Catecholamine Release In Response Research Articles

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.

Aorticorenal ganglion as a novel target for renal neuromodulation.

Clinical trials for renal artery (RA) ablation have shown limited efficacy. The purpose of this study was to investigate whether the aorticorenal ganglion (ARG) can be targeted for renal denervation. Twenty-eight pigs were studied under isoflurane or alpha-chloralose to examine hemodynamic responses and catecholamine release in response to RA or ARG stimulation. To assess the efficacy of ARG ablation, we randomized 16 pigs to either sham, RA, or ARG ablation, followed by occlusion of the left anterior descending coronary artery (LAD). Hemodynamic responses, cardiac electrophysiological parameters, and arrhythmias/sudden cardiac death were assessed following LAD occlusion. Absent hemodynamic responses to stimulation confirmed ARG or RA ablation. Invivo stellate ganglion neural activity was recorded to assess cardiac sympathetic signaling. Cadaveric dissections were performed to localize the ARG in humans for comparison to swine. The ARG is a purely sympathetic ganglion with cholinergic inputs and pass-through sensory afferent fibers. Compared to RA stimulation, ARG stimulation yielded greater hemodynamic responses during alpha-chloralose anesthesia. However, neither site yielded significant responses under isoflurane. Radiofrequency ablation of the ARG eliminated responses to both RA and ARG stimulation, whereas RA ablation did not eliminate responses to ARG stimulation. Ablation of the ARG did not impact the kidneys or adrenal glands. Compared to control and RA ablation, ARG ablation was protective against ventricular arrhythmias and sudden death. Human and swine ARG are similarly located in the aorticorenal region. Our findings indicate that the ARG may be a novel target for renal neuromodulation. Further studies are warranted to validate these findings.

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.

Tetrabenazine Facilitates Exocytosis by Enhancing Calcium-Induced Calcium Release through Ryanodine Receptors.

Vesicular monoamine transporter-2 is expressed in the presynaptic secretory vesicles membrane in the brain. Its blockade by tetrabenazine (TBZ) causes depletion of dopamine at striatal basal ganglia; this is the mechanism underlying its long-standing use in the treatment of Huntington's disease. In the frame of a project aimed at investigating the kinetics of exocytosis from vesicles with partial emptying of their neurotransmitter, we unexpectedly found that TBZ facilitates exocytosis; thus, we decided to characterize such effect. We used bovine chromaffin cells (BCCs) challenged with repeated pulses of high K+ Upon repeated K+ pulsing, the exocytotic catecholamine release responses were gradually decaying. However, when cells were exposed to TBZ, responses were mildly augmented and decay rate delayed. Facilitation of exocytosis was not due to Ca2+ entry blockade through voltage-activated calcium channels (VACCs) because, in fact, TBZ mildly blocked the whole-cell Ca2+ current. However, TBZ mimicked the facilitatory effects of exocytosis elicited by BayK8644 (L-subtype VACC agonist), an effect blocked by nifedipine (VACC antagonist). On the basis that TBZ augmented the secretory responses to caffeine (but not those of histamine), we monitored its effects on cytosolic Ca2+ elevations ([Ca2+]c) triggered by caffeine or histamine. While the responses to caffeine were augmented twice by TBZ, those of histamine were unaffected; the same happened in rat cortical neurons. Hence, we hypothesize that TBZ facilitates exocytosis by increasing Ca2+ release through the endoplasmic reticulum ryanodine receptor channel (RyR). Confirming this hypothesis are docking results, showing an interaction of TBZ with RyRs. This is consonant with the existence of a healthy Ca2+-induced-Ca2+-release mechanism in BCCs. SIGNIFICANCE STATEMENT: A novel mechanism of action for tetrabenazine (TBZ), a drug used in the therapy of Huntington's disease (HD), is described here. Such mechanism consists of facilitation by combining TBZ with the ryanodine receptor of the endoplasmic reticulum, thereby increasing Ca2+-induced Ca2+ release. This novel mechanism should be taken into account when considering the efficacy and/or safety of TBZ in the treatment of chorea associated with HD and other disorders. Additionally, it could be of interest in the development of novel medicines to treat these pathological conditions.

Regulation by L channels of Ca(2+)-evoked secretory responses in ouabain-treated chromaffin cells.

It is known that the sustained depolarisation of adrenal medullary bovine chromaffin cells (BCCs) with high K(+) concentrations produces an initial sharp catecholamine release that subsequently fades off in spite depolarisation persists. Here, we have recreated a sustained depolarisation condition of BCCs by treating them with the Na(+)/K(+) ATPase blocker ouabain; in doing so, we searched experimental conditions that permitted the development of a sustained long-term catecholamine release response that could be relevant during prolonged stress. BCCs were perifused with nominal 0Ca(2+) solution, and secretion responses were elicited by intermittent application of short 2Ca(2+) pulses (Krebs-HEPES containing 2mM Ca(2+)). These pulses elicited a biphasic secretory pattern with an initial 30-min period with secretory responses of increasing amplitude and a second 30-min period with steady-state, non-inactivating responses. The initial phase was not due to gradual depolarisation neither to gradual increases of the cytosolic calcium transients ([Ca(2+)]c) elicited by 2Ca(2+) pulses in BBCs exposed to ouabain; both parameters increased soon after ouabain addition. Νifedipine blocked these responses, and FPL64176 potentiated them, suggesting that they were triggered by Ca(2+) entry through non-inactivating L-type calcium channels. This was corroborated by nifedipine-evoked blockade of the L-type Ca(2+) channel current and the [Ca(2+)]c transients elicited by 2Ca(2+) pulses. Furthermore, the plasmalemmal Na(+)/Ca(2+) exchanger (NCX) blocker SEA0400 caused a mild inhibition followed by a large rebound increase of the steady-state secretory responses. We conclude that these two phases of secretion are mostly contributed by Ca(2+) entry through L calcium channels, with a minor contribution of Ca(2+) entry through the reverse mode of the NCX.

Stress-induced cardiomyopathy after negative pressure pulmonary edema during emergence from anesthesia -A case report-

Stress-induced cardiomyopathy (SICM) presenting as an acute myocardial dysfunction is characterized by transient left ventricular wall motion abnormality, which has been known to be associated with excessive catecholamine production caused due to various types of stress. Sympathetic hyperactivity is common during the perioperative period, and reports of SICM occurring during this period have actually increased. We present a case of SICM following negative pressure pulmonary edema due to upper airway obstruction during emergence from anesthesia. Excessive catecholamine release in response to respiratory difficulty could have been the underlying inciting factor.

Ouabain enhances exocytosis through the regulation of calcium handling by the endoplasmic reticulum of chromaffin cells

The augmentation of neurotransmitter and hormone release produced by ouabain inhibition of plasmalemmal Na+/K+-ATPase (NKA) is well established. However, the mechanism underlying this action is still controversial. Here we have shown that in bovine adrenal chromaffin cells ouabain diminished the mobility of chromaffin vesicles, an indication of greater number of docked vesicles at subplasmalemmal exocytotic sites. On the other hand, ouabain augmented the number of vesicles undergoing exocytosis in response to a K+ pulse, rather than the quantal size of single vesicles. Furthermore, ouabain produced a tiny and slow Ca2+ release from the endoplasmic reticulum (ER) and gradually augmented the transient elevations of the cytosolic Ca2+ concentrations ([Ca2+]c) triggered by K+ pulses. These effects were paralleled by gradual increments of the transient catecholamine release responses triggered by sequential K+ pulses applied to chromaffin cell populations treated with ouabain. Both, the increases of K+-elicited [Ca2+]c and secretion in ouabain-treated cells were blocked by thapsigargin (THAPSI), 2-aminoethoxydiphenyl borate (2-APB) and caffeine. These results are compatible with the view that ouabain may enhance the ER Ca2+ load and facilitate the Ca2+-induced-Ca2+ release (CICR) component of the [Ca2+]c signal generated during K+ depolarisation. This could explain the potentiating effects of ouabain on exocytosis.

Greater cytosolic and mitochondrial calcium transients in adrenal medullary slices of hypertensive, compared with normotensive rats

Pronounced differences in the kinetics of single-vesicle catecholamine release from adrenal chromaffin cells stimulated with acetylcholine or high potassium (K +) have been recently found between normotensive Wistar rats (NWRs) and spontaneously hypertensive rats (SHRs). Such differences could be explained on the basis of distinct mechanisms of calcium (Ca 2+) handling by chromaffin cells of NWRs and SHRs. We have explored here this hypothesis in adrenal medullary slices loaded with calcium fluorescent probes to measure the changes in Ca 2+ concentration in the cytosol ([Ca 2+] c), endoplasmic reticulum ([Ca 2+] er), and mitochondria ([Ca 2+] m). We found the following differences on calcium handling in SHRs, as compared with NWR: (i) higher basal [Ca 2+] c and basal [Ca 2+] m; (ii) greater [Ca 2+] c elevations elicited by acetylcholine and K +, with faster activation but slower inactivation; (iii) greater [Ca 2+] c elevations elicited by CRT (a mixture of caffeine, ryanodine, and thapsigargin) and by the mitochondrial protonophore FCCP (carbonylcyanide p-(trifluoromethoxy) phenylhydrazone). The higher basal [Ca 2+] c and [Ca 2+] m suggest an enhanced mitochondrial Ca 2+ uptake, and the greater [Ca 2+] c elevations produced by FCCP indicates a higher mitochondrial Ca 2+ release into the cytosol. This alteration of intracellular Ca 2+ movements could explain the greater quantal catecholamine release responses seen in SHRs, as compared with NWRs in previous studies. Furthermore, enhanced mitochondrial Ca 2+ cycling may be the basis for the dysfunction of mitochondrial bioenergetics, reported to be present in hypertensive states.

