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1.
J Endocrinol Invest ; 46(6): 1187-1195, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36495439

ABSTRACT

PURPOSE: Adult growth hormone deficiency (aGHD) is characterized by an altered metabolic profile and increased cardiovascular risk. Neudesin is a newly discovered protein mainly secreted from adipose tissue and brain, under evaluation for its possible activity as a negative regulator of energy expenditure. Liver-expressed antimicrobial peptide (LEAP)-2 is a competitive antagonist of ghrelin on its receptor. An observational cross-sectional study was performed to test the hypothesis that plasma neudesin levels may be modified in aGHD. Given the role played in the energy balance, any possible relationships between neudesin, LEAP-2 and metabolic and anthropometric parameters were evaluated. SUBJECTS AND METHODS: Thirty-eight patients were included: 18 aGHD patients (7 females and 11 males, aged 59.7 ± 2.6 years, BMI 30.2 ± 2.2 kg/m2); 20 healthy controls (12 females and 8 males, aged 47.1 ± 2.5 years, BMI 24.1 ± 0.9 kg/m2). All patients were evaluated for glucose, insulin, HOMA and QUICKI index, total/LDL/HDL cholesterol, triglycerides, uric acid, and IGF-1. Plasma neudesin, LEAP-2, and ghrelin were measured by ELISA. Fat mass was evaluated by DEXA. RESULTS: Neudesin levels were significantly higher in aGHD versus controls. We confirmed the finding of significantly lower ghrelin levels and significantly higher LEAP-2/ghrelin ratio in aGHD patients and found a significant direct correlation between neudesin and LEAP-2 levels. A significant direct correlation between neudesin and fat mass percentage was found in the whole population. CONCLUSION: These results suggest the onset of adaptive responses to an altered metabolic picture in aGHD. The changes in two distinct pathways that modulate food intake and the still limited knowledge about neudesin suggest future developments in this field.


Subject(s)
Ghrelin , Hepcidins , Male , Female , Adult , Humans , Cross-Sectional Studies , Body Mass Index , Cholesterol, LDL , Growth Hormone
2.
Eur Rev Med Pharmacol Sci ; 25(2): 941-949, 2021 01.
Article in English | MEDLINE | ID: mdl-33577049

ABSTRACT

OBJECTIVE: Kisspeptin, neuropeptide involved in puberty beginning and regulation of pituitary-gonadal axis, has been shown to stimulate antioxidant defenses in murine models. Its levels are greater in females than males and also in obese prepubertal girls. Therefore, our aim was to evaluate sex-related differences in prepubertal obese patients and the relationships of Kisspeptin with metabolic/hormonal parameters. PATIENTS AND METHODS: We studied Kisspeptin concentrations in 54 children (22 males and 32 females, Tanner stage 1), 5-12 ys, classified according to Cole's criteria into 17 overweight and 37 obese; 25 normal-weight children, aged 6-12 years, were studied as controls. We evaluated metabolic (glucose and insulin levels after oral glucose load, total- LDL- HDL-cholesterol, triglycerides, uric acid) and hormonal (fT3, fT4, TSH, IGF-1, leptin) parameters. Moreover, total antioxidant capacity (TAC) was evaluated by spectrophotometric method, using the system H202-metmyoglobin-ABTS. Kisspeptin levels were measured by RIA. RESULTS: We did not find significant differences between obese and normal-weight children, but obese males presented significantly lower levels than females. Kisspeptin did not correlate with BMI, HOMA-IR, Insulin peak levels and TAC; a significant correlation was found between Kisspeptin and fT3 (r2=0.25; p=0.003) in the obese group; leptin levels, significantly greater in obese vs. overweight and control children, significantly correlated with TAC (r2=0.39; p=0.03). CONCLUSIONS: These data suggest that both hormones could modulate antioxidants, Kisspeptin indirectly via influence on thyroid hormones, and Leptin by a direct effect. This mechanism seems to be sex-related, not attributable to peripheral steroid levels. Further studies can clarify the complex interrelationship between central and peripheral Kisspeptin secretion and oxidative stress in children obesity.


Subject(s)
Antioxidants/analysis , Kisspeptins/blood , Pediatric Obesity/blood , Body Mass Index , Case-Control Studies , Child , Child, Preschool , Female , Humans , Insulin Resistance , Leptin/analysis , Male , Sex Characteristics , Spectrophotometry
3.
Eur J Neurol ; 27(10): 2047-2055, 2020 10.
Article in English | MEDLINE | ID: mdl-32418281

ABSTRACT

BACKGROUND AND PURPOSE: The best therapeutic approach for aggressive relapsing-remitting multiple sclerosis remains unknown. The objective was to compare the efficacy and safety of autologous haematopoietic stem cell transplantation (aHSCT) and alemtuzumab in aggressive relapsing-remitting multiple sclerosis. METHODS: The time to first relapse, time to confirmed disability worsening, time to first evidence of magnetic resonance imaging (MRI) activity and time to first evidence of disease activity were compared between the two treatment groups. Secondary outcomes included the 12, 24 and 36 month annualized relapse rate (ARR) and the 6-month confirmed Expanded Disability Status Scale (EDSS) changes at months 12 and 24. RESULTS: Fifty-seven patients treated with aHSCT (n = 25) or alemtuzumab (n = 32) were included. At baseline, aHSCT patients had a higher EDSS (median score 6 vs. 3; P < 0.001), higher ARR (mean ARR 3.2 vs. 1.7; P = 0.001) and a higher number of baseline T1 gadolinium-enhancing lesions on MRI (mean number 15.5 vs. 1.6; P < 0.001). NEDA-3 (no evidence of disease activity) status was more frequently achieved in aHSCT-treated patients than in alemtuzumab-treated patients [75% vs. 56% of patients at the end of the observation period; hazard ratio (HR) 0.27, 95% confidence interval (CI) 0.08-0.84; P = 0.023]. aHSCT significantly reduced the risk of relapse (relapse-free survival 84% vs. 69%; HR 0.13, 95% CI 0.02-0.63; P = 0.012) and MRI activity (MRI-activity-free survival 85% vs. 59%; HR 0.13, 95% CI 0.03-0.59; P = 0.009). The ARR at 36 months was significantly lower in the aHSCT group (0.05 vs. 0.35, P = 0.02). A significant effect of aHSCT in promoting EDSS improvement compared with alemtuzumab was noted (P = 0.035). CONCLUSIONS: Alemtuzumab and aHSCT are effective treatment choices for aggressive multiple sclerosis. aHSCT seems to be superior to alemtuzumab in inducing complete disease control and in promoting short-term disability improvement.


Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Sclerosis, Relapsing-Remitting , Multiple Sclerosis , Alemtuzumab/therapeutic use , Humans , Multiple Sclerosis, Relapsing-Remitting/diagnostic imaging , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Neoplasm Recurrence, Local , Treatment Outcome
4.
Neurosci Lett ; 645: 106-112, 2017 04 03.
Article in English | MEDLINE | ID: mdl-28259657

ABSTRACT

Microglia and macrophages appear to be the most common cells in the GBM microenvironment. In the present study we investigated the status of macrophages/microglia activation in surgical specimens from 41 patients diagnosed with grade IV GBM. For each patient we analyzed both the center of tumor and the parenchyma surrounding the tumor. The specimens were stained for: i) IBA1, a 17-kDa EF hand protein specifically expressed in microglia/macrophages ii) CD163, a cell surface antigen associated with M2 phenotype; iii) iNOS, taken as a functional marker of M1 phenotype, and iv) ARG-I, taken as a functional marker of M2 phenotype. Staining was scored in a double-blinded score on a scale from 0 to 5. Our results suggest that CD163 expression is higher within the tumor than in surrounding periphery in both male and female patients; while iNOS is higher within the tumor in males, no significant difference was found for ARG-1. In addition, analyzing the data in TGCA database, we found that CD163 expression was significantly and inversely correlated with mean survival times, with average survival times ranging from 448days in patients having low expression, to 319 in mid, and 353 in patients with high CD163 expressing tumors. In contrast, no significant association was found between survival time and ARG-1 or iNOS expression.


Subject(s)
Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Arginase/metabolism , Biomarkers, Tumor/metabolism , Brain Neoplasms/metabolism , Glioblastoma/metabolism , Microglia/physiology , Nitric Oxide Synthase Type II/metabolism , Parenchymal Tissue/metabolism , Receptors, Cell Surface/metabolism , Adult , Aged , Brain Neoplasms/pathology , Cell Polarity , Female , Glioblastoma/pathology , Humans , Male , Middle Aged , Parenchymal Tissue/pathology , Survival Analysis
5.
Clin Microbiol Infect ; 23(5): 337.e1-337.e3, 2017 May.
Article in English | MEDLINE | ID: mdl-28057560

