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- The surging role of Chromogranin A in cardiovascular homeostasis. [Journal Article, Review]
- Front Chem 2014.:64.
Together with Chromogranin B and Secretogranins, Chromogranin A (CGA) is stored in secretory (chromaffin) granules of the diffuse neuroendocrine system and released with noradrenalin and adrenalin. Co-stored within the granule together with neuropeptideY, cardiac natriuretic peptide hormones, several prohormones and their proteolytic enzymes, CGA is a multifunctional protein and a major marker of the sympatho-adrenal neuroendocrine activity. Due to its partial processing to several biologically active peptides, CGA appears an important pro-hormone implicated in relevant modulatory actions on endocrine, cardiovascular, metabolic, and immune systems through both direct and indirect sympatho-adrenergic interactions. As a part of this scenario, we here illustrate the emerging role exerted by the full-length CGA and its three derived fragments, i.e., Vasostatin 1, catestatin and serpinin, in the control of circulatory homeostasis with particular emphasis on their cardio-vascular actions under both physiological and physio-pathological conditions. The Vasostatin 1- and catestatin-induced cardiodepressive influences are achieved through anti-beta-adrenergic-NO-cGMP signaling, while serpinin acts like beta1-adrenergic agonist through AD-cAMP-independent NO signaling. On the whole, these actions contribute to widen our knowledge regarding the sympatho-chromaffin control of the cardiovascular system and its highly integrated "whip-brake" networks.
- A Common Molecular Motif Characterizes Extracellular Allosteric Enhancers of GPCR Aminergic Receptors and Suggests Enhancer Mechanism of Action. [JOURNAL ARTICLE]
- Curr Med Chem 2014 Aug 26.
Several classes of compounds that have no intrinsic activity on aminergic systems nonetheless enhance the potency of aminergic receptor ligands three-fold or more while significantly increasing their duration of activity, preventing tachyphylaxis and reversing fade. Enhancer compounds include ascorbic acid, ethylenediaminetetraacetic acid, corticosteroids, opioid peptides, opiates and opiate antagonists. This paper provides the first review of aminergic enhancement, demonstrating that all enhancers have a common, in obvious molecular motif and work through a common mechanism that is manifested by three common characteristics. First, aminergic enhancers bind directly to the amines they enhance, suggesting that the common structural motif is reflected in common binding targets. Second, one common target is the first extracellular loop of aminergic receptors. Third, at least some enhancers are antiphosphodiesterases. These observations suggest that aminergic enhancers act on the extracellular surface of aminergic receptors to keep the receptor in its high affinity state, trapping the ligand inside the receptor. Enhancer binding produces allosteric modifications of the receptor structure that interfere with phosphorylation of the receptor, thereby inhibiting down-regulation of the receptor. The mechanism explains how enhancers potentiate aminergic activity and increase duration of activity and makes testable predictions about additional compounds that should act as aminergic enhancers. Key words: GPCR, epinephrine, norepinephrine, dopamine, histamine, serotonin, EDTA, vitamin C, ascorbic acid, opiate, opioid, morphine, naloxone, naltrexone, aldosterone, corticosteroid, allostery, allosteric, antiphosphodiesterase, phosphodiesterase inhibitors, down-regulation, potentiates, increased potency, potentiation, enhances, enhancement, supersensitivity, molecular complementarity.
- Caudal Blockade for Children Undergoing Infra-abdominal Surgery. [Journal Article]
- AORN J 2014 Sep; 100(3):306-22.
The assessment and management of pain in children can be complicated by their inability to communicate effectively; therefore, it is important that every attempt be made to circumvent the undertreatment of pain. Caudal blockade is associated with excellent pain relief and minimal side effects, and it is an established technique used in conjunction with general anesthesia for children undergoing infra-abdominal surgery. Available local anesthetic agents have a relatively short analgesic duration period, so anesthesia professionals often combine their use with adjuvant medications (eg, epinephrine, clonidine, fentanyl, morphine, preservative-free ketamine, neostigmine). Additional consideration should be given to intraoperative care, postoperative observation (eg, measuring sedation, motor blockade, postoperative nausea and vomiting, pain), and discharge instructions for the patient's caregiver.
- Do Stress Markers and Anesthetic Technique Predict Delirium in the Elderly? [JOURNAL ARTICLE]
- Dement Geriatr Cogn Disord 2014 Aug 26; 38(5-6):366-374.
Background: Postoperative delirium (PD) is a prevalent complication of elderly surgical patients, which predisposes to worsened cognitive recovery and dementia. Risk of PD has been associated with increasing magnitude of the hypothalamic-pituitary-adrenal stress response (serum cortisol, epinephrine and norepinephrine) to surgery. Anesthetics suppress this response; however, some (total intravenous anesthesia, TIVA) more than others (anesthetic gases). Prior comparisons of anesthetics have been equivocal but have not included stress markers. We hypothesized that TIVA would decrease serum stress markers and the incidence of PD. Methods: We performed a prospective cohort study of 76 elderly major surgical patients. Patients received TIVA or sevoflurane gas, and blood was drawn for serum markers pre-, intra-, and postoperatively. PD was assessed with the Confusion Assessment Method. We compared stress markers and PD between patients who received TIVA versus sevoflurane, and then modeled PD including stress and anesthetic. Results: The group that received TIVA during surgery demonstrated lower levels of all stress markers compared to the gas group, but no difference in PD. However, across groups, the postoperative norepinephrine level was much higher in patients who developed PD. Other markers and other times had no effect. Conclusion: The development of PD depends more on postoperative stress than intraoperative stress or anesthetic. © 2014 S. Karger AG, Basel.
- Epinephrine Evokes Renalase Secretion via α-Adrenoceptor/NF-κB Pathways in Renal Proximal Tubular Epithelial Cells. [JOURNAL ARTICLE]
- Kidney Blood Press Res 2014 Aug 6; 39(4):252-259.
Background/Aims : Renalase is a recently discovered, kidney-specific monoamine oxidase that metabolizes circulating catecholamines. These findings present new insights into hypertension and chronic kidney diseases. Previous data demonstrated that renalase was mainly secreted from proximal tubules which could be evoked by catecholamines. The purpose of this study is to investigate whether renalase expression is induced by epinephrine via α-adrenoceptor/NFκB pathways. Methods : HK2 cells were utilized to explore renalase expression in response to epinephrine in vitro. Phentolamine, an α-adrenoceptor antagonist, and Tosyl Phenylalanyl Chloromethyl Ketone (TPCK) were used to block α-adrenoceptor and to knock down the transcription factor NFκB, respectively. Renalase expression was analyzed using Western blot and quantitative PCR. Results : Both protein and mRNA levels of renalase in HK2 cells increased in response to epinephrine (P<0.05). Epinephrine-evoked renalase expression was attenuated by phentolamine and TPCK separately (P<0.05). Conclusion : Epinephrine evokes renalase secretion via α-adrenoceptor/NF-κB pathways in renal proximal tubular epithelial cells. © 2014 S. Karger AG, Basel.
- Endoscopic injection of autologous blood versus diluted epinephrine for control of actively bleeding gastroduodenal ulcers: a randomized-controlled study. [JOURNAL ARTICLE]
- Eur J Gastroenterol Hepatol 2014 Aug 28.
A preliminary report showed that autologous blood is an effective and easily applicable technique that can control actively bleeding gastroduodenal ulcers. The aim of this study was to test whether an endoscopic injection of autologous blood is comparable to an endoscopic injection of diluted epinephrine in controlling bleeding from gastroduodenal ulcers.A total of 100 patients with actively bleeding gastroduodenal ulcers were assigned randomly to either an autologous blood injection (group A, n=50) or a diluted epinephrine injection (group B, n=50) along the edges of the ulcers. Groups were compared for rates of initial hemostasis, rebleeding, and complications.All patients initially achieved hemostasis (100%). Rebleeding occurred in four patients from group A (8%) and five patients from group B (10%). Two patients in group B developed cardiovascular complications (arrhythmia and ischemic heart attack), whereas none in group A developed complications.Autologous blood is effective, comparable to diluted epinephrine in achieving initial hemostasis from actively bleeding gastroduodenal ulcers, associated with an 8% rebleeding rate, and led to no complications.
