Increased Catecholamine Secretion Research Articles

0363 Insomnia with Short Sleep Duration Is Associated with Increased Catecholamine Secretion in Young Adults

0363 Insomnia with Short Sleep Duration Is Associated with Increased Catecholamine Secretion in Young Adults

Nutrition of neonates and infants with severe congenital heart disease - the review of the literature

CHD is the most common birth defect with an incidence of 9 per 1,000 live births. The severity of the disease and the choice of treatment depend on the underlying anomaly. Despite advances in medical and surgical treatment that have led to more children with CHD reaching adulthood, disorders such as intestinal dysfunction, poor nutrition, and growth failure are still common in infants with CHD. Increased metabolic demand, decreased caloric intake, malabsorption, genetic factors, and fluid restriction can all result in an energy imbalance that negatively impacts morbidity and mortality in these patients. On the other hand, malnutrition is an important risk factor for adverse postoperative consequences. The state of nutrition affects growth and development, wound healing and the functioning of the immune system. Malnutrition affects both short-term and long-term postoperative outcomes. Recurrent infections caused by impaired immune system function and delayed healing of surgical wounds are considered short-term effects, while impaired growth, physical and cognitive development are seen as long-term effects. High postoperative mortality and morbidity, such as increased rates of hospitalization, delayed growth, prolonged recovery time, and longer hospital stays are associated with preoperative malnutrition. Appropriate nutrition protocols tailored to the requirements of patients with congenital heart disease help to improve short and long-term treatment outcomes. Nutritional and metabolic changes are age-dependent, and since this is a high-risk population, enteral and/or parenteral nutrition is difficult. Sources of increased metabolic demand in CHD include greater workload on the heart, pulmonary hypertension, and increased catecholamine secretion.

PS-R03-10: CASE REPORT: CUSHING SYNDROME IN A YOUNG MALE

A 27-year-old male without any significant past medical history was advised to visit a hospital for elevated blood pressure, elevated liver enzymes, and dyslipidemia in a workplace health checkup. His body weight had increased by more than 10 kg in the last two years. He presented to our department and underwent laboratory work-up. He had bilateral lower limb pitting edema, hypokalemia, and elevation of low-density lipoprotein. No sign of dysthyroidism, renin-angiotensin-aldosterone system disorder, or increased catecholamine secretion was found. Diet and exercise therapy and calcium channel blocker did not improve his hypertension, and he suffered from lumber vertebral fracture, refractory hypokalemia, and lower leg cellulitis. He was admitted to our department for detailed examination of worsening lower limb edema. On admission, he had striae on his abdomen and legs as well as edema of both lower extremities. The endocrinological data showed high levels of adrenocorticotropic hormone (ACTH) and cortisol. Overnight 1 mg dexamethasone suppression test resulted in a non-suppression response, and his circadian rhythm of cortisol was absent. Urine cortisol level was high. These findings confirmed the diagnosis of ACTH-dependent Cushing syndrome. A contrasted magnetic resonance imaging (MRI) scan demonstrated enlargement of the pituitary gland more than 1 cm in length. Taking into account drug-resistant hypokalemia and vulnerability to infection, he was administered with metyrapone 500 mg per day until he underwent transsphenoidal hypophysectomy. The pathological findings were consistent with that of a pituitary adenoma. Postoperative MRI scan showed remnant lesions which stretch to the bilateral cavernous sinuses and the right middle cranial fossa. Although a decrease in urine cortisol was observed, the absence of a circadian rhythm of cortisol, hypertension, and hypokalemia persisted. He is now treated with somatostatin analog and craniotomy followed by gamma knife surgery is planned. Cushing syndrome should be suspected in cases of early-onset hypertension with symptoms including weight gain, hypokalemia, and bone fracture.

Functional Gly297Ser Variant of the Physiological Dysglycemic Peptide Pancreastatin Is a Novel Risk Factor for Cardiometabolic Disorders.

