Inhibition Of Catecholamine Release Research Articles

Somatostatin modulation of initial fusion pores in Ca2+-triggered exocytosis from mouse chromaffin cells.

Somatostatin, a peptide hormone that activates G-protein-coupled receptors, inhibits the secretion of many hormones. This study investigated the mechanisms of this inhibition using amperometry recording of Ca2+-triggered catecholamine secretion from mouse chromaffin cells. Two distinct stimulation protocols, high-KCl depolarization and caffeine, were used to trigger exocytosis, and confocal fluorescence imaging was used to monitor the rise in intracellular free Ca2+. Analysis of single-vesicle fusion events (spikes) resolved the action of somatostatin on fusion pores at different stages. Somatostatin reduced spike frequency, and this reduction was accompanied by prolongation of pre-spike feet and slowing of spike rise times. This indicates that somatostatin stabilizes initial fusion pores and slows their expansion. This action on the initial fusion pore impacted the release mode to favour kiss-and-run over full-fusion. During a spike the permeability of a fusion pore peaks, declines and then settles into a plateau. Somatostatin had no effect on the plateau, suggesting no influence on late-stage fusion pores. These actions of somatostatin were indistinguishable between exocytosis triggered by high-KCl and caffeine, and fluorescence imaging showed that somatostatin had no effect on stimulus-induced rises in cytosolic Ca2+. Our findings thus demonstrate that the signalling cascades activated by somatostatin target the exocytotic machinery that controls the initial and expanding stages of fusion pores, while having no effect on late-stage fusion pores. As a result of its stronger inhibition of full-fusion compared to kiss-and-run, somatostatin will preferentially inhibit the secretion of large peptides over the secretion of small catecholamines. KEY POINTS: Somatostatin inhibits the secretion of various hormones by activating G-protein-coupled receptors. In this study, we used amperometry to investigate the mechanism by which somatostatin inhibits catecholamine release from mouse chromaffin cells. Somatostatin increased pre-spike foot lifetime and slowed fusion pore expansion. Somatostatin inhibited full-fusion more strongly than kiss-and-run. Our results suggest that the initial fusion pore is the target of somatostatin-mediated regulation of hormone release. The stronger inhibition of full-fusion by somatostatin will result in preferential inhibition of peptide release.

Effect of single bolus dose of intravenous magnesium sulfate in attenuating hemodynamic stress response to laryngoscopy and nasotracheal intubation in maxillofacial surgeries

Background: Nasotracheal intubation alters respiratory and cardiovascular physiology by reflex response mediated by both sympathetic and parasympathetic nervous systems and by the physical presence of the nasotracheal tube. Hypertension and tachycardia are the most common responses to intubation mediated by sympathetic efferent through cardio accelerator nerve and sympathetic chain ganglia. MgSO4 inhibits catecholamine release from adrenergic nerve endings and adrenal medulla resulting in attenuation of stress response. Aims and Objectives: In this study, we observed the effects of MgSO4 on the hemodynamic stress response. Materials and Methods: This prospective randomized controlled study was conducted on 60 patients after approval of the Institutional Ethics and Scientific Review committee over the period of 1 year. They were divided into two groups, Group M (MgSO4 group) received 40 mg/kg of intravenous magnesium sulfate in 100 ml normal saline and Group C (control group) received normal saline 10 min before induction. Hemodynamic parameters (HR, SBP, DBP, and MAP) were recorded at baseline, just before induction and at 1, 3, 5, 10, 15, and 30 min after intubation and every 15 min till the end of surgery. Results: After conducting this study, we observed that heart rates at 1, 3, 5, and 10 were significantly lower in the M group as compared to the C group (P<0.05). Systolic, diastolic, and mean blood pressure were also reduced significantly in the M group as compared to the C group (P<0.05). Conclusion: Magnesium sulfate when used at the dose of 40 mg/kg attenuates the hemodynamic stress response during laryngoscopy and nasotracheal intubation.

G Protein-Coupled Receptors-Receptors With New Tricks Up Their Sleeves.

G Protein-Coupled Receptors-Receptors With New Tricks Up Their Sleeves.

Serum catestatin level is increased in women with preeclampsia

Catestatin can inhibit catecholamine release from chromaffin cells and adrenergic neurons. Catestatin can also have a strong vasodilator effect. This may be useful in understanding the pathophysiology of preeclampsia and its treatment. In this study, we investigated the serum catestatin levels in pregnant women with and without preeclampsia. Fifty consecutive women with mild preeclampsia, 50 consecutive women with severe preeclampsia, and 100 consecutive pregnant women with a gestational age-matched (±1 week) uncomplicated pregnancy were evaluated in a cross-sectional study. Mean serum catestatin was significantly increased in the preeclampsia group compared to the control group (290.7 ± 95.5 pg/mL vs. 182.8 ± 72.0 pg/mL). Mean serum catestatin was comparable in mild and severe preeclampsia groups (282.7 ± 97.9 pg/mL vs. 298.7 ± 93.4 pg/mL, p = .431). Serum catestatin levels had positive correlations with systolic and diastolic blood pressure, urea, uric acid, and creatinine. In conclusion, serum catestatin levels are increased in preeclamptic pregnancies compared to gestational age-matched controls. IMPACT STATEMENT What is already known on this subject? The role of autonomic nervous system dysregulation in the pathophysiology of preeclampsia is known. The most obvious part of this dysregulation is the sympathetic nervous system activation. The adrenal medulla is one of the locations of the sympathetic nervous system in the body. What do the results of this study add? Serum catestatin levels were found to be correlated with clinical and laboratory data of preeclampsia. This highlights the importance of chromaffin cell secretions in the adrenal medulla in preeclampsia. What are the implications of these findings for clinical practice and/or further research? This study will help understand the role of the adrenal medulla in the autonomic nervous system dysregulation in preeclampsia. Also, control of serum catestatin levels may support the treatment of hypertension in preeclampsia.

Neural circuits of anxiolytic and antidepressant pherine molecules.

In this review, we describe proposed circuits mediating the mechanism of action of pherines, a new class of synthetic neuroactive steroids with demonstrated antianxiety and antidepressant properties, that engage nasal chemosensory receptors. We hypothesize that afferent signals triggered by activation of these peripheral receptors could reach subgroups of olfactory bulb neurons broadcasting information to gamma-aminobutyric acid (GABAergic) and corticotropin-releasing hormone (CRH) neurons in the limbic amygdala. We propose that chemosensory inputs triggered by pherines project to centrolateral (CeL) and centromedial (CeM) amygdala neurons, with downstream effects mediating behavioral actions. Anxiolytic pherines could activate the forward inhibitory GABAergic neurons that facilitate the release of neuropeptide S (NPS) in the locus coeruleus (LC) and GABA in the bed nucleus of the stria terminalis (BNST) and inhibit catecholamine release in the LC and ventral tegmental area (VTA) leading to rapid anxiolytic effect. Alternatively, antidepressant pherines could facilitate the CRH and GABAergic neurons that inhibit the release of NPS from the LC, increase glutamate release from the BNST, and increase norepinephrine (NE), dopamine (DA), and serotonin release from the LC, VTA, and raphe nucleus, respectively. Activation of these neural circuits leads to rapid antidepressant effect. The information provided is consistent with this model, but it should be noted that some steps on these pathways have not been demonstrated conclusively in the human brain.

May Salivary Chromogranin A Act as a Physiological Index of Stress in Transported Donkeys? A Pilot Study.

Simple SummaryTransportation is recognized as a stressful animal husbandry procedure, inducing both short term and prolonged effects on welfare. Donkeys are transported for several purposes; therefore, validating a reliable and non-invasive stress indicator is pivotal. This study aimed to investigate whether salivary chromogranin A (CgA) concentration, known as an index of stress in humans and pigs, could represent a novel index of transportation-induced stress in donkeys. The research involved the measurement of salivary CgA in 19 donkeys, 15 min before and 15 min after two transportations. The transportation, which took place on two consecutive days, followed the routine procedures of the farm. The analysis of salivary CgA was carried out by an enzyme-linked immunosorbent assay test. Results showed that CgA salivary levels significantly decreased after both transportations. The physiological mechanisms underlying this result may be related to catestatin acting as an inhibitor of catecholamine release; however, due to the limited number of subjects involved, this hypothesis requires further investigation. Road transport is known to be a stressful animal husbandry procedure as it induces the activation of two main physiological stress-related pathways: the hypothalamic-pituitary-adrenal cortex axis and the sympathetic-adrenal medulla axis. This preliminary study aimed to investigate whether salivary chromogranin A (CgA) concentration, known as a biomarker of the sympathetic activity system during psychological stress, may represent a novel physiological index of transportation-induced stress in donkeys. Nineteen Romagnolo donkeys, raised in groups on paddocks, were subject to two transportations, following the farm’s routine procedures, for a mean duration of 64 min each on two consecutive days. Salivary samples were gently collected 15 min before and 15 min after each transportation. Salivary CgA was measured by a commercially available enzyme-linked immunosorbent assay test. Results showed that CgA salivary levels significantly decreased after both transportations. The physiological mechanisms underlying this result may be related to catestatin activity, a bioactive product of the proteolytic cleavage of CgA, that acts as an inhibitor of catecholamine release. This hypothesis requires further investigation, particularly considering the limited number of subjects involved in this preliminary study. The identification of a reliable and non-invasive stress-marker would represent a useful tool for improving farm animals’ welfare in transport conditions.

Nanoliposomes codelivering bioactive peptides produce enhanced anti-aging effect in human skin

The present study aimed to develop nanoliposomes codelivering multiple bioactive peptides to achieve improved and comprehensive anti-aging effects in human skin. The nanoliposomes were simultaneously loaded with carnosine, palmitoyl tripeptide-5 and acetyl hexapeptide-3 (CPA-NLPs) for topical delivery. The CPA-NLPs were nano-scaled with narrow size distribution, and showed high encapsulation efficiency, high loading capacity and sustained release of bioactive peptides. Flow cytometry and confocal laser scanning microscopy showed that the nanoliposomes significantly enhanced the cellular uptake of the loaded cargo by human skin fibroblasts (HSF) cells. The CPA-NLPs also protected HSF cells from H2O2-induced oxidative stress damage and increased their expression levels of type Ι collagen and hyaluronic acid. In addition, treatment with CPA-NLPs inhibited catecholamine release in rat adrenal pheochromocytoma (PC12) cells. In a clinical trial, application of a lotion containing 2% CPA-NLPs in face led to a remarkable reduction of the volume, area and area ratio of wrinkles, and an improvement of skin elasticity. These results suggest that loading a combination of bioactive peptides into nanoliposomes is a promising strategy to enhance the topical delivery efficiency and the anti-aging efficacy.

Efficacy of Magnesium Sulphate to Prevent Arterial Pressure Increases During Laparoscopic Cholecystectomy

Background: Carbon dioxide pneumoperitoneum (PP) for laparoscopic surgery increases arterialpressure and systemic vascular resistance, these vasopressor responses are likely to be due to increasedrelease of catecholamine. Magnesium is well known to inhibit catecholamine release and attenuatevasopressin stimulated vasoconstriction. Objectives: This study has been undertaken with a view to find out the efficacy of magnesium sulphateto prevent arterial pressure increases associated with carbon dioxide pneumoperitoneum (PP) in patientsundergoing laparoscopic cholecystectomy. Methods: Sixty patients, of either sex, 18 60 years of age, undergoing elective laparoscopic cholecystectomywere randomly allocated in one of the two group’s containing 30 patients each. Magnesium SulphateGroup “M” received magnesium sulphate 30 mg/kg intravenously as a bolus beforecarbon dioxidepneumoperitoneum (PP).A control Group “C” received same volume of normal salinebefore carbon dioxidepneumoperitoneum (PP). Results: Mean arterial pressure was significantly less throughout the period ofpneumoperitoneum inpatients of Group M. Intravenous labetalol was required in 46.66% (14out of 30) of the patients in groupC to control intraoperative hypertension and it was clinicallysignificant in comparison to group M. Conclusion: Our study concluded that intravenous Magnesium Sulphate administered before carbondioxide pneumoperitoneum (PP) attenuates arterial pressure increases during laparoscopiccholecystectomy effectively and provides better hemodynamic stability. JBSA 2018; 31(2): 82-87

Spinal GABA-B receptor modulates neutrophil recruitment to the knee joint in zymosan-induced arthritis.

Recent studies have demonstrated that the central nervous system controls inflammatory responses by activating complex efferent neuroimmune pathways. The present study was designed to evaluate the role that central gamma-aminobutyric acid type B (GABA-B) receptor plays in neutrophil migration in a murine model of zymosan-induced arthritis by using different pharmacological tools. We observed that intrathecal administration of baclofen, a selective GABA-B agonist, exacerbated the inflammatory response in the knee after zymosan administration characterized by an increase in the neutrophil recruitment and knee joint edema, whereas saclofen, a GABA-B antagonist, exerted the opposite effect. Intrathecal pretreatment of the animals with SB203580 (an inhibitor of p38 mitogen-activated protein kinase) blocked the pro-inflammatory effect of baclofen. On the other hand, systemic administration of guanethidine, a sympatholytic drug that inhibits catecholamine release, and nadolol, a beta-adrenergic receptor antagonist, reversed the effect of saclofen. Moreover, saclofen suppressed the release of the pro-inflammatory cytokines into the knee joint (ELISA) and pain-related behaviors (open field test). Since the anti-inflammatory effect of saclofen depends on the sympathetic nervous system integrity, we observed that isoproterenol, a beta-adrenergic receptor agonist, mimics the central GABA-B blockade decreasing knee joint neutrophil recruitment. Together, these results demonstrate that the pharmacological manipulation of spinal GABAergic transmission aids control of neutrophil migration to the inflamed joint by modulating the activation of the knee joint-innervating sympathetic terminal fibers through a mechanism dependent on peripheral beta-adrenergic receptors and central components, such as p38 MAPK.

A molecular dynamics study of catestatin docked on nicotinic acetylcholine receptors to identify amino acids potentially involved in the binding of chromogranin A fragments.

Catestatin, a cationic and hydrophobic 21-amino acid fragment of chromogranin A, is known to be a non-competitive nicotinic antagonist acting through nicotinic acetylcholine receptors (nAChRs) to inhibit catecholamine release. Since this receptor is the target of several neuronal and non-neuronal disorder prophylaxes and treatments, this study aims at the elucidation of the binding of human catestatin to the entire nAChR reconstructed in lipid bilayers by means of docking followed by full atomistic molecular dynamics simulations. The obtained results show that the minimum free energy for the binding of the peptide and the receptor attains minimal values for locations at the pore site and in the outer beta subunit. This result is consistent with previous studies showing that catestatin occludes the pore opening. A new finding is an additional even stronger binding seat at the beta subunit and that membrane presence could be an important factor. Specific amino acids involved in catestatin binding have been identified, indicating targets for point mutation studies. In addition to improving the understanding of the interaction between the peptide and muscle-type and even other nAChR subtypes, the results of this study provide directions for future peptidomimetic research.

Novel Peptide Isomer Strategy for Stable Inhibition of Catecholamine Release

Although hypertension remains the most potent and widespread cardiovascular risk factor, its pharmacological treatment has achieved only limited success. The chromogranin A–derived fragment catestatin inhibits catecholamine release by acting as an endogenous nicotinic cholinergic antagonist and can rescue hypertension in the setting of chromogranin A–targeted ablation. Here, we undertook novel peptide chemistry to synthesize isomers of catestatin: normal/wild-type as well as a retro-inverso (R-I) version, with not only inversion of chirality (L→D amino acids) but also reversal of sequence (carboxyl→amino). The R-I peptide was entirely resistant to proteolytic digestion and displayed enhanced potency as well as preserved specificity of action toward nicotinic cholinergic events: catecholamine secretion, agonist desensitization, secretory protein transcription, and cationic signal transduction. Structural modeling suggested similar side-chain orientations of the wild-type and R-I isomers, whereas circular dichroism spectroscopy documented inversion of chirality. In vivo, the R-I peptide rescued hypertension in 2 mouse models of the human trait: monogenic chromogranin A–targeted ablation, with prolonged efficacy of the R-I version and a polygenic model, with magnified efficacy of the R-I version. These results may have general implications for generation of metabolically stable mimics of biologically active peptides for cardiovascular pathways. The findings also point the way toward a potential new class of drug therapeutics for an important risk trait and, more generally, open the door to broader applications of the R-I strategy in other pathways involved in cardiovascular biology, with the potential for synthesis of diagnostic and therapeutic probes for both physiology and disease.

Gabapentin Inhibits Catecholamine Release from Adrenal Chromaffin Cells

Gabapentin is most commonly prescribed for chronic pain, but acute perioperative effects, including preemptive analgesia and hemodynamic stabilization, have been reported. Adrenal chromaffin cells are a widely used model to investigate neurosecretion, and adrenal catecholamines play important physiologic roles and contribute to the acute stress response. However, the effects of gabapentin on adrenal catecholamine release have never been tested. Primary cultures of bovine adrenal chromaffin cells were treated with gabapentin or vehicle for 18-24 h. The authors quantified catecholamine secretion from dishes of cells using high-performance liquid chromatography and resolved exocytosis of individual secretory vesicles from single cells using carbon fiber amperometry. Voltage-gated calcium channel currents were recorded using patch clamp electrophysiology and intracellular [Ca2+] using fluorescent imaging. Gabapentin produced statistically significant reductions in catecholamine secretion evoked by cholinergic agonists (24 ± 3%, n = 12) or KCl (16 ± 4%, n = 8) (mean ± SEM) but did not inhibit Ca2+ entry or calcium channel currents. Amperometry (n = 51 cells) revealed that gabapentin inhibited the number of vesicles released upon stimulation, with no change in quantal size or kinetics of these unitary events. The authors show Ca2+ entry was not inhibited by gabapentin but was less effective at triggering vesicle fusion. The work also demonstrates that chromaffin cells are a useful model for additional investigation of the cellular mechanism(s) by which gabapentin controls neurosecretion. In addition, it identifies altered adrenal catecholamine release as a potential contributor to some of the beneficial perioperative effects of gabapentin.

Cardiovascular-a new novel source of catestatin and its precursor chromogranin A

ObjectiveTo investigate the expression and distribution of catestatin and its precursor phromogranin A in tissue and cardiovascular cell levels.MethodExtract RNA from Wistar rat heart tissue, vascular tissue, cardiomyocytes, cardiac fibroblasts,...

α2-Adrenoceptor-Mediated Inhibition of Catecholamine Release from the Adrenal Medulla of Spontaneously Hypertensive Rats is Preserved in the Early Stages of Hypertension

In this study, we evaluated the effect of α(2) -adrenoceptor activation on catecholamine release from the adrenal medulla of pre-hypertensive (6-week-old) and hypertensive (16-week-old) spontaneously hypertensive rats (SHR) and of age-matched normotensive control Wistar Kyoto (WKY) rats. Catecholamine overflow from isolated adrenal medullae was evoked by the nicotinic receptor agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) in the absence and presence of the α(2) -adrenoceptor agonist medetomidine (MED). The spontaneous outflow of adrenaline was similar between age-matched SHR and WKY rats. However, the spontaneous outflow of noradrenaline was significantly lower in SHR compared with age-matched WKY rats. DMPP (0.1-3 mM) increased the outflow of noradrenaline and adrenaline in a concentration-dependent manner. The E(max) values for adrenaline overflow were similar between strains, but the E(max) values for noradrenaline overflow were significantly lower in SHR. The EC(50) values for noradrenaline and adrenaline overflow were significantly higher in SHR compared with age-matched WKY rats. MED (0.1-300 nM) reduced the DMPP-evoked overflow (DMPP 500 μM) of noradrenaline and adrenaline in a concentration-dependent manner and was capable of totally inhibiting this effect. The inhibitory action of MED was similar between age-matched SHR and WKY rats. In the adrenals, the α(2A)- and α(2B)-adrenoceptor subtypes had the highest mRNA expression levels; the α(2C)-adrenoceptor subtype had the lowest mRNA expression levels. The mRNA levels for the three subtypes were similar between strains. In conclusion, in SHR during the development of hypertension, adrenal α(2) -adrenoceptor inhibitory function is conserved, accompanied by reduced noradrenaline release and unchanged adrenaline release.

A novel catestatin-induced antiadrenergic mechanism triggered by the endothelial PI3K–eNOS pathway in the myocardium

