Publications by authors named "María Pilar Martinez"

45 Publications

Differential contribution of renal cytochrome P450 enzymes to kidney endothelial dysfunction and vascular oxidative stress in obesity.

Biochem Pharmacol 2021 Nov 22;195:114850. Epub 2021 Nov 22.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain. Electronic address:

Arachidonic acid (AA)-derived cytochrome P450 (CYP) derivatives, epoxyeicosatrienoic acids (EETs) and 20-hidroxyeicosatetranoic acid (20-HETE), play a key role in kidney tubular and vascular functions and blood pressure. Altered metabolism of CYP epoxygenases and CYP hydroxylases has differentially been involved in the pathogenesis of metabolic disease-associated vascular complications, although the mechanisms responsible for the vascular injury are unclear. The present study aimed to assess whether obesity-induced changes in CYP enzymes may contribute to oxidative stress and endothelial dysfunction in kidney preglomerular arteries. Endothelial function and reactive oxygen species (ROS) production were assessed in interlobar arteries of obese Zucker rats (OZR) and their lean counterparts lean Zucker rats (LZR) and the effects of CYP2C and CYP4A inhibitors sulfaphenazole and HET0016, respectively, were examined on the endothelium-dependent relaxations and O and HO levels of preglomerular arteries. Non-nitric oxide (NO) non-prostanoid endothelium-derived hyperpolarization (EDH)-type responses were preserved but resistant to the CYP epoxygenase blocker sulfaphenazole in OZR in contrast to those in LZR. Sulfaphenazole did not further inhibit reduced arterial HO levels, and CYP2C11/CYP2C23 enzymes were downregulated in intrarenal arteries from OZR. Renal EDH-mediated relaxations were preserved in obese rats by the enhanced activity and expression of endothelial calcium-activated potassium channels (K). CYP4A blockade restored impaired NO-mediated dilatation and inhibited augmented O production in kidney arteries from OZR. The current data demonstrate that both decreased endothelial CYP2C11/ CYP2C23-derived vasodilator HO and augmented CYP4A-derived 20-HETE contribute to endothelial dysfunction and vascular oxidative stress in obesity. CYP4A inhibitors ameliorate arterial oxidative stress and restore endothelial function which suggests its therapeutic potential for the vascular complications of obesity-associated kidney injury.
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http://dx.doi.org/10.1016/j.bcp.2021.114850DOI Listing
November 2021

Altered production of reproductive neuropeptides in rats subjected to chronic intermittent hypoxia.

J Integr Neurosci 2021 Sep;20(3):651-657

Cátedra de Fisiología, Facultad de Odontología, Universidad de Buenos Aires, 1122 Buenos Aires, Argentina.

Hypobaric hypoxia is a stressful condition known to decrease fertility both in humans and animals. However, the mechanism by which the hypothalamus-pituitary-gonad axis is altered remains unknown. The aim of the present study was to analyze the effects of chronic intermittent and continuous exposure to hypoxia on hypothalamic-pituitary-gonadal axis regulation in male rats. Thirty adult male Wistar rats were assigned to one of the following three groups: control group; chronic intermittent hypoxia: subjected to 600 mbar for 18 h/d five days a week; and chronic continuous hypoxia: subjected to 600 mbar for 23.5 hours/day seven days a week, for 30 days. Plasma luteinizing hormone and testosterone concentration, hypothalamic , and mRNA levels and PGE content were determined. Levels of , a negative regulator of GnRH and LH release, were higher in intermittently exposed animals than in controls. Levels of Kiss1, a neuropeptide that stimulates the release of GnRH only increased in animals exposed to continuous hypoxia. Plasma luteinizing hormone and testosterone concentrations and body weight were lower in rats subjected to intermittent hypoxia as compared to the remaining groups. mRNA levels as well as PGE content remained unchanged in all groups. Taken together, results suggest that besides the well documented direct effects of hypoxia on the testes, infertility observed in male rats exposed to hypoxia may also be due to overexpression of negative regulators of GnRH and luteinizing hormone release. Intermittent, rather than continuous, to hypoxia exposure would seem to be more detrimental to fertility.
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http://dx.doi.org/10.31083/j.jin2003069DOI Listing
September 2021

Mandibular biomechanical behavior of rats submitted to chronic intermittent or continuous hypoxia and periodontitis.

Sleep Breath 2021 Mar 6;25(1):519-527. Epub 2020 Aug 6.

Cátedra de Fisiología, Facultad de Odontología, Universidad de Buenos Aires, M.T. de Alvear 2142, 3rd floor "A", Buenos Aires, Argentina.

Background: The aim of this study was to investigate the effects of exposure to continuous (CH) and intermittent (IH) hypoxia on biomechanical properties of the mandible and periodontal tissue of animals submitted to experimental periodontitis (EP) when applying loads in a hypoxic environment.

Methods: Adult female Wistar rats were exposed during 90 days to IH or CH (simulated high altitude of 4200 m above sea level). Fourteen days prior to the euthanasia, EP was induced to half of the animals of each group.

Results: Only in the rats with EP, IH decreased the maximum capacity of the mandible to withstand load and the limit of elastic load. Indicators of intrinsic properties of the bone material were significantly reduced by both types of hypoxia in rats with EP. Hypoxia enhanced the alveolar bone loss induced by EP in the buccal side of the mandible, without showing additional effects in lingual or interradicular bone. Hypoxia increased prostaglandin E content in gingival tissue of healthy animals and further elevated the E levels increased by EP.

Conclusions: When periodontitis is present, hypoxic stress induces a decrease in mineral properties that ultimately affects the ability of the mandible to resist load, mainly during intermittent exposure to hypoxia. These effects on bone may be related to the higher levels of prostaglandin E reached in the surrounding gingival tissue. The findings of this study may stimulate strategies to prevent unwanted effects of hypoxia on periodontal tissues.
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http://dx.doi.org/10.1007/s11325-020-02158-2DOI Listing
March 2021

Treatment of Frail Older Adults and Elderly Patients With Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia: Results of a Prospective Trial With Minimal Chemotherapy.

Clin Lymphoma Myeloma Leuk 2020 08 5;20(8):e513-e522. Epub 2020 Apr 5.

Hematology Department, Hospital Madrid Norte Sanchinarro, Madrid, Spain.

Background: The treatment of acute lymphoblastic leukemia (ALL) in older adults and elderly patients is a challenge, and modern protocols include targeted therapy and immunotherapy in combination with attenuated or minimal chemotherapy. However, frail patients are excluded from these trials, and reports on the outcome of this subgroup of patients are scarce. Our objective was to analyze the outcome of unfit older adults and elderly patients with Philadelphia chromosome-negative ALL included in a prospective trial (ALL-07FRAIL).

Patients And Methods: Older adults and elderly patients with Charlson Comorbidity Index (CCI) ≥ 4 were included. Induction therapy consisted of vincristine and dexamethasone, and maintenance therapy with mercaptopurine and methotrexate for 2 years.

Results: Seventy-two patients with a median age of 67 years (range, 57-89 years) and a median CCI of 5 (range, 4-12) were included. The rates of early withdrawal, early death, resistance, and complete response (CR) were 5%, 10%, 31%, and 54%, respectively. Six patients with CR abandoned the study, 5 died in CR, and 23 relapsed (cumulative relapse incidence 75%). The medians of disease-free and overall survival (OS) were 6.9 months (95% confidence interval [CI], 0.3-13.5 months) and 7.6 months (95% CI, 6.3-8.9 months), respectively. The most frequent toxic events were hematologic (neutropenia 77% and thrombocytopenia 54%, of grade III-IV in all cases). Eastern Cooperative Oncology Group score but not the CCI had significant impact on OS.

Conclusion: Complete remission with very attenuated chemotherapy can be attained in one-half of older or elderly infirm patients with ALL. These results suggest that some of these patients could benefit from the concomitant or subsequent use of immunotherapy and/or targeted therapy.
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http://dx.doi.org/10.1016/j.clml.2020.03.011DOI Listing
August 2020

Sleep quality and clinical and psychological manifestations in women with mild systemic lupus erythematosus activity compared to women with fibromyalgia: A preliminary study.

Mod Rheumatol 2020 Nov 14;30(6):1016-1024. Epub 2019 Nov 14.

Department of Nursing, Health Science Faculty, University of Granada, Granada, Spain.

This study analyzed sleep quality in fibromyalgia (FM) and systemic lupus erythematosus (SLE) and explored its relationship with other clinical and psychological manifestations. Twenty women with FM, 19 women with SLE and 22 healthy women participated in the study. Subjective sleep quality, fatigue, pain, depression and anxiety were evaluated with self-reports, and objective sleep measures were obtained with actigraphy. Comparisons were analyzed with Chi-square, Kruskal-Wallis's and Mann-Whitney's tests. Relationships between measurements were analyzed with Spearman's correlation coefficients. Subjective sleep quality was altered in the FM and SLE groups compared to the control group (15.53 ± 3.27, 8.47 ± 3.20, 4.91 ± 2.79,  < .05, respectively). FM and SLE patients reported higher levels of pain (22.65 ± 9.87, 10.21 ± 9.93, 2.30 ± 3.096,  < .05), fatigue (4.67 ± 0.37, 3.59 ± 3.04, 2.33 ± 0.59,  < .05) and depressive symptoms (9.90 ± 3.78, 4.53 ± 3.04, 4.17 ± 3.95,  < .05) than controls, respectively. Worse subjective quality of sleep was associated with higher pain intensity and more depressive symptoms in FM and SLE. Actigraphy measures showed that FM patients spent more time in bed than subjects in the remaining groups. Sleep deterioration is related to more pain and depressive symptoms in FM and SLE. Addressing sleep disturbances may improve not only sleep quality but also depressive symptoms and pain.
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http://dx.doi.org/10.1080/14397595.2019.1679973DOI Listing
November 2020

Differential contribution of Nox1, Nox2 and Nox4 to kidney vascular oxidative stress and endothelial dysfunction in obesity.

Redox Biol 2020 01 20;28:101330. Epub 2019 Sep 20.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain. Electronic address:

Oxidative stress-associated endothelial dysfunction is a key pathogenic factor underlying the microvascular complications of metabolic disease. NADPH oxidase (Nox) is a major source of oxidative stress in diabetic nephropathy and chronic kidney disease, despite Nox4 and Nox2 have been identified as relevant sources of vasodilator endothelial HO.The present study was sought to investigate the role of Nox enzymes in renal vascular oxidative stress and endothelial dysfunction in a rat model of genetic obesity. Endothelial function was assessed in intrarenal arteries of obese Zucker rats (OZR) and their counterparts lean Zucker rats (LZR) mounted in microvascular myographs, and superoxide (O) and HO production were measured. Impaired endothelium-dependent relaxations to acetylcholine (ACh) were associated to augmented O generation, but neither ROS scavengers nor the Nox inhibitor apocynin significantly improved these relaxant responses in renal arteries of OZR. Whereas NO contribution to endothelial relaxations was blunted, catalase-sensitive non-NO non-prostanoid relaxations were enhanced in obese rats. Interestingly, NADPH-dependent O production was augmented while NADPH-dependent HO generation was reduced, and cytosolic and mitochondrial SOD were up-regulated in kidney of obese rats. Nox4 was down-regulated in renal arteries and Nox4-dependent HO generation and endothelial relaxation were reduced in OZR. Up-regulation of both Nox2 and Nox1 was associated with augmented O production but reduced HO generation and blunted endothelial Nox2-derived HO-mediated in obese rats. Moreover, increased Nox1-derived O contributed to renal endothelial dysfunction in OZR. In summary, the current data support a main role for Nox1-derived O in kidney vascular oxidative stress and renal endothelial dysfunction in obesity, while reduced endothelial Nox4 expression associated to decreased HO generation and HO-mediated vasodilatation might hinder Nox4 protective renal effects thus contributing to kidney injury. This suggests that effective therapies to counteract oxidative stress and prevent microvascular complications must identify the specific Nox subunits involved in metabolic disease.
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http://dx.doi.org/10.1016/j.redox.2019.101330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812001PMC
January 2020

Bladder Dysfunction in an Obese Zucker Rat: The Role of TRPA1 Channels, Oxidative Stress, and Hydrogen Sulfide.

Oxid Med Cell Longev 2019 20;2019:5641645. Epub 2019 Aug 20.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.

Purpose: This study investigates whether functionality and/or expression changes of transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) channels, oxidative stress, and hydrogen sulfide (HS) are involved in the bladder dysfunction from an insulin-resistant obese Zucker rat (OZR).

Materials And Methods: Detrusor smooth muscle (DSM) samples from the OZR and their respective controls, a lean Zucker rat (LZR), were processed for immunohistochemistry for studying the expression of TRPA1 and TRPV1 and the HS synthase cystathionine beta-synthase (CBS) and cysthathionine--lyase (CSE). Isometric force recordings to assess the effects of TRPA1 agonists and antagonists on DSM contractility and measurement of oxidative stress and HS production were also performed.

Results: Neuronal TRPA1 expression was increased in the OZR bladder. Electrical field stimulation- (EFS-) elicited contraction was reduced in the OZR bladder. In both LZR and OZR, TRPA1 activation failed to modify DSM basal tension but enhanced EFS contraction; this response is inhibited by the TRPA1 blockade. In the OZR bladder, reactive oxygen species, malondialdehyde, and protein carbonyl contents were increased and antioxidant enzyme activities (superoxide dismutase, catalase, GR, and GPx) were diminished. CSE expression and CSE-generated HS production were also reduced in the OZR. Both TRPV1 and CBS expressions were not changed in the OZR.

Conclusions: These results suggest that an increased expression and functionality of TRPA1, an augmented oxidative stress, and a downregulation of the CSE/HS pathway are involved in the impairment of nerve-evoked DSM contraction from the OZR.
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http://dx.doi.org/10.1155/2019/5641645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721245PMC
February 2020

The Process of Acclimation to Chronic Hypoxia Leads to Submandibular Gland and Periodontal Alterations: An Insight on the Role of Inflammatory Mediators.

Mediators Inflamm 2018 9;2018:6794508. Epub 2018 Dec 9.

Cátedra de Fisiología, Facultad de Odontología, Universidad de Buenos Aires, Buenos Aires 1122, Argentina.

The exposition to hypoxia is a stressful stimulus, and the organism develops acclimation mechanisms to ensure homeostasis, but if this fails, it leads to the development of pathological processes. Considering the large number of people under hypoxic conditions, it is of utmost importance to study the mechanisms implicated in hypoxic acclimation in oral tissues and the possible alteration of some important inflammatory markers that regulate salivary and periodontal function. It is the aim of the present study to analyze submandibular (SMG) and periodontal status of animals chronically exposed to continuous (CCH) or intermittent (CIH) hypoxia in order to elucidate the underlying molecular mechanisms that may lead to hypoxic acclimation. Adult Wistar rats were exposed to CCH or CIH simulating 4200 meters of altitude during 90 days. Salivary secretion was decreased in animals exposed to hypoxia, being lower in CIH, together with increased prostaglandin E (PGE) content, TBARS concentration, and the presence of apoptotic nuclei and irregular secretion granules in SMG. AQP-5 mRNA levels decreased in both hypoxic groups. Only the CCH group showed higher HIF-1 staining, while CIH alone exhibited interradicular bone loss and increased concentration of the bone resorption marker CTX-I. In summary, animals exposed to CIH show a worse salivary secretion rate, which related with higher levels of PGE, suggesting a negative role of this inflammatory mediator during hypoxia acclimation. We link the weak immunorreactivity of HIF-1 in CIH with improper hypoxia acclimation, which is necessary to sustaining SMG physiology under this environmental condition. The alveolar bone loss observed in CIH rats could be due mainly to a direct effect of PGE, as suggested by its higher content in gingival tissue, but also to the indirect effect of hyposalivation. This study may eventually contribute to finding therapeutics to treat the decreased salivary flow, improving in that way oral health.
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http://dx.doi.org/10.1155/2018/6794508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304881PMC
April 2019

Hydrogen peroxide derived from NADPH oxidase 4- and 2 contributes to the endothelium-dependent vasodilatation of intrarenal arteries.

Redox Biol 2018 10 7;19:92-104. Epub 2018 Aug 7.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain. Electronic address:

The role of NADPH oxidase (Nox)-derived reactive oxygen species in kidney vascular function has extensively been investigated in the harmful context of oxidative stress in diabetes and obesity-associated kidney disease. