Utilidad de copeptina en el diagnóstico de síndrome coronario agudo en el departamento de urgencias de un hospital de tercer nivel / Usefulness of copeptin in the diagnosis of acute coronary syndrome in the emergency department of a tertiary hospital

Objetivos: Valorar la utilidad de copeptina (fragmento estable del precursor de vasopresina-arginina) en el diagnóstico diferencial del dolor torácico agudo de posible origen coronario. Material y métodos: Se han incluido en el estudio 82 pacientes que fueron evaluados inicialmente de acuerdo con el protocolo de pacientes con sospecha de síndrome coronario agudo (SCA) de nuestro Servicio de Urgencias, incluyendo la determinación de troponina y copeptina con seriación en admisión y a las 6 h. Resultados: Obtuvimos diferencias estadísticamente significativas en la concentración de copeptina a tiempo 0 entre los pacientes diagnosticados de SCASEST: 42,1±38,7pmol/L y los pacientes no SCASEST: 15,6±21,2pmol/L (p<0,01). Sin embargo, las diferencias no alcanzaron a ser estadísticamente significativas a las 6 h (p=0,093). El análisis del área bajo la curva ROC para la copeptina en los pacientes SCASEST a tiempo 0 fue de 0,713 con un intervalo de confianza del 95% de 0,592 a 0,834 y un grado de significación de p=0,001. Conclusiones: La concentración de copeptina representa un valor adicional en la diferenciación entre pacientes SCASEST y pacientes no SCASEST, así como entre pacientes SCA y pacientes con angina estable. El punto de corte de 10pmol/L proporciona los mejores valores de sensibilidad, valor predictivo negativo (VPN), cociente de probabilidad positivo (CPP) y cociente de probabilidad negativo (CPN) en el diagnóstico de pacientes SCASEST

Objectives: This study was conducted in order to evaluate the usefulness of copeptin (a stable fragment of the precursor of arginine vasopressin) in the differential diagnosis of acute chest pain of probable coronary origin. Material and methods: The study includes 82 patients who were initially evaluated according to the protocol of a patient with suspected acute coronary syndrome (ACS) in our Emergency Department, including the determination of troponin and copeptin with specimens taken on admission (time 0) and at 6h. Results: Statistically significant differences were observed in copeptin concentrations at time 0 among patients diagnosed with non-ST-segment elevation (NTEACS): 42.1±38.7pmol/L and non-NSTEACS patients: 15.6±21.2pmol/L (P<. 01). However, the differences did not reach statistical significance at 6h (P=.093). The analysis of the area under the ROC curve for Copeptin in NSTEACS patients at time 0 was 0.713, with a confidence interval of 95% from 0.592 to 0.834 and a significance level of P=.001. Conclusions: The concentration of copeptin represents an additional value in the differentiation between NSTEACS patients and non-NSTEACS patients, as well as between ACS patients and patients with stable angina. The cut-off point of 10pmol/L provides the best values for sensitivity, negative predictive value (NPV), positive likelihood ratio (LR+), and negative likelihood ratio (LR-) in the diagnosis of NSTEACS patients

Oestradiol effects on neuroendocrine responses induced by water deprivation in rats.

Water deprivation (WD) induces changes in plasma volume and osmolality, which in turn activate several responses, including thirst, the activation of the renin-angiotensin system (RAS) and vasopressin (AVP) and oxytocin (OT) secretion. These systems seem to be influenced by oestradiol, as evidenced by the expression of its receptor in brain areas that control fluid balance. Thus, we investigated the effects of oestradiol treatment on behavioural and neuroendocrine changes of ovariectomized rats in response to WD. We observed that in response to WD, oestradiol treatment attenuated water intake, plasma osmolality and haematocrit but did not change urinary volume or osmolality. Moreover, oestradiol potentiated WD-induced AVP secretion, but did not alter the plasma OT or angiotensin II (Ang II) concentrations. Immunohistochemical data showed that oestradiol potentiated vasopressinergic neuronal activation in the lateral magnocellular PVN (PaLM) and supraoptic (SON) nuclei but did not induce further changes in Fos expression in the median preoptic nucleus (MnPO) or subfornical organ (SFO) or in oxytocinergic neuronal activation in the SON and PVN of WD rats. Regarding mRNA expression, oestradiol increased OT mRNA expression in the SON and PVN under basal conditions and after WD, but did not induce additional changes in the mRNA expression for AVP in the SON or PVN. It also did not affect the mRNA expression of RAS components in the PVN. In conclusion, our results show that oestradiol acts mainly on the vasopressinergic system in response to WD, potentiating vasopressinergic neuronal activation and AVP secretion without altering AVP mRNA expression.

Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics.

We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V(1a), V(1b) and V(2) receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V(1b) receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V(1a) agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V(2) /V(1a) antagonist, conivaptan and the V(2) antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V(1a), V(1b) and V(2) antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences.

Vasopressin and oxytocin excite MCH neurons, but not other lateral hypothalamic GABA neurons.

Neurons that synthesize melanin-concentrating hormone (MCH) colocalize GABA, regulate energy homeostasis, modulate water intake, and influence anxiety, stress, and social interaction. Similarly, vasopressin and oxytocin can influence the same behaviors and states, suggesting that these neuropeptides may exert part of their effect by modulating MCH neurons. Using whole cell recording in MCH-green fluorescent protein (GFP) transgenic mouse hypothalamic brain slices, we found that both vasopressin and oxytocin evoked a substantial excitatory effect. Both peptides reversibly increased spike frequency and depolarized the membrane potential in a concentration-dependent and tetrodotoxin-resistant manner, indicating a direct effect. Substitution of lithium for extracellular sodium, Na(+)/Ca(2+) exchanger blockers KB-R7943 and SN-6, and intracellular calcium chelator BAPTA, all substantially reduced the vasopressin-mediated depolarization, suggesting activation of the Na(+)/Ca(2+) exchanger. Vasopressin reduced input resistance, and the vasopressin-mediated depolarization was attenuated by SKF-96265, suggesting a second mechanism based on opening nonselective cation channels. Neither vasopressin nor oxytocin showed substantial excitatory actions on lateral hypothalamic inhibitory neurons identified in a glutamate decarboxylase 67 (GAD67)-GFP mouse. The primary vasopressin receptor was vasopressin receptor 1a (V1aR), as suggested by the excitation by V1aR agonist [Arg(8)]vasotocin, the selective V1aR agonist [Phe(2)]OVT and by the presence of V1aR mRNA in MCH cells, but not in other nearby GABA cells, as detected with single-cell RT-PCR. Oxytocin receptor mRNA was also detected in MCH neurons. Together, these data suggest that vasopressin or oxytocin exert a minimal effect on most GABA neurons in the lateral hypothalamus but exert a robust excitatory effect on presumptive GABA cells that contain MCH. Thus, some of the central actions of vasopressin and oxytocin may be mediated through MCH cells.

A patient with essential hypernatremia had good response to desmopressin acetate therapy.

OBJECTIVES: Essential hypernatremia is very rare in clinical practice and the pathogenesis is unclear. We performed a set of clinical tests to a patient with chronic and sustained hypernatremia as well as absence of thirst in order to investigate the clinical characteristics and make the diagnosis, yet most importantly to analyze the possible pathogenesis and explore a possible therapy regime. METHODS: Water deprivation test and acute water intravenous loading test were performed to observe the changes of urinary osmolality, plasma osmolality and plasma sodium. Free water clearance (C(H2O) was calculated. Osmolality was detected using the method of freezing point depression, and thirst grade using visual analogue scales. Desmopressin acetate (0.05-0.1 mg/d) was administered to the patient in order to observe the therapeutic effects to his disorder. RESULTS: The patient had sustained hypernatremia over a long period of time, decreased thirst, normal renal function, as well as absence of clinical hypovoluemia. The plasma sodium was 160-190 mmol/L and plasma osmolality was 330-370 mOsm/L without any thirst perception which could not be corrected by water intake. An 18-hour period of water deprivation increased the urinary osmolality from 368 mOsm/L to 420 mOsm/L with plasma osmolality increasing from 362 mOsm/L to 369 mOsm/L and rising further to 857 mOsm/L after an injection of 5 u vasopresin. With the infusion of 1 250 ml 5%-glucose during 2 hours in an acute water loading test setting, plasma osmolality decreased from 350 mOsm/L to 334 mOsm/L associated with a plasma sodium decrease from 164.7 mmol/L to 155 mmol/L urinary osmolality dropped from a maximum of 632 mOsm/L to 135 mOsm/L urinary volume from 0.25 ml/min to 2.33 ml/min and C(H2O) from -0.18 ml/min to 1.19 ml/min after acute water loading with 1 250 ml glucose dissolved in water. Our results reveal that treatment of the patient with Desmopressin acetate relieved the adypsia, hypernatremia and hyperosmolality effectively. CONCLUSIONS: The patient was considered as suffering from essential hypernatremia which was associated with partial central diabetes insipidus and adypsia. Desmopressin acetate as a common therapeutic agent of central diabetes insipidus proved to be an effective treatment for essential hypernatremia.

Arginine vasopressin gene expression changes within the nucleus accumbens during environment elicited cocaine-conditioned response in rats.

It is known that changes in gene expression within the nucleus accumbens (NAc) occur during cocaine dependence development. However, identification of specific genes involved in cocaine conditioning awaits further investigation. We conducted a high throughput gene expression profile analysis of the NAc, during different stages of the environment-elicited cocaine conditioning. Rats were assigned to two different environmental conditions. Cocaine conditioned group received a cocaine injection (10mg/kg, i.p.) prior to being placed in the activity chambers. Control rats received saline injections before being exposed to their environment. Both groups received a saline injection in their home cage. Conditioning training lasted for 10 days. Animals were then re-exposed to their previously paired environments only on day 12 (test session). We found that the gene for arginine vasopressin (AVP) was differentially expressed on experimental subjects during all stages of environment-elicited cocaine conditioning. To further validate our molecular results, biochemical and immunolocalization experiments were conducted. We found the presence of AVP within accumbal fibers and changes in AVP protein levels following cocaine conditioning. Moreover, we tested the effects of accumbal microinfusions of either AVP receptor V(1A) agonist [pGlu(4), Cyt6, Arg(8)] AVP 4-9 1.0 ng/0.5 microl, or V(1A) antagonist (CH2) 5[Tyr (Me) 2] AVP, 1.0 ng/0.5 microl or vehicle solution (0.9% saline solution) during different stages of the cocaine conditioning. Blockade of V(1A) receptors within the NAc during acquisition interrupted the expression of the conditioned response, while activation leads to an increase in this response. Our findings propose a new role for AVP in cocaine addiction.

Tricyclic structures in medicinal chemistry: an overview of their recent uses in non-CNS pathologies.

Tricyclic compounds are sometimes considered as synonima of drugs healing central nervous system pathologies, although there are some well known examples of tricyclic derivatives marketed for different indications, such as antihistamines, antivirals and antiulceratives. Following the insertion of tricyclic structures in the "privileged structures" pool, several compounds bearing a central 7-membered ring and two aryl rings at its sides have been reported, and some of them have been progressed to advanced clinical trials. An overview of tricyclic derivatives reported in the literature since 1995, that are investigated for indications not directly related to central nervous system affections, shows the potential of these structures in a broad range of therapeutical indications, going from antiviral and anticancer compounds to the therapy of cardiovascular diseases. Very recent examples confirm the usefulness of tricyclic structures for the modern medicinal chemists.

Analogues of arginine vasopressin and its agonist and antagonist modified in the N-terminal part of the molecule with l-beta-homophenylalanine.

In continuation of our efforts to elucidate the role of positions 2 and 3 in arginine vasopressin (AVP) and its analogues, we designed and synthesized peptides modified in these positions with l-beta-homophenylalanine (beta-Hph). Two of them had just this single modification, the next two peptides are analogues of the V2 agonist, namely [3-mercaptopropionic acid (Mpa)1]AVP (dAVP). The last two compounds were designed by substitution of positions 2 or 3 of a potent V(1a) antagonist, [1-mercaptocyclohexaneacetic acid (Cpa)1]AVP, with beta-Hph. All the peptides were tested for their pressor and antidiuretic and uterotonic in vitro activities in the rat. All the activities tested have been found to be significantly decreased. Three analogues, i.e. [Mpa(1),beta-Hph2]AVP, [Cpa1,beta-Hph2]AVP, [Cpa1,beta-Hph3]AVP, turned out to be uterotonic antagonists with pA2 = 6.3 +/- 0.2, 6.3 +/- 0.1, 6.0 +/- 0.3 respectively. The last one exhibited antipressor properties also (pA2 = 6.4 +/- 0.1).

[The potentiation of adjuvant arthritis in rats by vasopressin and its V2 agonist]. / Potentsirovanie ad''iuvantnogo artrita u krys vazopressinom i ego V2-agonistom.

Experiments on C57B1/6 mice and Wistar rats have demonstrated that neuropeptide vasopressin inhibits activity of antigen-specific suppressors and potentiates development of adjuvant arthritis. Vasopressin involvement in pathogenesis of autoimmunity is discussed.

Arginine vasopressin inhibits nitric oxide synthesis in cytokine-stimulated vascular smooth muscle cells.

The purpose of this study was to investigate the effects of arginine vasopressin (AVP) on nitric oxide (NO) synthesis in vascular smooth muscle cells (VSMCs). We measured the production of nitrite, a stable metabolite of NO, and the expression of inducible NO synthase (iNOS) mRNA in cultured rat VSMCs. Incubation of VSMCs for 24 h with interleukin-1 beta (IL-1 beta) caused a significant increase in NO production. Both AVP and the V1a receptor agonist [Phe2, Ile3, Orn8]vasopressin inhibited NO synthesis in IL-1 beta-stimulated cells, but not in unstimulated cells, in a dose-dependent manner. The V1a receptor antagonist [d(CH2)5(1), O-Me-Tyr2, Arg8]vasopressin completely inhibited the effect of AVP. Incubation with IL-1 beta for 24 h induced the expression of iNOS mRNA in VSMCs, while AVP suppressed its expression. After functional depletion of protein kinase C activity by treating cells with phorbol 12-myristate 13-acetate for 24 h, AVP did not inhibit IL-1 beta-induced NO production. The effect of AVP was also inhibited in the presence of the protein kinase C inhibitor calphostin C in a dose-dependent manner. These results indicate that AVP inhibits IL-1 beta-induced iNOS expression in VSMCs through the V1a receptor, which is mediated at least partially via activation of protein kinase C.

Vasopressin receptor subtypes differentially modulate calcium-activated potassium currents in the horizontal limb of the diagonal band of Broca.

The actions of vasopressin on acutely dissociated neurons within the rat horizontal limb of the diagonal band of Broca were examined using the whole-cell patch-clamp technique. Vasopressin elicited two distinct responses in 45 of 62 neurons. In one group of cells, 300 nM vasopressin decreased voltage-activated outward currents (26/45 cells) whereas in a second group, vasopressin increased outward currents (19/45 cells). The vasopressin-mediated decrease in outward currents was blocked by 1 microM Manning compound, a V1 receptor antagonist, suggesting that this response was mediated via V1 receptors. In contrast, the vasopressin-induced increase in outward current was blocked by 1 microM d(CH2)5)1,D-Ile2,Ile4,Arg8,Ala9, a V2 receptor antagonist, indicating that V2 receptor activation underlies this second response. When cells were perfused with 0 Ca2+/50 microM Cd2+, application of vasopressin did not cause any change in voltage-activated outward currents, suggesting that vasopressin modulates a calcium-dependent conductance. In the presence of 25 nM charybdotoxin, an Ic channel antagonist, vasopressin application did not influence outward currents, indicating that vasopressin modulates Ic. Currents through voltage-gated calcium channels which are responsible for activation of Ic were unaffected by vasopressin, suggesting a direct effect of vasopressin on Ic channels. These observations indicate a differential modulation of Ic channels by vasopressin via V1 and V2 receptors in the horizontal limb of the diagonal band of Broca. Our data also demonstrate the ionic mechanisms whereby vasopressin may act at V1 for V2 receptors to influence the excitability of the horizontal limb of the diagonal band of Broca neurons.

Noradrenaline activates vasopressin neurons via alpha1-receptor-mediated Ca2+ signaling pathway.

Noradrenaline (NA) (1-10 microM), dibutyryl-cAMP (1-5 mM), and forskolin (10-20 microM) increased cytosolic Ca2+ concentration ([Ca2+]i) in isolated arginine-vasopressin (AVP)-containing neurons in the hypothalamic supraoptic nucleus (SON). The NA-induced increase in [Ca2+]i in AVP-containing neurons was abolished by a specific alpha1-antagonist, prazosin (1 microM) and was markedly reduced when treated with a protein kinase A (PKA) blocker, H89 (40 microM). The NA-induced [Ca2+]i was not altered by a protein kinase C (PKC) inhibitor, calphostin C (0.1 microM) and a PKC activator, TPA (100 nM). In general, NA, a known neurotransmitter in the SON, activates AVP-containing neurons via alpha1-receptor which is linked to stimulation of cAMP-PKA-regulated Ca2+ signaling pathway.

NLPR, an agonist of AVP4-8, increases NGF gene expression in memory-impaired rat brain.

Oral administration of the tetrapeptide Asn-Leu-Pro-Arg (NLPR) to memory-impaired rats results in improved acquisition and maintenance of behavioural response and also facilitates nerve growth factor (NGF) expression in the brain. It is suggested that NLPR can ameliorate memory disability by promoting NGF gene expression, so implying that NLPR is a potential drug candidate for curing memory impairment.