Catestatin (CST) is a chromogranin A (CgA)-derived peptide (hCgA352-372) with three identified human variants (G364S/P370L/R374Q-CST) that show differential potencies towards the inhibition of catecholamine release. Although CST affects several cardiovascular parameters, the mechanisms underlying CST action in the heart have remained elusive. Therefore, we sought to determine the mechanism of action of CST and its variants on ventricular myocardium and endothelial cells. Contractile force and Ca(2+) transients were measured, respectively, on rat papillary muscles and isolated cardiomyocytes (CC) under basal conditions and after β-adrenergic stimulation. Nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) phosphorylation (P(Ser1179)eNOS) were studied in bovine aortic endothelial (BAE-1) cells. Under basal conditions, wild-type CST (WT-CST, 10-50 nM) transiently enhanced myocardial contractility. CST variants (G364S and P370L) exerted a comparable positive inotropic effect. The H(1) histamine receptor antagonist mepyramine abolished the increase of contractile force induced by WT-CST. Moreover, WT-CST dose-dependently (5-50 nM) reduced the effect of β-adrenergic stimulation. This anti-adrenergic effect was not mediated by a direct action on CC, but involved a PI3K-dependent NO release from endocardial endothelial cells. Indeed, CST induced a wortmannin-sensitive, Ca(2+)-independent increase in NO production and eNOS phosphorylation on BAE-1 cells. While the anti-adrenergic and NO release effects of P370L-CST were comparable with those of WT-CST, the G364S variant was ineffective on the same parameters. Our results suggest that the anti-adrenergic action of CST depends on the endothelial PI3K-Akt-eNOS pathway and that its structural alterations entail functional features that correlate with the different anti-hypertensive potential described in humans.

PD123319 (AT2-receptor antagonist) inhibits catecholamine release from the isolated adrenal gland

PD123319 (AT2-receptor antagonist) inhibits catecholamine release from the isolated adrenal gland

Magnesium sulphate attenuates arterial pressure increase during laparoscopic cholecystectomy

Magnesium is well known to inhibit catecholamine release and attenuate vasopressin-stimulated vasoconstriction. We investigated whether i.v. magnesium sulphate attenuates the haemodynamic stress responses to pneumoperitoneum by changing neurohumoral responses during laparoscopic cholecystectomy. Thirty-two patients undergoing laparoscopic cholecystectomy were randomly assigned to two groups; a control group was given saline, and a magnesium group received magnesium sulphate 50 mg kg(-1) immediately before pneumoperitoneum. Arterial pressure, heart rate, serum magnesium, plasma renin activity (PRA), and catecholamine, cortisol, and vasopressin levels were measured. Systolic and diastolic arterial pressures were greater in the control group (P<0.05) than in the magnesium group at 10, 20, and 30 min post-pneumoperitoneum. Norepinephrine or epinephrine levels [pg ml(-1), mean (SD)] were higher in the control group than in the magnesium group at 5 [211 (37) vs 138 (18)] or 10 min [59 (19) vs 39 (9)] post-pneumoperitoneum, respectively (P<0.05). In the control group, vasopressin levels [pg ml(-1), mean (SD)] were higher compared with the magnesium group at 5 [64 (18) vs 35 (9), P<0.01] and 10 min [65 (18) vs 47 (11), P<0.05] post-pneumoperitoneum. There were no significant differences between the groups in PRA and cortisol levels. I.V. magnesium sulphate before pneumoperitoneum attenuates arterial pressure increases during laparoscopic cholecystectomy. This attenuation is apparently related to reductions in the release of catecholamine, vasopressin, or both.

Catestatin attenuates the effects of intrathecal nicotine and isoproterenol

Catestatin (Cts; human chromogranin A 352-372) is a neuropeptide derived from chromogranin A (ChgA). In the periphery it is released from the terminals of preganglionic neurons. In the adrenal medulla it inhibits catecholamine release by non-competitively antagonizing nicotinic cholinergic receptors. ChgA is present in the central nervous system, but the extent to which it is present within bulbospinal sympathoexcitatory neurons is unknown. We investigated the distribution of ChgA in the brainstem and its relationship to sympathoexcitatory neurons by combining immunofluorescence and in situ hybridization. A possible role for Cts in modulating the effect of other neurotransmitter systems in the spinal cord was examined by intrathecal injection of Cts, in conjunction with nicotine (1 μg–100 μg) and isoproterenol (0.12 μg–2.5 μg), in the anesthetized rat. Cts attenuated the hypotensive effect of isoproterenol on mean arterial pressure (maximum dose, 2.5 μg isoproterenol; − 27 mmHg pre-Cts to − 18 mmHg post-Cts), splanchnic sympathetic nerve activity (at 2.5 μg isoproterenol; 10.5% pre-Cts to 2.4% post-Cts), HR (at 2.5 μg isoproterenol; 1.1% pre-Cts to − 1.6% post-Cts), and the d p/d t max of carotid pulse pressure (at 2.5 μg isoproterenol 17.3% pre-Cts to 9.3% post-Cts). Cts attenuated the hypertensive effect of nicotine on mean arterial pressure (at 10 μg nicotine, 19.3 mmHg pre-Cts to 6.8 mmHg post-Cts), splanchnic sympathetic nerve activity (at 10 μg nicotine, 10.7% pre-Cts to 4.5% post-Cts), and HR (at 10 μg nicotine, 4.1% pre-Cts to 2.0% post-Cts). The results indicate that Cts antagonizes both central nicotinic acetylcholine receptors and β-adrenoceptors that are involved in cardiovascular regulation in vivo.