Differences in the quantal release of catecholamines in chromaffin cells of rat embryos and their mothers

Studies on the bulk catecholamine release from fetal and neonatal rat adrenals, adrenal slices, or isolated chromaffin cells stimulated with high K(+), hypoxia, hypercapnia, or acidosis are available. However, a study analyzing the kinetics of quantal secretion is lacking. We report here such a study in which we compare the quantal release of catecholamines from immature rat embryo chromaffin cells (ECCs) and their mothers' (MCCs). Cell challenging with a strong depolarizing stimulus (75 mM K(+)) caused spike bursts having the following characteristics. ECCs released more multispike events and wave envelopes than MCCs. This, together with narrower single-spike events, a faster decay, and a threefold smaller quantal size suggest a faster secretory machinery in ECCs. Furthermore, with a milder stimulus (25 mM K(+)) enhanced Ca(2+) entry by L-type Ca(2+) channel activator BAY K 8644 did not change the kinetic parameters of single spikes in ECCs; in contrast, augmentation of Ca(2+) entry increased spike amplitude and width, quantal size, and decay time in MCCs. This suggests that in mature MCCs, the last exocytotic steps are more tightly regulated than in immature ECCs. Finally, we found that quantal secretion was fully controlled by L-type voltage-dependent Ca(2+) channels (VDCCs) in ECCs, whereas both L- and non-L VDCCs (N and PQ) contributed equally to secretion control in MCCs. Our results have the following physiological, pharmacological, and clinical relevance: 1) they may help to better understand the regulation of adrenal catecholamine release in response to stress during fetal life and delivery; 2) if clinically used, L-type Ca(2+) channel blockers may augment the incidence of sudden infant death syndrome (SIDS); and 3) so-called Ca(2+) promotors or activators of Ca(2+) entry through L-type VDCCs may be useful to secure a healthy catecholamine surge upon violent stress during fetal life, at birth, or to prevent the SIDS in neonates at risk.

Developmental change of T‐type Ca2+ channel expression and its role in rat chromaffin cell responsiveness to acute hypoxia

Neonatal chromaffin cells of the adrenal medulla (AM) are intrinsic chemoreceptors that secrete catecholamines in response to hypoxia, thus contributing to fetal adaptation to extrauterine life. In most mammals studied, oxygen sensitivity of AM cells disappears a few days after birth, possibly due to innervation of the adrenal gland by the cholinergic fibres of the splanchnic nerve (approximately postnatal day 7 in the rat). The mechanisms underlying these homeostatic changes in chromaffin cells are unknown. Low voltage-activated, T-type, Ca(2+) channels regulate cell excitability and their expression is up-regulated by hypoxia. Hence, we hypothesized that these channels contribute to the developmental changes in the chemoreceptive properties of AM chromaffin cells. Using electrophysiological, immunocytochemical and molecular biology methodologies we show here that neonatal AM chromaffin cells express T-type Ca(2+) channels (of alpha1H or Ca(v)3.2 sub-type) and that the function of these channels is necessary for catecholamine release in response to acute hypoxia. T-type Ca(2+) channel expression, as well as chromaffin cell responsiveness to hypoxia, decrease with postnatal maturation. Adult chromaffin cell sensitivity to hypoxia reappears after AM denervation in parallel with the recruitment of T-type Ca(2+) channels. These observations indicate that T-type Ca(2+) channels are essential for the acute response of chromaffin cells to hypoxia and help explain the disappearance of O(2) sensitivity in adult AM chromaffin cells. Our results may also be relevant for understanding the pathogenesis of disorders associated with chronic hypoxia or maternal nicotine consumption.