- Rate, Triggers, Severity and Management of Anaphylaxis in Adults Treated in a Canadian Emergency Department. [JOURNAL ARTICLE]
- Int Arch Allergy Immunol 2014 Aug 26; 164(3):246-252.
Background: The Cross-Canada Anaphylaxis Registry (C-CARE) assesses the triggers and management of anaphylaxis and identifies predictors of the development of severe allergic reactions and of epinephrine use. Here, we present data from an urban adult tertiary care emergency department (ED) in Montreal, Canada. Methods: Potential anaphylaxis cases were identified using ICD-10 codes related to anaphylaxis or allergic reactions. Putative cases underwent chart review to ensure they met anaphylaxis diagnostic criteria. Demographic, clinical and management data were collected. Multivariate logistic regressions were conducted to assess the effect of demographic characteristics, triggers, and comorbidities on severity and management of reactions. Results: Among 37,730 ED visits, 0.26% (95% CI 0.21, 0.32) fulfilled the definition of anaphylaxis. Food was the suspected trigger in almost 60% of cases. Epinephrine was not administered in almost half of moderate-to-severe cases, and similar numbers of individuals with moderate-to-severe reactions were not prescribed an epinephrine autoinjector. Reaction to shellfish was associated with more severe reactions (OR 13.9; 95% CI 2.2, 89.4). Older individuals and those not receiving steroids were more likely managed without epinephrine (OR 1.04; 95% CI 1.01, 1.07 and OR 2.97; 95% CI 1.05, 8.39, respectively). Conclusions: Anaphylaxis accounted for a substantial number of ED visits in adults, and the most common trigger was food. There is non-adherence to guidelines recommending epinephrine use for all cases of anaphylaxis. We postulate that this may be related to concerns regarding the side effects of epinephrine in adults. © 2014 S. Karger AG, Basel.
- Safety of Enteral Feedings in Critically Ill Children Receiving Vasoactive Agents. [JOURNAL ARTICLE]
- JPEN J Parenter Enteral Nutr 2014 Aug 28.
Background: The objective of this retrospective study was to evaluate the safety of enteral feeding in children receiving vasoactive agents (VAs). Methods: Patients aged 1 month to 18 years with a pediatric intensive care unit stay for ≥96 hours during 2007 and 2008 who received any VA (epinephrine, norepinephrine, vasopressin, milrinone, dopamine, and dobutamine) were included and categorized into fed and nonfed groups. Their demographics, clinical characteristics, type and dose of VA, and presence of gastrointestinal (GI) outcomes were obtained. GI outcomes were compared between the groups by the χ(2) test, Mann-Whitney test, and logistic regression. Results: In total, 339 patients were included. Of these, 55% were in the fed group and 45% in the nonfed group. Patients in the fed group were younger (median age, 1.05 vs 2.75 years, respectively; P < .001) and tended to have a lower Pediatric Index of Mortality 2 (PIM2) risk of mortality (ROM) than those in the nonfed group (median, 3.33% vs 3.52%, respectively; P = .106). Mortality was lower in the fed group than the nonfed group (6.9% vs 15.9%, respectively; odds ratio [OR], 0.39; 0.18-0.84; P < .01, 95% CI), while GI outcomes did not differ between the groups. The vasoactive-inotropic score (VIS) did not differ between the groups except on day 1 (P = .017). The ROM did not differ between the groups after adjusting for age, PIM2 ROM, and VIS on day 1 (OR, 0.58; 0.26-1.28; P = .18, 95% CI). Conclusions: Enteral feeding in patients receiving VAs is associated with no difference in GI outcomes and a tendency towards lower mortality. Prospective studies are required to confirm the safety of enteral feedings in patients receiving VAs.
