no consensus regarding refractory chemotherapy for treatment of metastatic disease. In this report, we presented a case of a 43-year-old woman who was admitted to the hospital with a history of episodic headaches, diaphoresis, and weakness. Elevated plasma catecholamine levels and a right paraaortic mass were observed on computed tomography. The mass was excised, and a diagnosis of paraganglioma was confirmed. After 20 months of follow-up, local recurrence and metastases were detected in the thorax, abdomen, and skeletal system. Plasma and urinary catecholamine levels were high. Chemotherapy was administered, and no improvement was observed. Therefore, following this palliative conventional chemotherapy, sorafenib was administered for three months, and, finally, positron emission tomography showed that the patient's lesions had completely regressed.
Abdomen ; Adult ; Chromaffin Cells ; Consensus ; Diagnosis ; Drug Therapy ; Female ; Follow-Up Studies ; Headache ; Humans ; Neoplasm Metastasis ; Paraganglioma* ; Paraganglioma, Extra-Adrenal ; Pheochromocytoma ; Plasma ; Positron-Emission Tomography ; Recurrence ; Thorax

Paragangliomas are rare tumors that arise from the extra-adrenal chromaffin cells, and malignancy is defined by the presence of metastases to sites that normally lack chromaffin tissue. The main therapeutic targets are tumor reduction and control of excessive catecholamine secretion. Currently, the adjuvant therapy to surgery is radiotherapy treatment using high-dose MIBG; chemotherapy is currently evolving. We report herein a case of malignant paraganglioma with lung and spine metastasis that occurred 16 years after primary tumor excision and was treated with high dose MIBG radiotherapy and chemotherapy.
3-Iodobenzylguanidine ; Chromaffin Cells ; Drug Therapy ; Lung* ; Neoplasm Metastasis* ; Paraganglioma* ; Radiotherapy ; Spine*

The aim of the present study was to investigate whether ginsenoside-Rb2 (Rb2) can affect the secretion of catecholamines (CA) in the perfused model of the rat adrenal medulla. Rb2 (3~30 microM), perfused into an adrenal vein for 90 min, inhibited ACh (5.32 mM)-evoked CA secretory response in a dose- and time-dependent fashion. Rb2 (10 microM) also time-dependently inhibited the CA secretion evoked by DMPP (100 microM, a selective neuronal nicotinic receptor agonist) and high K+ (56 mM, a direct membrane depolarizer). Rb2 itself did not affect basal CA secretion (data not shown). Also, in the presence of Rb2 (50 microg/mL), the secretory responses of CA evoked by veratridine (a selective Na+ channel activator (50 microM), Bay-K-8644 (an L-type dihydropyridine Ca2+ channel activator, 10 microM), and cyclopiazonic acid (a cytoplasmic Ca2+-ATPase inhibitor, 10 microM) were significantly reduced, respectively. Interestingly, in the simultaneous presence of Rb2 (10 microM) and L-NAME (an inhibitor of NO synthase, 30 microM), the inhibitory responses of Rb2 on ACh-evoked CA secretory response was considerably recovered to the extent of the corresponding control secretion compared with the inhibitory effect of Rb2-treatment alone. Practically, the level of NO released from adrenal medulla after the treatment of Rb2 (10 microM) was greatly elevated compared to the corresponding basal released level. Collectively, these results demonstrate that Rb2 inhibits the CA secretory responses evoked by nicotinic stimulation as well as by direct membrane-depolarization from the isolated perfused rat adrenal medulla. It seems that this inhibitory effect of Rb2 is mediated by inhibiting both the influx of Ca2+ and Na+ into the adrenomedullary chromaffin cells and also by suppressing the release of Ca2+ from the cytoplasmic calcium store, at least partly through the increased NO production due to the activation of nitric oxide synthase, which is relevant to neuronal nicotinic receptor blockade.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester ; Adrenal Medulla ; Animals ; Calcium ; Catecholamines ; Chromaffin Cells ; Cytoplasm ; Dimethylphenylpiperazinium Iodide ; Membranes ; Neurons ; NG-Nitroarginine Methyl Ester ; Nitric Oxide Synthase ; Rats ; Receptors, Nicotinic ; Veins ; Veratridine

BACKGROUND: The aim of this study was to examine whether PD 123319 (an angiotensin II type 2 [AT2] receptor antagonist) can influence the release of catecholamines (CA) from the perfused model of the rat adrenal medulla. METHODS: The adrenal gland was isolated by the modification of Wakade method, and perfused with normal Krebs-bicarbonate solution. The content of CA was measured using the fluorospectrophotometer. RESULTS: During perfusion of PD 123319 (range, 5 to 50 nM) into an adrenal vein for 90 minutes the CA secretory responses evoked by acetylcholine (ACh), high K+, 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), and McN-A-343 was dose- and time-dependently inhibited. Furthermore, loading with PD 123319 for 90 minutes also markedly inhibited the CA secretory responses evoked by 4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoro-methyl-phenyl)-pyridine-5-carboxylate (Bay-K-8644), cyclopiazonic acid, veratridine, and angiotensin II (Ang II). PD 123319 did not affect basal CA output. Simultaneous perfusion of PD 123319 and CGP 42112 perfused into an adrenal vein for 90 minutes rather more potently inhibited the CA seretory responses evoked by Ach, high K+, DMPP, Bay-K-8644, veratridine, and Ang II compared to the inhibitory effect by PD123319-treated alone. CONCLUSIONS: Taken together, these results show that PD 123319 inhibits the CA secretion evoked by both cholinergic and Ang II receptor stimulation from the perfused rat adrenal medulla. This inhibitory effect of PD 123319 seems to be exerted by blocking the influx of both Na+ and Ca2+ through their voltage-dependent channels into the rat adrenomedullary chromaffin cells as well as by reducing the Ca2+ release from its cytoplasmic calcium store, which may be relevant to AT2 receptor blockade. Based on these present data, it is thought that PD 123319 has different activity from previously known AT2 antagonist activity in the perfused adrenal medulla, and that AT2 receptors may be involved in the rat adrenomedullary CA secretion.
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride ; 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester ; Acetylcholine ; Adrenal Glands ; Adrenal Medulla ; Angiotensin II ; Angiotensin II Type 2 Receptor Blockers ; Animals ; Calcium ; Catecholamines ; Chromaffin Cells ; Cytoplasm ; Dimethylphenylpiperazinium Iodide ; Imidazoles ; Indoles ; Oligopeptides ; Perfusion ; Pyridines ; Rats ; Veins ; Veratridine

Paraganglioma is a tumor originating from the extra-adrenal chromaffin cells, and functional paraganglioma causes paroxysmal hypertension, headache and tachycardia, due to excess excretion of catecholamine. However, rarely, ARDS, acute myocardial infarction, heart failure, arrhythmia, and pulmonary edema are also seen in patients with paraganglioma and clinical manifestations are depending on the patient's intravascular volume status. Seventy one-years-old male was presented with hypotension and pulmonary edema after intravenous midazolam injection during colonoscopy under conscious sedation. The patient was initially suspected with anaphylactic shock, due to midazolam injection. However, later, he was diagnosed with paraganglioma, and blood pressure was successfully controlled with alpha adrenergic blockade. We suggest that when we encounter heart failure, pulmonary edema and shock of unknown origin, pheochromocytoma must be taken into consideration.
Anaphylaxis ; Arrhythmias, Cardiac ; Blood Pressure ; Chromaffin Cells ; Colonoscopy ; Conscious Sedation ; Headache ; Heart Failure ; Humans ; Hypertension ; Hypotension ; Male ; Midazolam ; Myocardial Infarction ; Paraganglioma ; Pheochromocytoma ; Pulmonary Edema ; Shock ; Tachycardia

Pheochromocytoma is a rare neuroendocrine tumor that is usually derived from adrenal medulla or chromaffin cells along with sympathetic ganglia. In Western countries, the prevalence of pheochromocytoma is estimated to be between 1:6,500 and 1:2,500, compared with an incidence in the United States of 500 to 1,100 cases per year. Despite this low incidence, pheochromocytoma should always be considered for differential diagnoses because previous studies have shown that this condition can be cured in approximately 90% of cases. However, an untreated tumor is likely to be fatal due to catecholamine-induced malignant hypertension, heart failure, myocardial infarction, stroke, ventricular arrhythmias or metastatic disease. Symptoms that result primarily from excess circulating catecholamines and hypertension include severe headaches, generalized inappropriate sweating and palpitations (with tachycardia or occasionally bradycardia). Pheochromocytoma, however, has highly variable and heterogeneous clinical manifestations, including fever, general weakness and dyspepsia, and can be observed in patients who are suffering from infectious diseases. Several of such case reports have been presented, but most of these included infectious patients with high blood pressure and severe fluctuations. In this study, we presented the case of a 53-year-old male who showed normal blood pressure, but had a sustained fever. He was diagnosed with diabetic ketoacidosis, infective endocarditis and asymptomatic adrenal incidentaloma. Despite treatment with antibiotics and valve replacement, the fever persisted. After the patient underwent evaluation for the fever, adrenal incidentaloma was identified as pheochromocytoma. After removal of the abdominal mass, his fever improved.
Adrenal Gland Neoplasms ; Adrenal Medulla ; Anti-Bacterial Agents ; Arrhythmias, Cardiac ; Blood Pressure ; Catecholamines ; Chromaffin Cells ; Communicable Diseases ; Diabetic Ketoacidosis ; Diagnosis, Differential ; Dyspepsia ; Endocarditis ; Fever ; Ganglia, Sympathetic ; Headache ; Heart Failure ; Humans ; Hypertension ; Hypertension, Malignant ; Incidence ; Male ; Middle Aged ; Myocardial Infarction ; Neuroendocrine Tumors ; Pheochromocytoma ; Prevalence ; Stress, Psychological ; Stroke ; Sweat ; Sweating ; Tachycardia ; United States