Preconditioning stimuli that augment chromaffin cell secretion

We have investigated here whether a preconditioned stimulation of nicotinic and muscarinic receptors augmented the catecholamine release responses elicited by supramaximal 3-s pulses of 100 muM acetylcholine (100ACh) or 100 mM K(+) (100K(+)) applied to fast-perifused bovine adrenal chromaffin cells. Threshold concentrations of nicotine (1-3 muM) that caused only a tiny secretion did, however, augment the responses elicited by 100ACh or 100K(+) by 2- to 3.5-fold. This effect was suppressed by mecamylamine and by Ca(2+) deprivation, was developed with a half-time (t(1/2)) of 1 min, and was reversible. The nicotine effect was mimicked by threshold concentrations of ACh, choline, epibatidine, and oxotremorine-M but not by methacholine. Threshold concentrations of K(+) caused lesser potentiation of secretion compared with that of threshold nicotine. The data are compatible with an hypothesis implying 1) that continuous low-frequency sympathetic discharge places chromaffin cells at the adrenal gland in a permanent "hypersensitive" state; and 2) this allows an explosive secretion of catecholamines by high-frequency sympathetic discharge during stress.

A low nicotine concentration augments vesicle motion and exocytosis triggered by K + depolarisation of chromaffin cells

Tobacco smokers have an increased risk of cardiovascular disease; this is likely associated to an enhanced catecholamine release by circulating nicotine. Here, we have explored how low concentrations of nicotine in the range of those found in the blood of tobacco smokers, might affect the release of catecholamines in bovine chromaffin cells. We have combined patch-clamp and Ca 2+ imaging techniques to study cell excitability, cytosolic Ca 2+ transients, vesicle movement, and secretory responses. We found that low concentrations of nicotine (1.5–3 μM) did not enhance catecholamine release by themselves. However, they drastically augmented the catecholamine release response triggered by a supramaximal K + depolarising pulse. Furthermore, low nicotine concentrations caused slight depolarisation with superimposed action potentials, a transient elevation of [Ca 2+] c and augmented Ca 2+-dependent vesicle motion underneath the plasmalemma. We suggest that low nicotine concentrations overload the secretory machinery with secretory vesicles, which cause chromaffin cells to respond with an exaggerated adrenaline release into the circulation during stress. This might contribute to the higher cardiovascular risk of tobacco smokers.

A two-step model for acetylcholine control of exocytosis via nicotinic receptors

The view that Ca 2+ entry through voltage-dependent Ca 2+ channels (VDCC) and through nicotinic receptors for acetylcholine (nAChRs) causes equal catecholamine release responses in chromaffin cells, was reinvestigated here using new protocols. We have made two-step experiments consisting in an ACh prepulse followed by a depolarizing pulse (DP). In voltage-clamped bovine chromaffin cells an ACh prepulse caused a slow-rate release but augmented 4.5-fold the much faster exocytotic response triggered by a subsequent depolarizing pulse (measured with capacitance and amperometry). If the ACh prepulse was given with mecamylamine or in low external Ca 2+, the secretion increase disappeared. This suggests a two-step model for the effects of ACh: (1) meager Ca 2+ entry through nAChRs mostly serves to keep loaded with vesicles the secretory machine; and (2) in this manner, the cell is prepared to respond with an explosive secretion of catecholamine upon depolarization and fast high Ca 2+ entry through VDCC.

Single-Vesicle Catecholamine Release Has Greater Quantal Content and Faster Kinetics in Chromaffin Cells from Hypertensive, as Compared with Normotensive, Rats

In a previous study performed in the intact adrenal gland (Lim et al., 2002), stimulation with acetylcholine (ACh) or high K(+) concentrations (K(+)) produced greater catecholamine release in spontaneously hypertensive rats (SHR), as compared with normotensive animals. In this study, the time course of secretion was in the range of minutes. Hence, we do not know whether enhanced release is due to greater quantal content and/or distinct kinetics in SHRs and control animals. To get insight into the mechanism involved in such enhanced catecholamine secretory responses, we performed a single-vesicle release study in primary cultures of adrenal chromaffin cells, recorded with amperometry. Cells were stimulated with 2-s pulses of 1 mM ACh or 70 mM K(+). The secretory responses to ACh or K(+) pulses in SHR cells as compared with control cells had the following characteristics: 1) double number of secretory events, 2) 4-fold augmentation of total secretion, 3) cumulative secretion that saturated slowly, 4) 3-fold higher complex events with two to four superimposed spikes that may be explained by faster spike kinetics, 5) about 2- to 3-fold higher event frequency at earlier post stimulation periods, and 6) 2- to 5-fold higher quantal content of simple spikes. We conclude that SHR cells have faster and larger catecholamine release responses, explained by more vesicles ready to undergo exocytosis and greater quantal content of vesicles. This could have relevance to further understand the pathogenic mechanisms involved in the development of high blood pressure, as well as in the identification of new drug targets to treat hypertension.