ABSTRACT

OBJECTIVES: Faecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection (CDI). Although a single faecal infusion is usually sufficient to eradicate CDI, a considerable number of patients need multiple infusions to be cured. The aim of this study was to identify predictors of failure after single faecal infusion in patients with recurrent CDI. METHODS: We included patients with recurrent CDI prospectively treated with FMT by colonoscopy. By means of univariate and multivariate analysis, variables including female gender, age, number of CDI recurrences, severity of CDI, hospitalization, inadequate bowel preparation, unrelated donor, and use of frozen faeces, were assessed to predict failure after single faecal infusion. RESULTS: Sixty-four patients (39 women; mean age 74 years) were included. Of them, 44 (69%) were cured by a single faecal infusion, whereas 20 (31%) needed repeat infusions. Overall, FMT cured 62 of 64 (97%) patients. In the subgroup of patients with severe CDI, only eight of 26 (30%) were cured with a single infusion. At multivariate analysis, severe CDI (OR 24.66; 95% CI 4.44-242.08; p 0.001) and inadequate bowel preparation (OR 11.53; 95% CI 1.71-115.51; p 0.019) were found to be independent predictors of failure after single faecal infusion. CONCLUSIONS: Severe CDI and inadequate bowel preparation appear to be independent predictors of failure after single faecal infusion in patients treated with FMT by colonoscopy for recurrent CDI. Our results may help to optimize protocols and outcomes of FMT in patients with recurrent CDI.


Subject(s)
Clostridium Infections/therapy , Fecal Microbiota Transplantation , Adult , Aged , Aged, 80 and over , Clostridioides difficile , Cohort Studies , Colonoscopy , Feces/microbiology , Female , Gastrointestinal Microbiome , Humans , Male , Middle Aged , Prospective Studies , Recurrence , Treatment Failure
6.
Eur J Pain ; 16(8): 1148-57, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22392917

ABSTRACT

BACKGROUND: Gamma-aminobutyric acid (GABA) and glutamate (GLU) are involved in nociceptive signals processing in the trigeminal system. In this study, we investigated the influence of excitatory transmission on GABA release in nerve terminals isolated from the rat trigeminal caudal nucleus (TCN). METHODS: We utilize biochemical (superfused synaptosomes loaded with [(3) H]GABA) and morphological (immunofluorescence experiments with specific antibody) techniques. RESULTS: Our results show that GLU potentiates the release of [(3) H]GABA evoked by 9, 15 and 30 mM [K(+)](e); 15 mM [K(+)](e)-evoked [(3) H]GABA release was also reinforced by domoate and kainate (KA), two naturally occurring GLU-receptor agonists. The enhancement of 15 mM [K(+)](e)-evoked [(3) H]GABA release produced by 100 µM KA was abolished by NBQX, a mixed AMPA/KA receptor antagonist, but was not affected by GYKI52466, a selective AMPA receptor antagonist. ATPA, a selective agonist for KA receptors containing the GLUK1 subunit, had no effect on depolarization-induced [(3) H]GABA release, and UBP310, which selectively antagonizes these same receptors, failed to reverse the KA-induced potentiation of 15 mM [K(+)](e)-evoked [(3) H]GABA release. The KA-induced potentiation was also unaffected by concanavalin A (10 µM), a positive allosteric modulator of GLUK1- and GLUK2-containing KA receptors. Immunofluorescence experiments revealed that GABAergic nerve terminals in the TCN differentially expressed GLUK subunits, with GLUK2/3-positive terminals being twice more abundant than GLUK1-containing synaptosomes. CONCLUSIONS: These findings indicate that pre-synaptic KA receptors facilitating GABA release from TCN nerve terminals mainly express GLUK2/GLUK3 subunits, supporting the notion that different types of KA receptors are involved in the various stages of pain transmission.


Subject(s)
Receptors, Kainic Acid/metabolism , Trigeminal Caudal Nucleus/metabolism , gamma-Aminobutyric Acid/metabolism , Animals , Excitatory Amino Acid Agonists/pharmacology , Kainic Acid/analogs & derivatives , Kainic Acid/pharmacology , Male , Neurons/drug effects , Neurons/metabolism , Rats , Rats, Wistar , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Synaptosomes/drug effects , Synaptosomes/metabolism , Trigeminal Caudal Nucleus/drug effects , GluK2 Kainate Receptor , GluK3 Kainate Receptor
7.
Mult Scler ; 18(6): 835-42, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22127896

ABSTRACT

BACKGROUND: Over recent years numerous patients with severe forms of multiple sclerosis (MS) refractory to conventional therapies have been treated with intense immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT). The clinical outcome and the toxicity of AHSCT can be diverse, depending on the various types of conditioning protocols and on the disease phase. OBJECTIVES: To report the Italian experience on all the consecutive patients with MS treated with AHSCT with an intermediate intensity conditioning regimen, named BEAM/ATG, in the period from 1996 to 2008. METHODS: Clinical and magnetic resonance imaging outcomes of 74 patients were collected after a median follow-up period of 48.3 (range = 0.8-126) months. RESULTS: Two patients (2.7%) died from transplant-related causes. After 5 years, 66% of patients remained stable or improved. Among patients with a follow-up longer than 1 year, eight out of 25 subjects with a relapsing-remitting course (31%) had a 6-12 months confirmed Expanded Disability Status Scale improvement > 1 point after AHSCT as compared with one out of 36 (3%) patients with a secondary progressive disease course (p = 0.009). Among the 18 cases with a follow-up longer than 7 years, eight (44%) remained stable or had a sustained improvement while 10 (56%), after an initial period of stabilization or improvement with median duration of 3.5 years, showed a slow disability progression. CONCLUSIONS: This study shows that AHSCT with a BEAM/ATG conditioning regimen has a sustained effect in suppressing disease progression in aggressive MS cases unresponsive to conventional therapies. It can also cause a sustained clinical improvement, especially if treated subjects are still in the relapsing-remitting phase of the disease.


Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Sclerosis, Chronic Progressive/surgery , Multiple Sclerosis, Relapsing-Remitting/surgery , Transplantation Conditioning/methods , Adolescent , Adult , Chi-Square Distribution , Disability Evaluation , Disease Progression , Disease-Free Survival , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/mortality , Humans , Italy , Kaplan-Meier Estimate , Magnetic Resonance Imaging , Middle Aged , Multiple Sclerosis, Chronic Progressive/diagnosis , Multiple Sclerosis, Chronic Progressive/mortality , Multiple Sclerosis, Relapsing-Remitting/diagnosis , Multiple Sclerosis, Relapsing-Remitting/mortality , Predictive Value of Tests , Registries , Severity of Illness Index , Time Factors , Transplantation Conditioning/adverse effects , Transplantation Conditioning/mortality , Transplantation, Autologous , Treatment Outcome , Young Adult
8.
Pharmacol Res ; 64(4): 397-409, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21740972

ABSTRACT

Voltage-dependent type 7 K+ (KV7) channels play important physiological roles in neurons and muscle cells. The aims of the present study were to investigate the motor effects of KV7 channel modulators in the rat gastric fundus and the expression of KV7 channels in this tissue. Muscle tone and electrical field stimulation (EFS)-evoked relaxations of precontracted longitudinal muscle strips of the rat gastric fundus were investigated under nonadrenergic noncholinergic conditions by organ bath studies. Gene expression was studied by real-time PCR and tissue localization of channels was investigated by immunohistochemistry. The KV7 channel blocker XE-991 induced concentration-dependent contractions, with mean pD2 and Emax of 5.4 and 48% of the maximal U46619-induced contraction, respectively. The KV7 channel activators retigabine and flupirtine concentration-dependently relaxed U46619-precontracted strips, with pD2s of 4.7 and 4.4 and Emax of 93% and 91% of the maximal relaxation induced by papaverine, respectively. XE-991 concentration-dependently inhibited retigabine-induced relaxation with a pIC50 of 6.2. XE-991 and DMP-543, another KV7 channel blocker, increased by 13-25% or reduced by 11-21% the relaxations evoked by low- or high-frequency EFS, respectively. XE-991 also reduced the relaxation induced by vasoactive intestinal polypeptide (VIP) by 33% of controls. Transcripts encoded by all KV7 genes were detected in the fundus, with 7.4 and 7.5 showing the highest expression levels. KV7.4 and 7.5 channels were visualized by confocal immunofluorescence in both circular and longitudinal muscle layers. In conclusion, in the rat proximal stomach, KV7 channels appear to contribute to the resting muscle tone and to VIP- and high-frequency EFS-induced relaxation. KV7 channel activators could be useful relaxant agents of the gastric smooth muscle.


Subject(s)
Gastric Fundus/drug effects , KCNQ Potassium Channels/agonists , KCNQ Potassium Channels/antagonists & inhibitors , Muscle Relaxation/drug effects , Muscle Tonus/drug effects , 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology , Animals , Anticonvulsants/pharmacology , Carbamates/pharmacology , Female , Gastric Fundus/metabolism , KCNQ Potassium Channels/metabolism , Male , Phenylenediamines/pharmacology , Rats , Rats, Wistar
10.
Eur Rev Med Pharmacol Sci ; 12 Suppl 1: 53-62, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18924444

ABSTRACT

The proximal third of the stomach (fundus plus oral corpus) relaxes during swallowing so that it can hold large amounts of food with limited increases in intraluminal pressure. This mechanism has been called "receptive relaxation" and is mediated by a vago-vagal reflex. When the food bolus reaches the stomach, gastric relaxation is maintained by another reflex starting from mechanoreceptors in the gastric wall. This second mechanism has been named "adaptive relaxation" or "gastric accommodation" and involves both intramural and vagal reflex pathways, whose inhibitory neurons are always intramural. There was initially a great deal of controversy about the identity of the neurotransmitter/s released by inhibitory neurons, but at present nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) are considered to be the most likely candidates. Several lines of evidence indicate that adenosine triphosphate (ATP) might be implicated too. It seems that these neurotransmitters are co-released from the inhibitory motor neurons and are responsible for the different features of the NANC relaxation induced by low- or high-frequency neuronal firing. NO (and perhaps ATP) would be responsible for the rapid beginning and the initial rapid development of the relaxation evoked by neuronal firing at low- or high-frequency and VIP for the long duration of the relaxation evoked by high-frequency neuronal activation. This review will deal mainly with the physiological characteristics and pharmacological features of the NANC relaxation of the proximal stomach and the evidences favoring or excluding a role as inhibitory neurotransmitters of ATP, NO and VIP in different species.


Subject(s)
Autonomic Nervous System/physiology , Neurotransmitter Agents/physiology , Stomach/innervation , Stomach/physiology , Adenosine Triphosphate/physiology , Animals , Humans , Nitric Oxide/physiology , Vasoactive Intestinal Peptide/physiology
11.
Cephalalgia ; 27(8): 868-76, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17640294

ABSTRACT

In this work we have developed and characterized primary cultures of neonatal rat trigeminal ganglia neurones; calcitonin-gene-related-peptide (CGRP) released from cells was taken as a marker of neuronal function. A significant and consistent increase in CGRP secretion was elicited by non-specific (56 mm KCl or veratridine) or specific (capsaicin) depolarizing stimuli. This paradigm was subsequently used to investigate the effects of nociceptin, an opioid-like peptide involved in central and peripheral control of nociception. We found that the nociceptin analogue nociceptin (1-13)NH2 (NOC) did not affect baseline CGRP release, but it reduced in a concentration-dependent manner CGRP release induced by all tested stimuli. NOC-induced reduction was statistically significant from 0.01 nm onward and achieved maximal effects at 10 nm. Such effects of NOC were seemingly mediated by the activation of specific ORL1 receptors, as a well-known nociceptin antagonist, N(Phe1)nociceptin (1-13)NH2, was able to completely revert NOC inhibition of capsaicin-stimulated CGRP release.


Subject(s)
Calcitonin Gene-Related Peptide/metabolism , Neurons/metabolism , Opioid Peptides/metabolism , Trigeminal Ganglion/metabolism , Analgesics, Non-Narcotic/pharmacology , Animals , Animals, Newborn , Calcitonin Gene-Related Peptide/drug effects , Capsaicin/pharmacology , Cells, Cultured , Immunoassay , Immunohistochemistry , Neurons/drug effects , Opioid Peptides/drug effects , Rats , Rats, Wistar , Receptors, Opioid/metabolism , Trigeminal Ganglion/drug effects , Nociceptin Receptor , Nociceptin
12.
Gene ; 266(1-2): 139-45, 2001 Mar 21.
Article in English | MEDLINE | ID: mdl-11290428

ABSTRACT

Pharmacological and receptor-ligand binding studies of the cloned orphanin FQ (OFQ) receptor suggest that multiple forms of this receptor may exist. To further characterize the OFQ receptor (OFQR), we attempted to isolate the gene encoding this receptor in rat. The OFQR gene exceeds 10 kb in length and contains six exons ranging from 34 to 524 bp that are interrupted by five introns. The ATG translation initiation codon is located in exon 2, and the open reading frame consists of 1283 bp. Primer extension analysis of the gene revealed two major transcription initiation sites: one in the 5' flanking region and the other in intron 1. The rat OFQR gene appeared to be alternatively spliced to yield multiple mRNAs. Four splice variants deleted for exon 1 were expressed only in brain. In contrast, five isoforms containing exon 1 were expressed in various tissues, such as brain, testes, and gastrointestinal tract. These data suggest that unique regions in intron 1 and in the 5' flanking region of the OFQR gene contribute to the regulation of its expression in different tissues.


Subject(s)
Alternative Splicing , Gene Expression Profiling , Receptors, Opioid/genetics , Amino Acid Sequence , Animals , Base Sequence , Cloning, Molecular , DNA/chemistry , DNA/genetics , Female , Molecular Sequence Data , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Sequence Analysis, DNA , Tissue Distribution , Nociceptin Receptor
13.
Neurochem Int ; 38(4): 359-65, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11137631

ABSTRACT

Rat brain hypothalami were exposed to various depolarizing stimuli and vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI) release was measured by means of a radioimmunoassay (RIA) procedure. Under conditions of noradrenergic blockade, exposure to high K(+) (40-100 mM) produced dose-dependent increases in the VIP-LI release in a Ca(2+)-dependent manner. Exposure to veratridine (3-100 microM) also induced concentration-dependent increases in VIP-LI release, an effect that was Ca(2+)-dependent and tetrodotoxin (TTX)-sensitive. Specific ligands for the L, N, and P/Q-type voltage-operated Ca(2+) channels (VOCCs) were used to determine which channel subtypes were involved in the K(+)-evoked VIP-LI release. The L-type VOCC ligand, nifedipine (10 microM), had no effect on release. In contrast, the N-type VOCC blocker, omega-conotoxin GVIA (omega-CgTx GVIA) (0.1-100 nM), markedly reduced the K(+)-evoked response, with maximal inhibition of approximately 60+/-8%. omega-Agatoxin IVA (omega-Aga IVA) (1-50 nM), which binds P-type and, at high doses, also Q-type VOCCs, produced dose-dependent inhibition of up to 25+/-3%, while the maximal inhibition observed with the non-selective VOCCs ligand, omega-conotoxin MVIIC (omega-CmTx MVIIC) (1 nM-3 microM), amounted to 85+/-8%. These findings indicate that N and P-type Ca(2+) channels play predominant roles in the high K(+)-evoked release of VIP-LI from the rat hypothalamus.


Subject(s)
Calcium Channels/metabolism , Hypothalamus/metabolism , Potassium/metabolism , Vasoactive Intestinal Peptide/metabolism , Adrenergic Agents/pharmacology , Animals , Calcium/metabolism , Calcium Channel Blockers/pharmacology , Culture Media, Conditioned/analysis , Culture Media, Conditioned/metabolism , Dose-Response Relationship, Drug , Guanethidine/pharmacology , Hypothalamus/chemistry , Hypothalamus/drug effects , In Vitro Techniques , Ionophores/pharmacology , Male , Potassium/pharmacology , Rats , Rats, Wistar , Stimulation, Chemical , Tetrodotoxin/pharmacology , Veratridine/pharmacology , Yohimbine/pharmacology
14.
Eur J Pharmacol ; 365(1): 59-64, 1999 Jan 15.
Article in English | MEDLINE | ID: mdl-9988124

ABSTRACT

8-Iso-prostaglandin F2alpha, release from isolated and perfused guinea-pig lung was measured by radioimmunoassay. 8-Iso-prostaglandin F2alpha release was detectable under basal conditions and increased 10-fold during antigen-induced bronchoconstriction, concomitant with the increase of thromboxane B2 and prostaglandin E2. The anti-8-iso-prostaglandin F2alpha serum used in the radioimmunoassay seems to be quite specific for this compound. Pretreatment of lungs with indomethacin (a non-selective inhibitor of cyclooxygenase) reduced 8-iso-prostaglandin F2alpha release under basal conditions and completely abolished the increase observed during lung anaphylaxis. Pretreatment of lungs with NS 398 (N-[2-cyclohexyl]-4-nitrophenyl methanesulphonamide), a selective inhibitor of cyclooxygenase-2, did not change basal or antigen-induced 8-iso-prostaglandin F2alpha release at all. We conclude that under basal conditions guinea-pig lung perfusates contain low levels of 8-iso-prostaglandin F2alpha-like immunoreactivity, which increase 10-fold during antigen-induced bronchoconstriction. This isoprostane seems to be derived from the cyclooxygenation of arachidonic acid via the constitutive form of cyclooxygenase.


Subject(s)
Anaphylaxis/physiopathology , Dinoprost/analogs & derivatives , Lung/metabolism , Animals , Bronchoconstriction/drug effects , Cyclooxygenase Inhibitors/pharmacology , Dinoprost/analysis , Dinoprost/metabolism , Dinoprostone/metabolism , F2-Isoprostanes , Guinea Pigs , In Vitro Techniques , Indomethacin/pharmacology , Lung/drug effects , Male , Nitrobenzenes/pharmacology , Ovalbumin/pharmacology , Sulfonamides/pharmacology , Thromboxane B2/metabolism
15.
Gen Pharmacol ; 31(5): 697-703, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9809465

ABSTRACT

1. Receptive and adaptive relaxations of the proximal third of the stomach are reflex responses that enable the stomach to accommodate large volumes with minimal increases in intraluminal pressure. The smooth muscle relaxations are termed non-adrenergic non-cholinergic (NANC). 2. Nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) are considered to be the principal neurotransmitters of NANC relaxation of the rat stomach. NO appears to be mainly responsible for the speed of the relaxation and VIP appears to be responsible for the duration. 3. Studies indicate that inhibitory neurons may also release other neurotransmitters, such as adenosine triphosphate (ATP) and peptide histidine isoleucine (PHI). 4. NANC relaxation of the rat stomach is a complex phenomenon that appears to involve many neurotransmitters, each with a specific role.


Subject(s)
Muscle, Smooth/physiology , Neurotransmitter Agents/metabolism , Stomach/physiology , Adenosine Triphosphate/physiology , Animals , Electric Stimulation , Gastric Mucosa/metabolism , In Vitro Techniques , Muscle Relaxation/physiology , Muscle, Smooth/innervation , Muscle, Smooth/metabolism , Neurons/metabolism , Nitric Oxide/physiology , Rats , Reflex/physiology , Stomach/innervation , Vasoactive Intestinal Peptide/physiology
17.
Ann Thorac Surg ; 64(5): 1354-9, 1997 Nov.
Article in English | MEDLINE | ID: mdl-9386704

ABSTRACT

BACKGROUND: The technique of intermittent antegrade warm blood cardioplegia (IAWBC) exposes the heart to brief periods of normothermic ischemia. This may impair endothelial function in coronary arteries. METHODS: Three cardioplegic technique were tested in porcine hearts arrested for 32 to 36 minutes and reperfused for 30 minutes: IAWBC, antegrade cold blood cardioplegia (ACBC), and antegrade cold crystalloid cardioplegia (ACCC). In the hearts arrested with IAWBC, three different intervals of ischemia were used: three 10-minute intervals (IAWBC1), two 15-minute intervals (IAWBC2), and one 30-minute interval (IAWBC3). Rings from the coronary arteries were used to evaluate in vitro the contractile responses to U46619 and the relaxant responses to bradykinin, A23187, and sodium nitroprusside. RESULTS: All six groups (treatment groups and control group) displayed similar responses to U46619 (30 nmol/L) and nitroprusside. In the IAWBC1, IAWBC2, AND ACBC groups, endothelium-dependent relaxations to bradykinin and A23187 were preserved compared with controls, whereas those of the ACCC and IAWBC3 groups were significantly impaired (bradykinin: control, 8.72 +/- 0.07; IAWBC1, 8.73 +/- 0.03; IAWBC2, 8.65 +/- 0.05; IAWBC3, 8.30 +/- 0.07 [p < 0.05]; ACBC, 8.50 +/- 0.03; ACCC, 8.25 +/- 0.09 [p < 0.05]; A23187: control, 7.07 +/- 0.08; IAWBC1, 7.07 +/- 0.06; IAWBC2, 7.04 +/- 0.03; IAWBC3, 6.64 +/- 0.01 [p < 0.05]; ACBC, 6.80 +/- 0.05; ACCC, 6.60 +/- 0.08 [p < 0.05]; nitroprusside: control, 6.19 +/- 0.1; IAWBC1, 6.19 +/- 0.07; IAWBC2, 6.03 +/- 0.03; IAWBC3, 6.08 +/- 0.05; ACBC, 6.04 +/- 0.2; ACCC, 6.05 +/- 0.03; all values are expressed as the negative logarithm of the concentration producing 50% of the maximal response). CONCLUSIONS: Myocardial preservation with IAWBC with ischemic intervals of 15 minutes or shorter does not alter the endothelium-dependent relaxation to bradykinin or A23187 in porcine coronary arteries, but these responses are significantly impaired by ACCC and IAWBC with an ischemic interval of 30 minutes.


Subject(s)
Coronary Vessels/physiology , Endothelium, Vascular/physiology , Heart Arrest, Induced/methods , Vasodilation/physiology , 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology , Animals , Blood , Bradykinin/pharmacology , Calcimycin/pharmacology , Cardioplegic Solutions , Crystalloid Solutions , Female , In Vitro Techniques , Isotonic Solutions , Nitroprusside/pharmacology , Plasma Substitutes , Swine , Temperature , Time Factors , Vasoconstrictor Agents/pharmacology , Vasodilation/drug effects , Vasodilator Agents/pharmacology
18.
Br J Pharmacol ; 121(6): 1105-12, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9249245

ABSTRACT

1. Nicotine-induced relaxation and release of vasoactive intestinal polypeptide (VIP)- and peptide histidine isoleucine (PHI)-like immunoreactivity (LI) were measured in longitudinal muscle strips from the rat gastric fundus. 2. Under non-cholinergic conditions (0.3 microM atropine), nicotine (3-300 microM) produced concentration-dependent relaxations of the 5-hydroxytryptamine (3 microM)-precontracted strips. Under non-adrenergic non-cholinergic (NANC) conditions (0.3 microM atropine + 1 microM phentolamine + 1 microM nadolol), relaxations induced by sub-maximal nicotine concentrations (10 and 30 microM) were significantly smaller, while that produced by the highest concentration used (300 microM) was similar to that seen under non-cholinergic conditions. 3. Re-exposure to the same nicotine concentration 1 h later induced smaller relaxations, indicating desensitization. The reductions seen in the second responses were proportional to the concentration used. 4. Under non-cholinergic conditions, the relaxant response to 30 microM nicotine was abolished by hexamethonium (100 microM) and significantly reduced by tetrodotoxin (TTX, 3 microM). The TTX-resistant component was not observed under NANC conditions. 5. NANC relaxation induced by 30 microM nicotine was significantly reduced by a specific anti-VIP serum (approximately 35% less than that seen with normal rabbit serum). 6. Nicotine (30-300 microM) caused significant, concentration-dependent increases in the outflow of VIP- and PHI-LI from the strips; these effects were also diminished with re-exposure. The increases in both types of immunoreactivity evoked by nicotine (300 microM) were abolished by hexamethonium (300 microM), TTX (3 microM) and a calcium-free medium. 7. These findings indicate that VIP and possibly PHI are involved in NANC relaxation of the rat gastric fundus induced by nicotine.


Subject(s)
Gastric Fundus/drug effects , Nicotine/pharmacology , Vasoactive Intestinal Peptide/physiology , Animals , Culture Media , Female , Gastric Fundus/physiology , Immune Sera , In Vitro Techniques , Male , Muscle Relaxation/drug effects , Neutralization Tests , Peptide PHI/physiology , Rats , Rats, Wistar , Reproducibility of Results , Vasoactive Intestinal Peptide/immunology
19.
Eur J Pharmacol ; 313(1-2): R1-3, 1996 Oct 10.
Article in English | MEDLINE | ID: mdl-8905345

ABSTRACT

Two tachykinin NK2 receptor antagonists, MEN 10.627 c(Met-Asp-Trp-Phe-Dap-Leu) and MEN 10.376 [(Tyr5,Trp6,8,9,Lys10]neurokinin A-(4-10), were used to investigate the role of tachykinins in in vitro guinea-pig lung anaphylaxis. Both antagonists dose-dependently decreased bronchoconstriction and the release of thromboxane and prostaglandin E2 induced by antigen challenge in perfused sensitized lungs, but neither had any effect on the basal release of either eicosanoid. The findings indicated that tachykinins released by sensory nerve fibers may contribute to anaphylactic reactions by increasing arachidonic acid metabolite release.


Subject(s)
Dinoprostone/metabolism , Lung/metabolism , Neurokinin A/analogs & derivatives , Peptide Fragments/pharmacology , Peptides, Cyclic/pharmacology , Thromboxane B2/metabolism , Anaphylaxis/metabolism , Animals , Bronchoconstriction , Dinoprostone/biosynthesis , Dinoprostone/physiology , Dose-Response Relationship, Drug , Guinea Pigs , In Vitro Techniques , Lung/drug effects , Muscle, Smooth/physiology , Neurokinin A/pharmacology , Receptors, Tachykinin/physiology , Thromboxane B2/biosynthesis , Thromboxane B2/physiology
20.
Br J Pharmacol ; 117(4): 717-23, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8646419

ABSTRACT

1. In the presence of atropine (1 microM) and guanethidine (5 microM), electrical field stimulation (EFS, 120 mA, 1 ms, 0.5-16.0 Hz, trains of 2 min) induced frequency-dependent relaxations of 5-hydroxytryptamine (3 microM)-precontracted longitudinal muscle strips from the rat gastric fundus. 2. L-Citrulline concentrations were measured in the incubation medium of precontracted strips before and after EFS to investigate nitric-oxide (NO) synthase activity and its possible relation to non-adrenergic non-cholinergic (NANC) relaxation. 3. Basal NO synthase activity was reflected by the finding of prestimulation levels of L-citrulline of approximately 30 nM. These levels were unaffected by tetrodotoxin (3 microM) and NG-nitro-D-arginine methyl ester (D-NAME, 100 microM), slightly reduced by a calcium-free medium and halved by NG-nitro-L-arginine methyl ester (L-NAME, 100 microM). 4. EFS evoked significant, frequency-dependent increases in bath levels of L-citrulline at all frequencies tested. The increases evoked by 16-Hz EFS were abolished by tetrodotoxin (3 microM), a calcium-free medium and L-NAME (100 microM) but not by D-NAME (100 microM). 5. L-NAME (0.1 microM-1.0 mM) produced significant reduction of 4-Hz EFS-induced L-citrulline production (100% inhibition at 10 microM), but had less marked effects on basal production (approximately 50% reduction at 100 microM) and 4-Hz EFS-induced NANC relaxation (approximately 50% reduction at 1 mM). 6. L-Arginine (1 mM), but not D-arginine (1 mM), increased basal L-citrulline levels and reversed the inhibitory effect of L-NAME (10 microM). 7. These findings represent clear biochemical evidence of both basal and EFS-stimulated NO synthase activity in the rat gastric fundus.


Subject(s)
Gastric Fundus/drug effects , Nitric Oxide Synthase/metabolism , Animals , Arginine/analogs & derivatives , Arginine/pharmacology , Atropine/pharmacology , Citrulline/metabolism , Dose-Response Relationship, Drug , Electric Stimulation , Female , Gastric Fundus/enzymology , Gastric Fundus/physiology , Guanethidine/pharmacology , In Vitro Techniques , Isotonic Solutions/pharmacology , Male , NG-Nitroarginine Methyl Ester , Nitric Oxide Synthase/antagonists & inhibitors , Rats , Rats, Wistar , Serotonin/pharmacology , Tetrodotoxin/pharmacology
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