Pancreastatin (PST), a chromogranin A-derived potent physiological dysglycemic peptide, regulates glucose/insulin homeostasis. We have identified a nonsynonymous functional PST variant (p.Gly297Ser; rs9658664) that occurs in a large section of human populations. Association analysis of this single nucleotide polymorphism with cardiovascular/metabolic disease states in Indian populations (n = 4,300 subjects) displays elevated plasma glucose, glycosylated hemoglobin, diastolic blood pressure, and catecholamines in Gly/Ser subjects as compared with wild-type individuals (Gly/Gly). Consistently, the 297Ser allele confers an increased risk (∼1.3-1.6-fold) for type 2 diabetes/hypertension/coronary artery disease/metabolic syndrome. In corroboration, the variant peptide (PST-297S) displays gain-of-potency in several cellular events relevant for cardiometabolic disorders (e.g., increased expression of gluconeogenic genes, increased catecholamine secretion, and greater inhibition of insulin-stimulated glucose uptake) than the wild-type peptide. Computational docking analysis and molecular dynamics simulations show higher affinity binding of PST-297S peptide with glucose-regulated protein 78 (GRP78) and insulin receptor than the wild-type peptide, providing a mechanistic basis for the enhanced activity of the variant peptide. In vitro binding assays validate these in silico predictions of PST peptides binding to GRP78 and insulin receptor. In conclusion, the PST 297Ser allele influences cardiovascular/metabolic phenotypes and emerges as a novel risk factor for type 2 diabetes/hypertension/coronary artery disease in human populations.

Interpreting Normetanephrines-the Significance of Clinical Context

Introduction: Pheochromocytoma ranges in presentation, but the diagnostic hallmarks are increased catecholamine secretion in patients with an adrenal mass. However, interpretation requires consideration of the clinical state. Case: A 60-year-old man presented with 6 months of episodic flushing, night sweats, fatigue, back pain, and 20-pound weight loss. Vitals were notable for hypotension and mild tachycardia. He was thin with evidence of hyperpigmentation. Contrasted CT showed 15 cm heterogeneous masses of both adrenals and a rib lesion. Plasma normetanephrines were elevated on two separate measures (526 and 1,398 pg/mL, nl <=148). Plasma metanephrines were normal. Urine normetanephrines were increased 4-fold (2,165mcg/g Cr, n 108–524). Labs noted low DHEA-S (2 mcg/dL, n 38–313), high ACTH (204 pg/mL, n 6–50), random cortisol (5.2 mcg/dL, n 3.5–18.3), undetectable aldosterone, and high plasma renin activity (83 ng/mL/h, n 2.9–10.8). Cortisol peaked at 6.7 mcg/dL 1 hour after 250mcg of cosyntropin. MRI revealed over 15cm infiltrating masses arising from adrenals with modest flare on T2 imaging. Dotatate PET/CT showed mild uptake of bilateral adrenals and metastases to liver and bone. He was started on steroid replacement and doxazosin for presumed pheochromocytoma.He was transferred to our facility where he remained hypotensive despite adequate glucocorticoid and mineralocorticoid replacement. Once stabilized, repeat plasma normetanephrines were insignificant (218 pg/mL, n 0–145) and chromogranin was normal (68 ng/mL, n<93). Biopsy of the rib lesion confirmed diffuse large B-cell lymphoma. Discussion: Pheochromocytoma classically presents in the outpatient setting with palpitations, diaphoresis, pallor, and paroxysmal hypertension. Rarely, it results in hypertensive emergencies requiring hospitalization. In patients with catecholamine excess and an adrenal mass, pheochromocytoma is usually suspected. 3-fold or more increases of normetanephrines or metanephrines above upper cutoffs are rarely false-positives. However, this assumes clinical stability. Sympathoadrenal activation is a physiologic response to acute illness. Metanephrines in critically ill patients without pheochromocytoma approached those of pheochromocytoma in one study. Levels normalized upon recovery from illness, highlighting the importance of verifying biochemistries once the patient is stable. The degree of elevation in normetanephrines seen in this patient was a physiologic response to adrenal insufficiency and clinical instability. Pathology confirmed lymphoma rather than pheochromocytoma for which he was started on chemotherapy. Conclusion: Elevated normetanephrines is an appropriate physiological response in the acutely ill. Careful consideration of the clinical picture in conjunction with biochemical data is critical.

Mechanisms underlying the promotion of 5-hydroxytryptamine secretion in enterochromaffin cells of constipation mice by Bifidobacterium and Lactobacillus.

5-Hydroxytryptamine (5-HT) could play a role in alleviating symptoms in constipation. However, the mechanism underlying the role of intestinal flora in the promotion of 5-HT secretion by enterochromaffin cells (ECs) and regulation of the gastrointestinal endocrine system remains unclear. A constipation mouse model was constructed, and the 5-HT, chromogranin A (CGA), substance P (SP), motilin (MTL), dopamine, and noradrenaline expression levels were measured using enzyme-linked immunosorbent assay(Elisa) and immunofluorescence, and key proteins, such as the transient receptor potential (TRP) ion channels/tryptophan hydroxylase (TPH) and olfactory receptor (OR), were determined using western blot. Flow cytometry and in vivo imaging were used to observe microbial colonization in the intestinal tracts of mice. Bifidobacterium animalis F1-7 (F1-7), Lactobacillus paraccasei F34-3 (F34-3), and Lactobacillus plantarum FWDG (FWDG) promoted 5-HT secretion. F1-7 and F34-3 induced CGA expression, increased catecholamine secretion, and activated the CGA/α2A adrenoreceptor (ADRα2A) cascade signal in ECs. FWDG increased noradrenaline levels and activated the ADRα2A signal in ECs. SP content increased in F1-7 and F34-3, and MTL expression increased in FWDG via the above signal. F1-7 and F34-3 downregulated TRPV4 and upregulated TPH, whereas FWDG upregulated OR2A4 for promoting 5-HT secretion by ECs. Finally, we observed that F1-7, F34-3, and FWDG were well colonized in the large intestine. F1-7, F34-3, and FWDG promoted 5-HT secretion in ECs of constipation mice by activating the CGA/ADRα2A cascade signal and regulating the TRP/TPH-OR pathways.

MESA 3: DIABETES MELLITUS TIPO 2 Y ACTIVIDAD FÍSICA

La prevalencia de diabetes mellitus (DM) actividad física es cada vez mayor asociada a bajos niveles de actividad física (AF) y aumento de sobrepeso-obesidad.Los beneficios de la AF incluyen la prevención de la DM, reducción de hemoglobina glicosilada y glucemia postprandial, mejoría del perfil cardiovascular (descenso Presión arterial y triglicéridos, aumento de colesterol HDL), descenso significativo de biomarcadores proinflamatorios. Además, la AF mejora la disfunción sexual, la función endotelial, el óxido nítrico biodisponible y la insulinosensibilad, incrementa la testosterona, mejora el humor y la autoestima, la ansiedad y la depresión.El ejercicio incrementa la producción de glucosa, la secreción de insulina compensatoria está alterada y se exacerba por una mayor secreción de catecolaminas. Las personas con insulinopenia marcada tienen riesgo de cetosis. El aumento de hipoglucemias está dado por una mayor captación de glucosa. La AF mejora la polineuropatía y la neuropatía autonómica cardíaca, previene la enfermad renal crónica y se asocia a menores niveles de retinopatía diabética. En pacientes con retinopatía preproliferativa y proliferativa o degradación macular, se desaconsejan las actividades que aumentan considerablemente la presión intraocular. Está contraindicado el ejercicio en caso de hemorragia vítrea.El requerimiento energético depende del tipo, intensidad y duración del ejercicio. Se debe considerar el cuidado del pie. Las recomendaciones son disminuir el tiempo sedentario, ejercicio aeróbico al menos 150 min/semana y ejercicio de resistencia.Al aumentar la intensidad o ante riesgo elevado se debe realizar chequeo que incluya electrocardiograma y test de esfuerzo. Considerar ecocardiograma bidimensional y doppler.

Complementary role of MRI and positron emission tomography in diagnosing cerebral abscess in a patient with metastatic paraganglioma.

Technological advances have increased the ability of imaging to provide an accurate preoperative diagnosis of an intracranial mass. We present the case of a patient with metastatic paraganglioma, who presented with headache and depressed conscious state. We had chronic tachycardia and low-grade fevers due to increased catecholamine secretion, which limited his clinical assessment. The combination of novel positron emission tomography tracers and advanced magnetic resonance imaging techniques was able to provide a confident preoperative diagnosis of a pyogenic intracranial abscess, which was not suspected clinically. This allowed appropriate therapy to be instituted until the patient's clinical state improved sufficiently for neurosurgery to be performed.

Low pHo boosts burst firing and catecholamine release by blocking TASK-1 and BK channels while preserving Cav1 channels in mouse chromaffin cells.

Mouse chromaffin cells (MCCs) generate spontaneous burst-firing that causes large increases of Ca2+ -dependent catecholamine release, and is thus a key mechanism for regulating the functions of MCCs. With the aim to uncover a physiological role for burst-firing we investigated the effects of acidosis on MCC activity. Lowering the extracellular pH (pHo ) from 7.4 to 6.6 induces cell depolarizations of 10-15 mV that generate bursts of ∼330ms at 1-2Hz and a 7.4-fold increase of cumulative catecholamine-release. Burst-firing originates from the inhibition of the pH-sensitive TASK-1-channels and a 60% reduction of BK-channel conductance at pHo 6.6. Blockers of the two channels (A1899 and paxilline) mimic the effects of pHo 6.6, and this is reverted by the Cav1 channel blocker nifedipine. MCCs act as pH-sensors. At low pHo , they depolarize, undergo burst-firing and increase catecholamine-secretion, generating an effective physiological response that may compensate for the acute acidosis and hyperkalaemia generated during heavy exercise and muscle fatigue. Mouse chromaffin cells (MCCs) generate action potential (AP) firing that regulates the Ca2+ -dependent release of catecholamines (CAs). Recent findings indicate that MCCs possess a variety of spontaneous firing modes that span from the common 'tonic-irregular' to the less frequent 'burst' firing. This latter is evident in a small fraction of MCCs but occurs regularly when Nav1.3/1.7 channels are made less available or when the Slo1β2-subunit responsible for BK channel inactivation is deleted. Burst firing causes large increases of Ca2+ -entry and potentiates CA release by ∼3.5-fold and thus may be a key mechanism for regulating MCC function. With the aim to uncover a physiological role for burst-firing we investigated the effects of acidosis on MCC activity. Lowering the extracellular pH (pHo ) from 7.4 to 7.0 and 6.6 induces cell depolarizations of 10-15mV that generate repeated bursts. Bursts at pHo 6.6 lasted ∼330ms, occurred at 1-2Hz and caused an ∼7-fold increase of CA cumulative release. Burst firing originates from the inhibition of the pH-sensitive TASK-1/TASK-3 channels and from a 40% BK channel conductance reduction at pHo 7.0. The same pHo had little or no effect on Nav, Cav, Kv and SK channels that support AP firing in MCCs. Burst firing of pHo 6.6 could be mimicked by mixtures of the TASK-1 blocker A1899 (300nm) and BK blocker paxilline (300nm) and could be prevented by blocking L-type channels by adding 3μm nifedipine. Mixtures of the two blockers raised cumulative CA-secretion even more than low pHo (∼12-fold), showing that the action of protons on vesicle release is mainly a result of the ionic conductance changes that increase Ca2+ -entry during bursts. Our data provide direct evidence suggesting that MCCs respond to low pHo with sustained depolarization, burst firing and enhanced CA-secretion, thus mimicking the physiological response of CCs to acute acidosis and hyperkalaemia generated during heavy exercise and muscle fatigue.

Nicotinic acetylcholine receptors in glucose homeostasis: the acute hyperglycemic and chronic insulin-sensitive effects of nicotine suggest dual opposing roles of the receptors in male mice.

Cigarette smoking causes insulin resistance. However, nicotine induces anti-inflammation and improves glucose tolerance in insulin-resistant animal models. Here, we determined the effects of nicotine on glucose metabolism in insulin-sensitive C57BL/J6 mice. Acute nicotine administration (30 min) caused fasting hyperglycemia and lowered insulin sensitivity acutely, which depended on the activation of nicotinic-acetylcholine receptors (nAChRs) and correlated with increased catecholamine secretion, nitric oxide (NO) production, and glycogenolysis. Chlorisondamine, an inhibitor of nAChRs, reduced acute nicotine-induced hyperglycemia. qRT-PCR analysis revealed that the liver and muscle express predominantly β4 > α10 > α3 > α7 and β4 > α10 > β1 > α1 mRNA for nAChR subunits respectively, whereas the adrenal gland expresses β4 > α3 > α7 > α10 mRNA. Chronic nicotine treatment significantly suppressed expression of α3-nAChR (predominant peripheral α-subunit) in liver. Whereas acute nicotine treatment raised plasma norepinephrine (NE) and epinephrine (Epi) levels, chronic nicotine exposure raised only Epi. Acute nicotine treatment raised both basal and glucose-stimulated insulin secretion (GSIS). After chronic nicotine treatment, basal insulin level was elevated, but GSIS after acute saline or nicotine treatment was blunted. Chronic nicotine exposure caused an increased buildup of NO in plasma and liver, leading to decreased glycogen storage, along with a concomitant suppression of Pepck and G6Pase mRNA, thus preventing hyperglycemia. The insulin-sensitizing effect of chronic nicotine was independent of weight loss. Chronic nicotine treatment enhanced PI-3-kinase activities and increased Akt and glycogen synthase kinase (GSK)-3β phosphorylation in an nAChR-dependent manner coupled with decreased cAMP response element-binding protein (CREB) phosphorylation. The latter effects caused suppression of Pepck and G6Pase gene expression. Thus, nicotine causes both insulin resistance and insulin sensitivity depending on the duration of the treatment.

Syndapin 3 modulates fusion pore expansion in mouse neuroendocrine chromaffin cells

Adrenal neuroendocrine chromaffin cells receive excitatory synaptic input from the sympathetic nervous system and secrete hormones into the peripheral circulation. Under basal sympathetic tone, modest amounts of freely soluble catecholamine are selectively released through a restricted fusion pore formed between the secretory granule and the plasma membrane. Upon activation of the sympathoadrenal stress reflex, elevated stimulation drives fusion pore expansion, resulting in increased catecholamine secretion and facilitating release of copackaged peptide hormones. Thus regulated expansion of the secretory fusion pore is a control point for differential hormone release of the sympathoadrenal stress response. Previous work has shown that syndapin 1 deletion alters transmitter release and that the dynamin 1-syndapin 1 interaction is necessary for coupled endocytosis in neurons. Dynamin has also been shown to be involved in regulation of fusion pore expansion in neuroendocrine chromaffin cells through an activity-dependent association with syndapin. However, it is not known which syndapin isoform(s) contributes to pore dynamics in neuroendocrine cells. Nor is it known at what stage of the secretion process dynamin and syndapin associate to modulate pore expansion. Here we investigate the expression and localization of syndapin isoforms and determine which are involved in mediating fusion pore expansion. We show that all syndapin isoforms are expressed in the adrenal medulla. Mutation of the SH3 dynamin-binding domain of all syndapin isoforms shows that fusion pore expansion and catecholamine release are limited specifically by mutation of syndapin 3. The mutation also disrupts targeting of syndapin 3 to the cell periphery. Syndapin 3 exists in a persistent colocalized state with dynamin 1.

Increased Catecholamine Secretion from Single Adrenal Chromaffin Cells in DOCA-Salt Hypertension Is Associated with Potassium Channel Dysfunction

The mechanism of catecholamine release from single adrenal chromaffin cells isolated from normotensive and DOCA-salt hypertensive rats was investigated. These cells were used as a model for sympathetic nerves to better understand how exocytotic release of catecholamines is altered in this model of hypertension. Catecholamine secretion was evoked by local application of acetylcholine (1 mM) or high K+ (70 mM), and continuous amperometry was used to monitor catecholamine secretion as an oxidative current. The total number of catecholamine molecules secreted from a vesicle, the total number of vesicles fusing and secreting, and the duration of secretion in response to a stimulus were all significantly greater for chromaffin cells from hypertensive rats as compared to normotensive controls. The greater catecholamine secretion from DOCA-salt cells results, at least in part, from functionally impaired large conductance, Ca2+-activated (BK) and ATP-sensitive K+ channels. This work reveals that there is altered vesicular release of catecholamines from these cells (and possibly from perivascular sympathetic nerves) and this may contribute to increased vasomotor tone in DOCA-salt hypertension.