Regulation of catecholamine release and tyrosine hydroxylase in human adrenal chromaffin cells by interleukin‐1β: role of neuropeptide Y and nitric oxide

Adrenal chromaffin cells synthesize and secrete catecholamines and neuropeptides that may regulate hormonal and paracrine signaling in stress and also during inflammation. The aim of our work was to study the role of the cytokine interleukin-1beta (IL-1beta) on catecholamine release and synthesis from primary cell cultures of human adrenal chromaffin cells. The effect of IL-1beta on neuropeptide Y (NPY) release and the intracellular pathways involved in catecholamine release evoked by IL-1beta and NPY were also investigated. We observed that IL-1beta increases the release of NPY, norepinephrine (NE), and epinephrine (EP) from human chromaffin cells. Moreover, the immunoneutralization of released NPY inhibits catecholamine release evoked by IL-1beta. Moreover, IL-1beta regulates catecholamine synthesis as the inhibition of tyrosine hydroxylase decreases IL-1beta-evoked catecholamine release and the cytokine induces tyrosine hydroxylase Ser40 phosphorylation. Moreover, IL-1beta induces catecholamine release by a mitogen-activated protein kinase (MAPK)-dependent mechanism, and by nitric oxide synthase activation. Furthermore, MAPK, protein kinase C (PKC), protein kinase A (PKA), and nitric oxide (NO) production are involved in catecholamine release evoked by NPY. Using human chromaffin cells, our data suggest that IL-1beta, NPY, and nitric oxide (NO) may contribute to a regulatory loop between the immune and the adrenal systems, and this is relevant in pathological conditions such as infection, trauma, stress, or in hypertension.

Treatment recommendations to prevent myocardial ischemia and infarction in patients undergoing vascular surgery

During major vascular surgery (MVS), patients are at high risk for developing unrecognized myocardial infarction (MI) and myocardial ischemia. In reducing postoperative morbidity and mortality, preoperative cardiac risk stratification and adequate medical therapy play a pivotal role. Based on literature and current opinions, medical treatment should comprise at least a combination of beta-blockers, aspirin, and statins. beta-Blockers exert their beneficial effects predominantly through heart rate control, leading to reduced oxygen demand during surgery. A heart rate between 65 and 70 bpm should be achieved. Irrespective of their lipid-lowering effects, statins seem to improve postoperative cardiac outcome by stabilizing coronary artery plaques, thereby preventing atherosclerotic plaque rupture. Aspirin reduces platelet activation and vasoconstriction, thereby limiting ischemic events and reducing nonfatal MI by 34%. Adding clopidogrel to low-dose aspirin might be beneficial toward postoperative cardiac outcomes; however, the effect on the incidence of postoperative bleeding complications may be a problem for future studies to resolve. Whereas beta-blockers inhibit the effect of catecholamines, alpha(2)-agonists inhibit catecholamine release and may be used in the perioperative setting when beta-blockers are contraindicated. Despite the blood pressure-lowering effect and anti-inflammatory properties of angiotensin-converting enzyme inhibitors, the literature does not support their use in patients undergoing MVS. The possible use of calcium antagonists before MVS should be further evaluated in high-risk patients with contraindications to beta-blockers, such as asthma, conduction abnormalities, or a history of stroke. Although nitrates are widely used for treating angina pectoris, the beneficial effect of their use in patients undergoing MVS remains controversial. Therefore, nitrates are not routinely used in the perioperative setting. The current American College of Cardiology/American Heart Association guidelines do not recommend prophylactic coronary revascularization before noncardiac surgery in patients with stable coronary artery disease.