- Attenuated aortic vasodilation and sympathetic prejunctional facilitation in epinephrine-deficient mice: selective impairment of β2-adrenoceptor responses. [JOURNAL ARTICLE]
- J Pharmacol Exp Ther 2014 Aug 26.
It has been suggested that there is a link between epinephrine synthesis and the development of β2-adrenoceptor-mediated effects, but it remains to be determined if this development is triggered by epinephrine. The aim of this study was to characterize the β-adrenoceptor-mediated relaxation and facilitation of norepinephrine release in the aorta of phenylethanolamine-N-methyltransferase-knockout (Pnmt-KO) mice. Catecholamines were quantified by reverse-phase HPLC-ED. Aorta rings were mounted in a myograph to determine concentration-response curves to selective β1- or β2-adrenoceptor agonists in the absence or presence of selective β1- or β2-adrenoceptor antagonists. Aortic rings were also preincubated with (3)H-norepinephrine to measure tritium overflow elicited by electrical stimulation in the presence of increasing concentrations of non-selective β or selective β2-adrenoceptor agonists. β2-adrenoceptor protein density was evaluated by western-blotting and β2-adrenoceptor localization by immunohistochemistry. Epinephrine is absent in Pnmt-KO mice. The potency and the maximal effect of β2-adrenoceptor agonist terbutaline were lower in Pnmt-KO than in WT mice. The selective β2-adrenoceptor antagonist ICI-118551 antagonized the relaxation caused by terbutaline in wild type (WT) but not in Pnmt-KO mice. Isoproterenol and terbutaline induced concentration-dependent increase in tritium overflow in WT mice only. β2-Adrenoceptor protein density was decreased in membrane aorta homogenates of Pnmt-KO mice and this finding was supported by immunofluorescence confocal microscopy. In conclusion, epinephrine is crucial for β2-adrenoceptor-mediated vasodilation and facilitation of norepinephrine release. In the absence of epinephrine, β2-adrenoceptor protein density was decreased in aorta cell membranes, thus potentially hindering its functional activity.
- Dexmedetomidine utilisation and outcomes of children with trisomy 21 undergoing congenital heart disease surgery. [JOURNAL ARTICLE]
- Cardiol Young 2014 Aug 27.:1-5.
Introduction: The diagnosis of trisomy 21 in children has been associated with failed extubation after CHD surgery. Dexmedetomidine may be a useful agent to improve postoperative outcomes in these patients, such as ventilator time, ICU length of stay, or hospital length of stay. Materials and methods: The Pediatric Health Information System database was queried from January, 2008 to December, 2010 for patients with trisomy 21 who underwent CHD surgery. Patients who received dexmedetomidine were matched to patients who did not by propensity score. The primary outcome was ventilator days charged, and secondary outcomes included ICU and hospital length of stay. Results: A total of 1088 patients (544 matched pairs) met inclusion criteria. Patient characteristics were similar, with the exception of more patients in the dexmedetomidine group undergoing repair of complete atrioventricular canal and fewer undergoing mechanical valve replacement (p<0.01). More patients in the dexmedetomidine group were administered milrinone, epinephrine, vasopressin, benzodiazepines, opiates, and adjunct pain and sedative medications (p<0.01). The dexmedetomidine group had greater time on the ventilator [7 (4.5-11) versus 6 (4-10) days (median, interquartile range) p<0.01] and similar ICU length of stay, hospital length of stay, and mortality compared with controls. Mixed-effects modelling clustered on institution did not show beneficial effect of dexmedetomidine on ventilator time, ICU stay, or hospital length of stay. Conclusions: The use of dexmedetomidine was not associated with the decreased ventilatory time. Routine use of dexmedetomidine is not warranted in this patient population.