Enhanced adenosine A2b receptor signaling facilitates stimulus-induced catecholamine secretion in chronically hypoxic carotid body type I cells

Chronic hypoxia (CHox) augments chemoafferent activity in sensory fibers innervating carotid body (CB) chemoreceptor type I cells; however, the underlying mechanisms are poorly understood. We tested the hypothesis that enhanced paracrine signaling via adenosine (Ado) A2b receptors is involved. Dissociated rat CB cultures were exposed for 24 h to normoxia (Nox, 21% O2) or CHox (2% O2) or treated with the hypoxia mimetic deferoxamine mesylate (DFX), and catecholamine secretion from type I cells was monitored by amperometry. Catecholamine secretion was more robust in CHox and DFX type I cells than Nox controls after acute exposure to acid hypercapnia (10% CO2, pH 7.1) and high K(+) (75 mM). Exogenous Ado increased catecholamine secretion in a dose-dependent manner, and the EC50 was shifted to the right from ∼21 μM Ado in Nox cells to ∼78 μM in CHox cells. Ado-evoked secretion in Nox and CHox cells was markedly inhibited by MRS-1754, an A2b receptor blocker, but was unaffected by SCH-58261, an A2a receptor blocker. Similarly, MRS-1754, but not SCH-58261, partially inhibited high-K(+)-evoked catecholamine secretion, suggesting a contribution from paracrine activation of A2b receptors by endogenous Ado. CB chemostimuli, acid hypercapnia, and hypoxia elicited a MRS-1754-sensitive rise in intracellular Ca(2+) that was more robust in CHox and DFX than Nox cells. Taken together, these data suggest that paracrine Ado A2b receptor signaling contributes to stimulus-evoked catecholamine secretion in Nox and CHox CB chemoreceptors; however, the effects of Ado are more robust after CHox.

Endogenous H2S is required for hypoxic sensing by carotid body glomus cells

H(2)S generated by the enzyme cystathionine-γ-lyase (CSE) has been implicated in O(2) sensing by the carotid body. The objectives of the present study were to determine whether glomus cells, the primary site of hypoxic sensing in the carotid body, generate H(2)S in an O(2)-sensitive manner and whether endogenous H(2)S is required for O(2) sensing by glomus cells. Experiments were performed on glomus cells harvested from anesthetized adult rats as well as age and sex-matched CSE(+/+) and CSE(-/-) mice. Physiological levels of hypoxia (Po(2) ∼30 mmHg) increased H(2)S levels in glomus cells, and dl-propargylglycine (PAG), a CSE inhibitor, prevented this response in a dose-dependent manner. Catecholamine (CA) secretion from glomus cells was monitored by carbon-fiber amperometry. Hypoxia increased CA secretion from rat and mouse glomus cells, and this response was markedly attenuated by PAG and in cells from CSE(-/-) mice. CA secretion evoked by 40 mM KCl, however, was unaffected by PAG or CSE deletion. Exogenous application of a H(2)S donor (50 μM NaHS) increased cytosolic Ca(2+) concentration ([Ca(2+)](i)) in glomus cells, with a time course and magnitude that are similar to that produced by hypoxia. [Ca(2+)](i) responses to NaHS and hypoxia were markedly attenuated in the presence of Ca(2+)-free medium or cadmium chloride, a pan voltage-gated Ca(2+) channel blocker, or nifedipine, an L-type Ca(2+) channel inhibitor, suggesting that both hypoxia and H(2)S share common Ca(2+)-activating mechanisms. These results demonstrate that H(2)S generated by CSE is a physiologic mediator of the glomus cell's response to hypoxia.

Impaired K+ channel function leads to increased catecholamine secretion by adrenal chromaffin cells in DOCA‐salt hypertension

Sympathetic nerve activity is increased in deoxycorticosterone acetate (DOCA) salt model of hypertension and catecholamine secretion from adrenal chromaffin cells is increased in DOCA‐salt rats. This includes the number of vesicles released by stimulation (acetylcholine, 1 mM). We tested the hypothesis that individual chromaffin granule size was increased and that K+ channel function was impaired in chromaffin cells from DOCA‐salt rats. Using the charge value obtained from individual events a vesicle radius can be determined by taking the cubed root of the charge. These data showed a positive shift in the mean Q1/3 value for DOCA‐salt release events compared to sham events suggesting that the increase in charge observed is due in part to increased vesicle radii. To determine why DOCA‐salt cells have increased release frequency compared to sham cells, K+ channel function was investigated. We used the K+ channel blockers paxilline (BK), 4‐aminopyridine (Kv1), glibenclamide (ATP‐sensitive) and apamin (SK). Paxilline and glibenclamide (but not apamin or glibenclamide) increased the number of secretory events and total number of catecholamines oxidized from sham chromaffin cells, however did not effect release from DOCA‐salt cells. We conclude that increased vesicle radius and impaired potassium channel function contribute to increased secretion and quantal charge in DOCA‐salt chromaffin cells.

Increased catecholamine secretion contributes to hypertension in TRPM4-deficient mice

Hypertension is an underlying risk factor for cardiovascular disease. Despite this, its pathogenesis remains unknown in most cases. Recently, the transient receptor potential (TRP) channel family was associated with the development of several cardiovascular diseases linked to hypertension. The melastatin TRP channels TRPM4 and TRPM5 have distinct properties within the TRP channel family: they form nonselective cation channels activated by intracellular calcium ions. Here we report the identification of TRPM4 proteins in endothelial cells, heart, kidney, and chromaffin cells from the adrenal gland, suggesting that they have a role in the cardiovascular system. Consistent with this hypothesis, Trpm4 gene deletion in mice altered long-term regulation of blood pressure toward hypertensive levels. No changes in locomotor activity, renin-angiotensin system function, electrolyte and fluid balance, vascular contractility, and cardiac contractility under basal conditions were observed. By contrast, inhibition of ganglionic transmission with either hexamethonium or prazosin abolished the difference in blood pressure between Trpm4-/- and wild-type mice. Strikingly, plasma epinephrine concentration as well as urinary excretion of catecholamine metabolites were substantially elevated in Trpm4-/- mice. In freshly isolated chromaffin cells, lack of TRPM4 was shown to cause markedly more acetylcholine-induced exocytotic release events, while neither cytosolic calcium concentration, size, nor density of vesicles were different. We therefore conclude that TRPM4 proteins limit catecholamine release from chromaffin cells and that this contributes to increased sympathetic tone and hypertension.

Stress Cardiomyopathy Induced by Common Surgical and Medical Interventions. When Patients Get More Than They Asked for

Aim: The aim of this study was to report a series of patients with Stress cardiomyopathy triggered by different medical or surgical therapeutic interventions. Background: Stress cardiomyopathy is a recently described entity characterized by reversible left ventricular dysfunction in response to acute stress. Exaggerated sympathetic stimulation is believed to play a central role in the pathogenesis of this condition. Methods: Patients diagnosed with this condition were evaluated and followed prospectively between January 2006 to January 2009. All patients underwent coronary angiography and noninvasive cardiac investigation including transthoracic echocardiogram. Possible triggers or stressors were investigated. Results: We observed 29 consecutive cases diagnosed with Stress cardiomyopathy. In almost half of the individuals (14 patients, 48.27%), a medical therapeutic intervention (pseudoephedrine or beta-2 adrenergic agonist treatment) or a surgical procedure (liver, renal biopsies, minor surgeries) was identified as the potential stressor. Patients were mainly female, (27 females, 2 males) mean age of 68 years SD 7.96 and all but two had T wave inversion in the ECG.The totality of the patients showed troponin I elevation (mean peak TnI 1.68, SD 1.77), decreased ejection fraction (mean EF 33.92%, SD 11.97) and no obstructive coronary artery disease in the coronary angiogram. Conclusions: Stress cardiomyopathy commonly presents as a complication of medical and surgical interventions. Increased catecholamine secretion in response to stress generated by therapeutic interventions may play a role in the pathogenesis of this entity in these cases. Prevention, early recognition and avoidance of certain medications are imperative in the management of these patients.

Enhanced cAMP production mediates the stimulatory action of pituitary adenylate cyclase activating polypeptide (PACAP) on in vitro catecholamine secretion from bovine adrenal chromaffin cells.

The 38 amino acid peptide pituitary adenylate cyclase activating polypeptide (PACAP) induced a dose dependent increase of catecholamine secretion in cultures of bovine chromaffin cells. This secretagogue activity of PACAP was strictly dependent on the presence of calcium in the culture medium. If calcium was omitted from the medium no effect of PACAP on catecholamine secretion could be detected during an incubation of 20 min. Preincubation of cells with 1 nM PACAP for 5 min facilitated the subsequent nicotine stimulated catecholamine secretion during a 20 min incubation without addition of the peptide. PACAP induced catecholamine secretion was clearly accompanied by a dose dependent increase of intracellular cAMP concentrations. The percentage of cells responding to PACAP with increased catecholamine secretion was assessed by immunocytochemistry of the transient appearance of dopamine-beta-hydroxylase, associated with the membranes of the chromaffin granules on the cell surface during the secretory process. About 70% of adrenal medullary cells responded to 100 nM PACAP with enhanced secretory activity. Though PACAP stimulated catecholamine secretion, we did not observed major effects on intracellular free calcium concentrations ([Ca2+]i) as determined with fura-2 by single cell fluorescence microscopy. In maximally 20% of the cells a rise in [Ca2+]i in response to a challenge with 500 nM PACAP was observed. Lower concentrations of PACAP were without an effect on [Ca2+]i. These data indicate that the stimulatory action of PACAP on in vitro catecholamine secretion from bovine chromaffin cells is linked to a rise of intracellular cAMP.

Orthostatic hypotension as an unusual clinical manifestation of pheochromocytoma: a case report

Pheochromocytoma is a rare endocrine tumor which can have a highly variable presentation related to increased catecholamine secretion. We report the case of a 74-year-old man in whom recurrent episodes of syncope due to orthostatic hypotension were the only clinical manifestations of this challenging entity. Diagnosis of pheochromocytoma was achieved by biochemical test samples and computed tomography scans. Surgical excision of the tumor resulted in clinical improvement with normalization of catecholamine concentrations and no more episodes of orthostatic hypotension during a follow-up of 24 months. Although rare, pheochromocytoma may frequently cause disorders of orthostatic tolerance; because of its meaningful implications, screening for this entity should be considered in case of recurrent syncopal episodes due to new-onset orthostatic hypotension.

Peripartum Hypertension from Pheochromocytoma: A Rare and Challenging Entity

Pheochromocytoma, a rare and usually curable cause of hypertension, is characterized by symptoms and signs related to increased catecholamine secretion. Pregnancy can elicit clinical manifestations of otherwise unrecognized pheochromocytoma. Four women, ranging in age from 27 to 37 years, were referred to the hypertension clinic with the following presentations: 1) a 35-year-old woman, diagnosed with gestational hypertension and headaches during the third trimester of her pregnancy and 5 months after delivery, was hospitalized with pulmonary edema. Echocardiography revealed severe dilated left ventricular (LV) dysfunction. Cardiac function was normalized after surgical resection of a pheochromocytoma from her left adrenal; 2) a 37-year-old woman suffered from preeclampsia, persistent hypertension and orthostatic hypotension after a cesarean section. A diagnostic work-up revealed a catecholamine-secreting paraganglioma in the retroperitoneum. The patient underwent a laparosopic resection of the tumor; 3) a 27-year-old woman suffered from hypertension and episodes of palpitations, sweating, and dyspnea in the first trimester of her pregnancy. An ultrasound revealed a 5-cm mass in the left adrenal. She underwent a left adrenalectomy at the 17th week of pregnancy, which confirmed the diagnosis of pheochromocytoma; 4) a 34-year-old woman, at the 26th week of pregnancy, presented with an acute loss of vision and blood pressure of 230/140 mm Hg. Fundoscopy showed papilledema with soft exudates in both eyes. Chemical studies were positive and imaging revealed a left adrenal pheochromocytoma. Despite aggressive medical treatment, fetal distress mandated a laparotomy at the end of the 28th week of pregnancy. A healthy newborn was delivered and resection of the adrenal tumor confirmed the diagnosis of pheochromocytoma. Although rare, pheochromocytoma can cause severe peripartum hypertension. Screening for pheochromocytoma, ideally with plasma-free metanephrines, should be considered in cases of peripartum hypertension.