Increased Catecholamine Release Research Articles

Obstructive sleep apnoea and coronary revascularisation outcomes.

Obstructive sleep apnoea (OSA) is achronic sleep disorder characterised by recurrent cyclical episodes of upper airway collapse causing apnoea or hypopnoea. Despite being highly prevalent in patients with cardiovascular conditions, OSA has been aneglected component in cardiovascular practice. Fortunately, in the past few decades, increasing acknowledgement of the vulnerability of cardiac patients to OSA-related stressors and its adverse cardiovascular outcomes has made it arecognised cardiovascular risk factor in practice guidelines. Consequences of OSA include oxidative stress, endothelial dysfunction, autonomic dysfunction, and increased catecholamine release. The perturbations caused by OSA not only provide aclear mechanistic link to cardiovascular disease but also to poor outcomes after coronary revascularisation. This review article focuses on the correlation of OSA to coronary revascularisation outcomes. Our team reported that OSA is present in approximately 50% of patients undergoing coronary revascularisation. Importantly, untreated OSA was found to be an independent predictor of adverse events after both percutaneous coronary intervention and coronary artery bypass grafting. Although randomised trials did not confirm the benefits of OSA treatment in improving cardiovascular outcomes, these early trials were limited by poor treatment adherence. For now, systematic screening for OSA in patients undergoing coronary revascularisation is not indicated. Yet, with the proven benefit of OSA treatment in improving blood pressure control and quality of life, screening for and treatment of OSA is still indicated if patients have reported excessive daytime sleepiness and/or suboptimally controlled hypertension.

PSUN139 Leukemoid Reaction in Severe Diabetic Ketoacidosis: An Indicator of Severity or Predictor of Infection?

Abstract Background Acute infectious illness can precipitate episodes of ketoacidosis in patients with diabetes mellitus. For this reason, a diligent search for a focus is essential in the initial evaluation of patients with DKA since patients often appear ill and may have non-specific symptoms. Clinical Case An 18-year old Filipino with Type 1 Diabetes Mellitus sought consult due to abdominal pain. He is on premixed NPH/regular insulin twice daily but was lost to follow-up due to the COVID-19 pandemic. He has no other comorbidities but asserted a prior history of poor compliance with both diet and insulin therapy besides an erratic sleep-wake cycle. Prior to consult, he reported 5 episodes of vomiting associated with generalized abdominal pain. Due to poor appetite, he missed due doses of insulin with subsequent worsening of condition. On admission, he was lethargic with Kussmaul's breathing. Initial vital signs were stable. He had dry lips and oral mucosa, sunken eyeballs and generalized abdominal tenderness. COVID-19 PCR was negative. Serum lipase (8.79, n: 8-78) and CT scan of abdomen were likewise unremarkable. Initial CBG was HIGH with elevated ketones (5.4, n: <0.6) and arterial blood gas revealed a pH of 7.0, pCO2 22, HCO3 incalculable, lactate 3.9, with high anion gap. The initial WBC was high (44.3×109/uL, n: 4.4-11) with 84% neutrophils, 10% lymphocytes, 1% metamyelocytes, and 5% monocytes. Hemoglobin (18.5 g/dl), hematocrit (51.7%) and platelet count (614k/uL) were also elevated. Peripheral blood smear revealed normal cell morphology. Urinalysis revealed elevated specific gravity, marked glycosuria and ketonuria, negative nitrites and leukocyte esterases. Blood specimen were obtained for culture. Therapy was instituted with intravenous fluids, insulin drip and broad spectrum antibiotics. The following day, glucose was 218 mg/dl, pH 7.16, bicarbonate 7.8 meq/L, hematocrit 44%, WBC 25.21×109/uL and platelet count was 401k/uL. LAP score was requested but was unavailable. On the fourth hospital day, the patient was well and tolerating diet, with normalization of blood glucose, WBC 9.87 (85% neutrophils, 10% lymphocytes, 5% monocytes) and control of acidosis. Since cultures were negative and patient was afebrile, antibiotics were discontinued. He was discharged stable on with basal-bolus insulin. Conclusion The association between DKA and leukocytosis in the absence of infection is described in literature. Exact mechanism is unknown but may in part be attributed to increased catecholamine release in response to stress and hemoconcentration from marked dehydration. Studies show a statistically significant relationship between pH, bicarbonate and leukocytes which denotes that WBC in DKA can be an indicator of the severity of ketoacidosis rather than a predictor of infection. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Alterations of the Sympathoadrenal Axis Related to the Development of Alzheimer's Disease in the 3xTg Mouse Model.

Simple SummaryAlzheimer’s disease (AD), the most common form of dementia, is becoming a global health problem and public health priority. In the advanced stages of AD, besides the initial cognitive symptoms, behavioral problems, particularly agitation and aggressiveness, become prevalent in AD patients. These non-cognitive symptoms could be related to alterations in the regulatory mechanism of the sympathetic nervous system. In this study, we used chromaffin cells (CCs) isolated from the adrenal gland of 3xTg (an AD mouse model) mice to characterize potential alterations in the regulation of the responses to stress mediated by the secretion of catecholamines. We compared these regulatory mechanisms in mice at two different ages: in 2-month-old mice, where no AD symptoms were observed, and in mice over 12 months of age, when AD-related cognitive impairment related was fully established. We found that the modulation of neurotransmitter release was stronger in CCs isolated from the adrenal medulla of 3xTg mice older than 12 months of age, an effect likely related to disease progression as it was not observed in CCs from age-matched wild-type (WT) mice. This enhanced modulation leads to an increased catecholamine release in response to stressful situations, which may explain the non-cognitive behavioral problems found in AD patients.Alzheimer’s disease (AD), the most common form of dementia, is becoming a global health problem and public health priority. In the advanced stages of AD, besides the initial cognitive symptoms, behavioral problems, particularly agitation and aggressiveness, become prevalent in AD patients. These non-cognitive symptoms could be related to a noradrenergic overactivation. In this study, we used chromaffin cells (CCs) isolated from the adrenal gland of 3xTg AD model mice to characterize potential alterations in the autocrine-paracrine modulation of voltage-dependent calcium channels (VDCCs), which in turn serve to regulate the release of catecholamines. We used mice at the presymptomatic stage (2 months) and mice over 12 months of age, when AD-related cognitive impairment was fully established. We found that the modulation of inward currents through VDCCs induced by extracellular ATP was stronger in CCs isolated from the adrenal medulla of 3xTg mice older than 12 months of age, an effect likely related to disease progression as it was not observed in CCs from age-matched WT mice. This enhanced modulation leads to increased catecholamine release in response to stressful situations, which may explain the non-cognitive behavioral problems found in AD patients.

Spontaneous Bilateral Adrenal Hemorrhage in Pregnancy

Introduction: Spontaneous Adrenal Hemorrhage (SAH) in pregnancy is a rare occurrence with estimated prevalence of 0.03% to 1.8%. SAH usually involves the right gland and can be easily mistaken with other conditions due to its nonspecific symptoms. We hereby report 2 cases of spontaneous bilateral SAH that occurred during the 3rd trimester of pregnancy. Case 1: 28-year-old female with history of IBS presented during 35th week of her first pregnancy with right-sided abdominal pain. Abdominal MRI revealed a 4.7 x 2.8 cm right adrenal hemorrhage. Due to stability of her vitals, steroids were not initiated and she was discharged. She returned 4 days later with similar pain but this time on the left side. MRI did not reveal adrenal bleeding. Due to Blood Pressure (BP) of 90/70 mmHg, hydrocortisone IV 50mg every 8 hours was started. 36 hour later she became tachycardic and tachypneic. CT angiogram (CTa) ruled out Pulmonary Emboli (PE), but was remarkable for interval development of a 5.3 x 3 cm left adrenal hemorrhage. There were no findings indicative of Primary Adrenal Insufficiency (PAI). Patient was discharged home on physiologic dose of hydrocortisone and delivered a healthy baby 2 weeks later at term. Case 2: 30-year-old female with history of hypertension and polycystic kidney disease presented at 31st week of her 2nd pregnancy with left-sided abdominal pain. Abdominal CT scan showed a 2.3 x 3.1 cm left adrenal hemorrhage. Due to BP of 85/50 mmHg at presentation, she was started on hydrocortisone IV 50 mg one dose followed by 25 mg every 8 hours, which improved her BP. 3 days later she developed new right flank pain. MRI was remarkable for features indicative of adrenal hyperplasia but did not confirm presence of hemorrhage. 1 day later she developed hypoxia and underwent CTa to rule out PE, which was remarkable for a new right adrenal hemorrhage. She did not have findings indicative of PAI and was discharged home on physiologic dose of hydrocortisone. Unfortunately, the pregnancy resulted in intrauterine fetal death at 36 weeks. Discussion: Adrenal cortex hyperplasia secondary to physiological elevation of ACTH plus adrenal venous constriction due to increased catecholamine release, have been suggested as possible mechanisms for increased risk of SAH in pregnancy. Common manifestations of SAH include abdominal pain, fever, fatigue, dizziness, anemia and hypotension. Features of PAI such as hyponatremia and hyperkalemia should be expected in cases of over 90% damage of adrenal cortices. Management in pregnancy involves fluid resuscitation, close monitoring for findings suggestive of adrenal crisis, fetal monitoring and glucocorticoid +/- mineralocorticoid replacement if indicated. Possibility for development of bilateral SAH should always be considered in patients who develop unilateral SAH. If left unrecognized, SAH is associated with poor outcomes and high fatality rate for both mother and fetus.

392 Seasonal Presentation Patterns for Congestive Heart Failure Within a Cohort of Southern Coastal US Emergency Department Patients

Seasonal differences in disease occurrence may inform adjustments to therapeutic regimens. A previous study of emergency department (ED) visits in New Jersey for congestive heart failure (CHF), showed a marked increase in the colder months (35% higher in December compared to August). The authors speculated that this was due in part to increased catecholamine release in response to cold weather. We hypothesized that less harsh winter temperatures in the southern coastal U.S. region might blunt this effect, resulting in a smaller winter-summer difference than the authors observed in New Jersey. We conducted a retrospective cohort study utilizing data from 287 emergency departments within the southern coastal U.S. region. Patients with a primary diagnosis of CHF or pulmonary edema from 01/01/07 to 08/05/19 were included. We aggregated data electronically from medical records and tabulated the number of visits by month, correcting for the length of month. We utilized chi-square to assess for non-uniformity in distribution of visits by month. We calculated the relative difference between the month with the most and least visits along with the 95% confidence interval (CI). There were 285,561 visits for CHF during the study period. Of these, 52% were female and the mean age was 69 +/-16 years. Chi-square rejected uniformity for CHF visits by month (p<0.0001). There were more CHF visits in the colder months. There were 34% more visits in January the peak month versus August the month with the least (95% CI 32% to 36%, p < 0.0001). Contrary to our hypothesis we found a similar winter-summer difference in the southern coastal US region as that in New Jersey. It is unclear why this difference persists despite the fact that winters in the southern coastal region are less harsh than in New Jersey.

Controlled delay of the expulsive phase of foaling affects sympathoadrenal activity and acid base balance of foals in the immediate postnatal phase

Stress at foaling has been demonstrated to delay birth. In this study, we followed the hypothesis that even a short delay of foaling increases catecholamine and cortisol release in foals, induces acidosis and impairs neonatal adaptation. Foaling was prolonged for 5 min by transferring mares to an unfamiliar environment at rupture of the allantochorion (group delay, n = 6) while control mares (n = 5) were left undisturbed. In their foals, times from birth to first standing and first suckling, heart rate, heart rate variability (HRV) and salivary cortisol concentration were analysed. Blood for analysis of epinephrine, norepinephrine, hematology and blood gases was collected directly and 30 min after birth. Statistical comparisons were made by repeated measures ANOVA. Times to first standing and suckling did not differ between groups. Fetal heart rate remained unchanged during birth and increased within 15 min postnatum (p < 0.001) while HRV decreased during the first hour of life in foals of both groups (p < 0.05). Immediately after birth, actual base excess was lower in foals with delayed birth than in control foals (p < 0.05). Epinephrine concentration immediately after birth was higher in group delay foals and increased from 0 to 30 min after birth in control foals (time p < 0.001, time x group p = 0.001). Cortisol concentration peaked at 1 h after birth in both groups (p < 0.001). Leukocyte and PMN count decreased from 0 to 30 min after birth (p < 0.001). In conclusion, a 5-min delay at foaling affected epinephrine release and acid base balance, but was without further effect on neonatal adaptation.

Guggulsterone Activates Adipocyte Beiging through Direct Effects on 3T3-L1 Adipocytes and Indirect Effects Mediated through RAW264.7 Macrophages.

Background: Plant-derived phytochemicals have been of emerging interest as anti-obesity compounds due to their apparent effects on promoting reduced lipid accumulation in adipocytes. Despite such promising evidence, little is known about the potential mechanisms behind their anti-obesity effects. The aim of this study is to establish potential anti-obesity effects of the phytochemical guggulsterone (GS). Methods: Mature 3T3-L1 adipocytes were treated with GS, derived from the guggul plant native in northern India, to investigate its effects on mitochondrial biogenesis and adipocyte “beiging.” Further, to explore the relationship between macrophages and adipocytes, 3T3-L1s were treated with conditioned media from GS-treated RAW264.7 macrophages. Markers of mitochondrial biogenesis and beiging were measured by western blot. Results: GS treatment in adipocytes resulted in increased mitochondrial density, biogenesis (PGC1α and PPARγ), and increased markers of a beige adipocyte phenotype (UCP1, TBX1, and β-3AR). This upregulation in mitochondrial expression was accompanied by increases oxygen consumption. In GS-treated macrophages, markers of M2 polarization were elevated (e.g., arginase and IL-10), along with increased catecholamine release into the media. Lastly, 3T3-L1 adipocytes treated with conditioned media from macrophages induced a 167.8% increase in UCP1 expression, suggestive of a role of macrophages in eliciting an anti-adipogenic response to GS. Conclusions: Results from this study provide the first mechanistic understanding of the anti-obesity effects of GS and suggests a role for both direct GS-signaling and indirect stimulation of M2 macrophage polarization in this model.

Kv7(KCNQ)-K+-Channels Influence Total Peripheral Resistance in Female but Not Male Rats, and Hamper Catecholamine Release in Hypertensive Rats of Both Sexes.

K+-channels of the Kv7/KCNQ-family hyperpolarize and stabilize excitable cells such as autonomic neurons and vascular smooth muscle cells (VSMC). Kv7 may therefore play a role in blood pressure (BP) homeostasis, and prevent a high total peripheral vascular resistance (TPR), a hallmark of hypertensive disease. The present study analyzed if Kv7 channels influence catecholamine release and TPR in normotensive (WKY) and spontaneously hypertensive rats (SHR), and if they may contribute to the antihypertensive protection seen in young, female SHR. Tyramine-stimulated norepinephrine release evokes an adrenergic cardiovascular response, and also allows modulation of release to be reflected in the overflow to plasma. The experiment itself activated some secretion of epinephrine. The results show: (1) XE-991 (Kv7.1-7.4-inhibitor), but not chromanol 293B (Kv7.1-inhibitor), increased tyramine-stimulated norepinephrine overflow and epinephrine secretion in both sexes in SHR, but not WKY. (2) Surprisingly, the Kv7-openers retigabine (Kv7.2-7.5) and ICA-27243 (Kv7.2-7.3-preferring) increased catecholamine release in female SHR. (3) The rise in TPR following tyramine-stimulated norepinephrine release was increased by XE-991 but not chromanol in the female WKY only. (4) Retigabine and ICA-27243 reduced the TPR-response to tyramine in the female SHR only. These results suggested: (1) Up-regulation of Kv7.2-7.3 function in sympathetic neurons and chromaffin cells hampered catecholamine release in SHR of both sexes. (2) The increase catecholamine release observed after channel openers in the female SHR may possibly involve reduced transmission in cholinergic neurons which hamper catecholamine release. These two mechanisms may serve to counter-act the hyperadrenergic state in SHR. (3) Kv7.4, most likely in the vasculature, opposed the tension-response to norepinephrine in the female WKY. (4) Vascular Kv7.4-7.5 could be stimulated and then opposed norepinephrine-induced vasoconstriction in the female SHR. (5) Vascular Kv7 channels did not counter-act norepinephrine induced vasoconstriction in male rats, possibly due to different Kv7 channel regulation. Kv7 channels may represent a novel target for antihypertensive therapy.

Human nicotinic receptors in chromaffin cells: characterization and pharmacology.

During the last 10years, we have been working on human chromaffin cells obtained from the adrenal gland of organ donors that suffered encephalic or cardiac death. We first electrophysiologically characterized the nicotinic acetylcholine receptors (nAChRs) activated by acetylcholine, and their contribution to the exocytosis of chromaffin vesicles and release of catecholamines. We have shown that these cells possess an adrenergic phenotype. This phenotype may contribute to an increased expression of α7 nAChRs in these cells, allowing for recording of α7 nAChR currents, something that had previously not been achieved in non-human species. The use of α-conotoxins allowed us to characterize non-α7 nAChR subtypes and, together with molecular biology experiments, conclude that the predominant nAChR subtype in human chromaffin cells is α3β4* (asterisk indicates the posible presence of additional subunits). In addition, there is a minor population of αxβ2 nAChRs. Both α7 and non-α7 nAChR subtypes contribute to the exocytotic process. Exocytosis mediated by nAChRs could be as large in magnitude as that elicited by calcium entry through voltage-dependent calcium channels. Finally, we have also investigated the effect of nAChR-targeted tobacco cessation drugs on catecholamine release in chromaffin cells. We have concluded that at therapeutic concentrations, varenicline alone does not increase the frequency of action potentials evoked by ACh. However, varenicline in the presence of nicotine does increase this frequency, and thus, in the presence of both drugs, the probability of increased catecholamine release in human chromaffin cells is high.

α2-Adrenoreceptor Constraint of Catecholamine Release and Blood Pressure Is Enhanced in Female Spontaneously Hypertensive Rats.

α2-adrenoceptors (α2AR) lower central sympathetic output and peripheral catecholamine release, and may therefore prevent sympathetic hyperactivity and hypertension. The α2AR are dysfunctional in male spontaneously hypertensive rats (SHR). Premenopausal females are less hypertensive than males. The purpose of this study was to test if this difference could be explained by functional α2AR in the female SHR. A 15-min tyramine-infusion was used to stimulate norepinephrine release through the re-uptake transporter, consequently preventing re-uptake. Presynaptic control of vesicular release will therefore be reflected as differences in overflow to plasma. The surgical trauma activates secretion of epinephrine, also subjected to α2AR auto-inhibition. Blood pressure was monitored through a femoral artery catheter and cardiac output by ascending aorta flow in 12-14 weeks-old (early hypertension) SHR and normotensive rats (WKY). Total peripheral vascular resistance (TPR) was calculated. Female SHR, unlike male, were close to normotensive. Pre-treatment with none-selective (clonidine) or non-A-selective (ST-91) α2AR agonist reduced, and none-selective α2AR antagonist (L-659,066) increased tyramine-induced norepinephrine overflow in female WKY and SHR. L-659,066 also increased secretion of epinephrine. The L-659,066-induced increase in catecholamine release was further enhanced by additional pre-treatment with ST-91 or angiotensin AT1 receptor antagonist (losartan) in SHR only. L-659,066 eliminated the tyramine-induced rise in TPR in both strains in female rats. Conclusion: α2AR-mediated control of catecholamine release and vascular tension was therefore functional in female SHR, unlike that previously observed in male SHR. Functional α2AR is likely to have a protective function and may explain the lack of hypertension in the young female SHR.

The role of pendrin in blood pressure regulation.

Pendrin is a Na(+)-independent Cl(-)/HCO3(-) exchanger found in the apical regions of type B and non-A, non-B intercalated cells within the aldosterone-sensitive region of the nephron, i.e., the distal convoluted tubule (DCT), the connecting tubule (CNT), and the cortical collecting duct (CCD). Type B intercalated cells mediate Cl(-) absorption and HCO3(-) secretion primarily through pendrin-mediated Cl(-)/HCO3(-) exchange. This exchanger is upregulated with angiotensin II administration and in models of metabolic alkalosis, such as following administration of aldosterone or NaHCO3. In the absence of pendrin-mediated HCO3(-) secretion, an enhanced alkalosis is observed following aldosterone or NaHCO3 administration. However, probably of more significance is the role of pendrin in the pressor response to aldosterone. Pendrin mediates Cl(-) absorption and modulates aldosterone-induced Na(+) absorption mediated by the epithelial Na channel (ENaC). Pendrin changes ENaC activity by changing both channel open probability (Po) and surface density (N), at least partly by altering luminal HCO3(-) and ATP concentration. Thus aldosterone and angiotensin II stimulate pendrin expression and function, which stimulates ENaC activity, thereby contributing to the pressor response of these hormones. However, pendrin may modulate blood pressure partly through its extrarenal effects. For example, pendrin is expressed in the adrenal medulla, where it modulates catecholamine release. The increase in catecholamine release observed with pendrin gene ablation likely contributes to the increment in vascular contractile force observed in the pendrin null mouse. This review summarizes the signaling mechanisms that regulate pendrin abundance and function as well as the contribution of pendrin to distal nephron function.

Stress weakens prefrontal networks: molecular insults to higher cognition.

A variety of cognitive disorders are worsened by stress exposure and involve dysfunction of the newly evolved prefrontal cortex (PFC). Exposure to acute, uncontrollable stress increases catecholamine release in PFC, reducing neuronal firing and impairing cognitive abilities. High levels of noradrenergic α1-adrenoceptor and dopaminergic D1 receptor stimulation activate feedforward calcium-protein kinase C and cyclic AMP-protein kinase A signaling, which open potassium channels to weaken synaptic efficacy in spines. In contrast, high levels of catecholamines strengthen the primary sensory cortices, amygdala and striatum, rapidly flipping the brain from reflective to reflexive control of behavior. These mechanisms are exaggerated by chronic stress exposure, where architectural changes lead to persistent loss of PFC function. Understanding these mechanisms has led to the successful translation of prazosin and guanfacine for treating stress-related disorders. Dysregulation of stress signaling pathways by genetic insults likely contributes to PFC deficits in schizophrenia, while age-related insults initiate interacting vicious cycles that increase vulnerability to Alzheimer's degeneration.

Reduced availability of voltage-gated sodium channels by depolarization or blockade by tetrodotoxin boosts burst firing and catecholamine release in mouse chromaffin cells.

Mouse chromaffin cells (MCCs) of the adrenal medulla possess fast-inactivating Nav channels whose availability alters spontaneous action potential firing patterns and the Ca(2+)-dependent secretion of catecholamines. Here, we report MCCs expressing large densities of neuronal fast-inactivating Nav1.3 and Nav1.7 channels that carry little or no subthreshold pacemaker currents and can be slowly inactivated by 50% upon slight membrane depolarization. Reducing Nav1.3/Nav1.7 availability by tetrodotoxin or by sustained depolarization near rest leads to a switch from tonic to burst-firing patterns that give rise to elevated Ca(2+)-influx and increased catecholamine release. Spontaneous burst firing is also evident in a small percentage of control MCCs. Our results establish that burst firing comprises an intrinsic firing mode of MCCs that boosts their output. This occurs particularly when Nav channel availability is reduced by sustained splanchnic nerve stimulation or prolonged cell depolarizations induced by acidosis, hyperkalaemia and increased muscarine levels. Action potential (AP) firing in mouse chromaffin cells (MCCs) is mainly sustained by Cav1.3 L-type channels that drive BK and SK currents and regulate the pacemaking cycle. As secretory units, CCs optimally recruit Ca(2+) channels when stimulated, a process potentially dependent on the modulation of the AP waveform. Our previous work has shown that a critical determinant of AP shape is voltage-gated sodium channel (Nav) channel availability. Here, we studied the contribution of Nav channels to firing patterns and AP shapes at rest (-50 mV) and upon stimulation (-40 mV). Using quantitative RT-PCR and immunoblotting, we show that MCCs mainly express tetrodotoxin (TTX)-sensitive, fast-inactivating Nav1.3 and Nav1.7 channels that carry little or no Na(+) current during slow ramp depolarizations. Time constants and the percentage of recovery from fast inactivation and slow entry into closed-state inactivation are similar to that of brain Nav1.3 and Nav1.7 channels. The fraction of available Nav channels is reduced by half after 10 mV depolarization from -50 to -40 mV. This leads to low amplitude spikes and a reduction in repolarizing K(+) currents inverting the net current from outward to inward during the after-hyperpolarization. When Nav channel availability is reduced by up to 20% of total, either by TTX block or steady depolarization, a switch from tonic to burst firing is observed. The spontaneous occurrence of high frequency bursts is rare under control conditions (14% of cells) but leads to major Ca(2+)-entry and increased catecholamine release. Thus, Nav1.3/Nav1.7 channel availability sets the AP shape, burst-firing initiation and regulates catecholamine secretion in MCCs. Nav channel inactivation becomes important during periods of high activity, mimicking stress responses.

Serotonin Activates Catecholamine Neurons in the Solitary Tract Nucleus by Increasing Spontaneous Glutamate Inputs

Serotonin (5-HT) is a critical neurotransmitter in the control of autonomic functions. 5-HT(3) receptors participate in vagal afferent feedback to decrease food intake and regulate cardiovascular reflexes; however, the phenotype of the solitary tract nucleus (NTS) neurons involved is not known. A(2)/C(2) catecholamine (CA) neurons in the NTS are directly activated by visceral afferents and are important for the control of food intake and cardiovascular function, making them good candidates to respond to and mediate the effects of serotonin at the level of the NTS. This study examines serotonin's effects on NTS-CA neurons using patch-clamp techniques and transgenic mice expressing an enhanced green fluorescent protein driven by the tyrosine hydroxylase (TH) promoter (TH-EGFP) to identify catecholamine neurons. Serotonin increased the frequency of spontaneous glutamate excitatory postsynaptic currents (sEPSCs) in >90% of NTS-TH-EGFP neurons, an effect blocked by the 5-HT(3) receptor antagonist ondansetron and mimicked by the 5-HT(3) receptor agonists SR5227 and mCPBG. In contrast, 5-HT(3) receptor agonists increased sEPSCs on a minority (<30%) of non-TH neurons. 5-HT(3) receptor agonists increased the frequency, but not the amplitude, of mini-EPSCs, suggesting that their actions are presynaptic. 5-HT(3) receptor agonists increased the firing rate of TH-EGFP neurons, an effect dependent on the increased spontaneous glutamate inputs as it was blocked by the ionotropic glutamate antagonist NBQX, but independent of visceral afferent activation. These results demonstrate a cellular mechanism by which serotonin activates NTS-TH neurons and suggest a pathway by which it can increase catecholamine release in target regions to modulate food intake, motivation, stress, and cardiovascular function.

Functional expression of the α7 and α4-containing nicotinic acetylcholine receptors on the neonatal rat carotid body

The carotid bodies (CBs) are chemosensory organs that respond to hypoxemia with transmitter neurosecretion, leading to a respiratory reflex response. It has been proposed that acetylcholine is a key regulator of transmitter release through activation of presynaptic nicotinic acetylcholine receptors (nAChRs). In the present work, we studied the identity of such nAChRs and their contribution to catecholamine release from CBs.Neonatal rat CBs were placed in a recording chamber for electrochemical recordings or disassociated for voltage-clamp studies on isolated cells. Fast nicotine superfusion increases catecholamine release from intact CBs. This response was diminished reversibly by the non-selective nAChR blocker hexamethonium, by the selective α7 blocker α-bungarotoxin and by the α4-containing nAChR blocker erysodine.In isolated CB cells the nAChR agonists nicotine, acetylcholine and cytisine all evoke inward currents with similar potencies. The nicotine-evoked current was fully blocked by mecamylamine and partially inhibited by α-bungarotoxin or erysodine. However, the combination of both α-bungarotoxin an erysodine failed to suppress this response. Immunodetection studies confirm the presence of α7 and α4 subunits in isolated dopaminergic CB cells. Our results show that activation of α7 and/or α4-containing nAChR subtypes have the ability to regulate catecholamine release from intact CB due to activation of fast inward currents expressed in chemoreceptor cells. Therefore, our results suggest that both nAChR subtypes contribute to the cholinergic nicotinic regulation of catecholamine signaling in the carotid body system.

Dietary methyl-consuming compounds and metabolic syndrome

The metabolic syndrome, a major risk factor for type 2 diabetes and cardiovascular disease, is a cluster of metabolic abnormalities including obesity, insulin resistance, hypertension and dyslipidemia. Although systemic oxidative stress and aberrant methylation status are known to have important roles in the development of metabolic syndrome, how they occur remains unclear. The metabolism of methyl-consuming compounds generates reactive oxygen species and consumes labile methyl groups; therefore, a chronic increase in the levels of methyl-consuming compounds in the body can induce not only oxidative stress and subsequent tissue injury, but also methyl-group pool depletion and subsequent aberrant methylation status. In the past few decades, the intake amount of methyl-consuming compounds has substantially increased primarily due to pollution, food additives, niacin fortification and high meat consumption. Thus, increased methyl consumers might have a causal role in the development and prevalence of metabolic syndrome and its related diseases. Moreover, factors that decrease the elimination/metabolism of methyl-consuming compounds and other xenobiotics (for example, sweat gland inactivity and decreased liver function) or increase the generation of endogenous methyl-consuming compounds (for example, mental stress-induced increase in catecholamine release) may accelerate the progression of metabolic syndrome. Based on current nutrition knowledge and the available evidence from epidemiological, ecological, clinical and laboratory studies on metabolic syndrome and its related diseases, this review outlines the relationship between methyl supply-consumption imbalance and metabolic syndrome, and proposes a novel mechanism for the pathogenesis and prevalence of metabolic syndrome and its related diseases.

Nuclear translocation of calpain‐2 regulates propensity toward apoptosis in cardiomyocytes of tail‐suspended rats

The compensatory increase in catecholamine release does not reverse orthostatic intolerance after returning from a long-term spaceflight, but it is unclear whether high dose of catecholamine induces cardiac damage. The tail-suspended rat model was used to simulate the effects of weightlessness on the heart. Apoptotic rates in the left ventricular myocardium did not increase in 4-week of tail-suspended rats compared with the synchronous control. On the contrary, isoproterenol (intraperitoneal injection) and 1-day recovery from the 4-week tail-suspension increased apoptotic rates in the myocardium. Propranolol and PD150606 inhibited cardiomyocyte apoptosis in the recovery group. PD150606 and calpain-2 knockdown also blocked isoproterenol-induced cardiomyocyte apoptosis in tail-suspended rats. The activity and nuclear translocation of calpain-2 increased, but the expression of calpain-1, calpain-2, and calpastatin was unchanged in the myocardium of tail-suspended rats. The Ser-16-phosphorylated phospholamban of the nuclear envelope was higher in tail-suspended rats than in the control rats under isoproterenol stimulation. Isoproterenol treatment also induced a large intranuclear Ca(2+) transient of cardiomyocytes in tail-suspended rats. These results suggest that high-dose isoproterenol phosphorylates phospholamban of the nuclear envelope and increases intranuclear Ca(2+) transient. Larger intranuclear Ca(2+) further activates nuclear calpain-2 and hence induces cardiomyocyte apoptosis.

Effects of acute hypoxia on postural and kinetic tremor

Human physiological tremor is a complex phenomenon that is modulated by numerous mechanical, neurophysiological, and environmental conditions. Researchers investigating tremor have suggested that acute hypoxia increases tremor amplitude. Based on the results of prior studies, we hypothesized that human participants exposed to a simulated altitude of 4,500 m would display an increased tremor amplitude within the 6-12 Hz frequency range. Postural and kinetic tremors were recorded with a laser system in 23 healthy male participants before, during, and after 1 h of altitude-induced hypoxia. A large panel of tremor characteristics was used to investigate the effect of hypoxia. Acute hypoxia increased tremor frequency content between 6 and 12 Hz during both postural and kinetic tremor tasks (P < 0.05, F = 6.142, Eta(2) = 0.24 and P < 0.05, F = 3.767 Eta(2) = 0.14, respectively). Although the physiological mechanisms underlying the observed changes in tremor are not completely elucidated yet, this study confirms that acute hypoxia increases tremor frequency in the 6-12 Hz range. Furthermore, this study indicates that changes in physiological tremor can be detected at lower hypoxemic levels than previously reported (blood saturation in oxygen = 80.9%). The effects of hypoxia mainly result from a cascade of events starting with the activation of the hypothalamic-pituitary-adrenal axis causing in turn an increase in catecholamine release, leading to an augmentation of tremor amplitude in the 6- to 12-Hz interval and heart rate increase.

Smoking Interaction with Clopidogrel; Another Smoker's Paradox?

The American Heart Association estimates that one in five deaths from cardiovascular disease are directly linked to cigarette smoking. Individuals who smoke are two to six times more likely to develop coronary artery disease than nonsmokers. However, individuals who quit smoking will reduce their risk to levels equivalent to those of a nonsmoker within three years. Refer to the page 119-124 Exposure to cigarette smoke is an established risk factor for coronary heart disease in both Western and Asian countries. The multivariate relative risk of coronary heart disease mortality for current smokers was 1.8-3.7 compared to nonsmokers.1) Poor prognosis in smokers results from: 1) induction of hypercoagulability due to increased platelet activation, dyslipidemia, and endothelial dysfunction; 2) increased catecholamine release leading to increased heart rate, blood pressure, coronary vasoconstriction, and even arrhythmogenic effect; and 3) reduction in oxygen delivery due to increased carbon monoxide levels.2) The term of smoker's paradox has been coined by Barbash et al.3) who reported better outcomes among the smokers receiving thrombolytic therapy for acute myocardial infarction. Similarly, Cohen et al.4) reported that cigarette smoking was associated with a lower rate of subsequent target lesion revascularization in patients undergoing percutaneous coronary intervention (PCI). Hasdai et al.5) reported that current smokers during an index percutaneous intervention had fewer adverse events in the univariable analysis than the nonsmokers and former smokers. This improved can be explained in part by better covariables such as younger age or a more favorable clinical and angiographic profile. Therefore, this term may be misleading.6) Clopidogrel, an inhibitor of the platelet P2Y12 adenosine diphosphate receptor, improves prognosis in patients with acute coronary syndrome (ACS). However, there is significant response variability and a diminished clopidogrel response is associated with an increased risk of ischemic events.7) Smoking induces cytochrome P450 1A2 (CYP1A2), a hepatic enzyme involved in the metabolism of clopidogrel. Clopidogrel shows better inhibition of platelet aggregation in smokers than nonsmokers,8) and smokers are less likely to be hyporesponders than nonsmokers.9) In this issue of the Journal, Cho et al.10) investigated the association between smoking status and post-clopidogrel platelet reactivity in patients with acute myocardial infarction. Differences in the clinical situation and timing of the platelet test could explain the differences with the Bliden study.8) The decreases in CYP1A2 activity induced by smoking may also disappear after three days. The CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial compared long-term clopidogrel 75 mg/day vs. placebo in patients at high risk for cardiovascular events, and clopidogrel significantly reduced mortality in smokers but not in former or never-smokers.11) In addition to CYP1A2 activation by smoking, smokers may simply be a higher-risk group because of enhanced platelet activity and therefore benefit more from antithrombotic intervention. The Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis In Myocardial Infarction 28 (CLARITY-TIMI 28) trial compared the effect of clopidogrel on angiographic and clinical outcomes in 3,429 ST elevation myocardial infarction patients by smoking intensity: not current smokers (n=1,732), and smokers of 1 to 9 (n=206), 10 to 19 (n=354), 20 to 29 (n=715), and ≥30 cigarettes/day (n=422). Clopidogrel reduced the primary end point of a closed infarct-related artery or death/myocardial infarction, particularly among those who smoked ≥10 cigarettes/day.12) The CURRENT-OASIS 7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions) trial, which tested high-dose vs. usual-dose clopidogrel in ACS patients undergoing PCI, showed that smokers (vs. nonsmokers) had significant benefit with the higher clopidogrel dose. Smoking increases the risk for cardiovascular events and mortality in patients with established cardiovascular disease, but clopidogrel treatment may be more effective in smokers. Therefore, the interaction of smoking with acute myocardial infarction deserves further study in more patients using designs that show fewer time limitations.

DOC2B Acts as a Calcium Switch and Enhances Vesicle Fusion

Calcium-dependent exocytosis is regulated by a vast number of proteins. DOC2B is a synaptic protein that translocates to the plasma membrane (PM) after small elevations in intracellular calcium concentration. The aim of this study was to investigate the role of DOC2B in calcium-triggered exocytosis. Using biochemical and biophysical measurements, we demonstrate that the C2A domain of DOC2B interacts directly with the PM in a calcium-dependent manner. Using a combination of electrophysiological, morphological, and total internal reflection fluorescent measurements, we found that DOC2B acts as a priming factor and increases the number of fusion-competent vesicles. Comparing secretion during repeated stimulation between wild-type DOC2B and a mutated DOC2B that is constantly at the PM showed that DOC2B enhances catecholamine secretion also during repeated stimulation and that DOC2B has to translocate to the PM to exert its facilitating effect, suggesting that its activity is dependent on calcium. The hypothesis that DOC2B exerts its effect at the PM was supported by the finding that DOC2B affects the fusion kinetics of single vesicles and interacts with the PM SNAREs (soluble NSF attachment receptors). We conclude that DOC2B is a calcium-dependent priming factor and its activity at the PM enables efficient expansion of the fusion pore, leading to increased catecholamine release.