Ouabain augments and maintains the catecholamine release responses evoked by repetitive pulses of potassium, caffeine or histamine in perifused bovine chromaffin cells

Cardiac glycosides such as ouabain augment the release of neurotransmitters and hormones from various organs, tissues and cell systems. Here we have investigated novel aspects of the ouabain effects on fast-perifused bovine adrenal chromaffin cells subjected to repetitive stimulation during long-time periods with secretagogues that enhance Ca 2+ entry (i.e. 100 mM K +solution) or causing the release into the cytosol of the Ca 2+ stored in the endoplasmic reticulum (i.e. 20 mM caffeine or 100 μM histamine). After 1 h of intermittent stimulation, the amperometrically measured catecholamine release responses decayed to 50% with K + pulses, and to 10–15% with caffeine or histamine pulses. Ouabain (10 μM) augmented 2-fold the K + secretory responses and kept them high, along an hour. When given after the responses had decayed upon repetitive caffeine or histamine pulsing, ouabain gradually restored such responses to their initial control values. On the basis of these results, we raise the hypothesis that ouabain may facilitate the handling by the cell of the endoplasmic reticulum Ca 2+ fluxes that are known to be involved in secretory vesicle transport and the regulation of exocytosis. This may have physiological and pathological interest in the light of an endogenous ouabain steroid found in the adrenal cortex.

Attenuated stress-induced catecholamine release in mice lacking the vasopressin V1b receptor

Vasopressin V(1b) receptor is specifically expressed in the pituitary and mediates adrenocorticotropin release, thereby regulating stress responses via its corticotropin releasing factor-like action. In the present study we examined catecholamine release in response to two types of stress in mice lacking the V(1b) receptor gene (V(1b)R(-/-) mice) vs. wild-type mice. There were no significant differences in the basal plasma levels of catecholamines between the two genotypes. In response to stress induced by forced swimming, norepinephrine (NE), but not epinephrine (E) or dopamine (DA), was increased in wild-type mice, whereas the increases in NE and DA were not observed in V(1b)R(-/-) mice. In wild-type mice, E, but not NE or DA, was increased in response to social isolation stress, whereas the increase in E was not observed in V(1b)R(-/-) mice. These results suggest that the V(1b) receptor regulates stress-induced catecholamine release. Because it has been suggested that arginine-vasopressin (AVP) is related to the development of depression, we also evaluated immobility time in the forced swimming test, and we found no significant change in V(1b)R(-/-) mice. Taken together, these findings suggest that, in addition to the previously elucidated effect on the hypothalamic-pituitary-adrenal axis, vasopressin activity via V(1b) receptors regulates stress-induced catecholamine release.

Hospital Admissions for Congestive Heart Failure Decrease with Increasing Temperature in a Tropical Climate

Study Objectives: A previous study of emergency department visits for congestive heart failure (CHF) to hospitals in New Jersey, USA revealed a marked increase in the colder months. This was attributed in part to increased catecholamine release in response to cold weather. We hypothesized that the extreme high temperatures in the tropics would also place an additional burden on the heart and therefore there should be an increase in the number of hospital admissions for CHF during the warmest months compared to the coolest months in a tropical climate.

Protease inhibitors in acute pancreatitis: Lessons from the bench and failed clinical trials

Protease inhibitors in acute pancreatitis: Lessons from the bench and failed clinical trials

Neuroendocrine changes in adult female rats prenatally exposed to phenytoin

Neuroendocrine changes in fetal hydantoin syndrome have not been described yet. This study was aimed to verify the hypothesis that prenatal exposure to phenytoin influences the stress response of adult female offspring in an animal model. To study possible development of depression like state, hedonic behavior and long-term changes in neuropeptide gene expression in the hypothalamus were investigated. Treatment consisted of per os administration of 150 mg/kg of phenytoin or water daily, from day 7–18 of gestation. Adult female offspring (6 animals per group) were acutely stressed by 1 min handling. Blood was collected in conscious rats via tail artery cannulas before, 1, 15 and 30 min after the handling. Exposure to phenytoin in uterus resulted in increased catecholamine and corticosterone concentrations in response to a mild stressor of 1min handling in adult offspring. The gestational treatment used in this study did not induce a depression like state nor long-term changes in neuropeptide gene expression in the adult offspring. In conclusion, prenatal exposure to phenytoin treatment enhanced the stress response of adult female offspring. Possible new component of fetal hydantoin syndrome is the increase in catecholamine release in response to a mild stressor in adulthood.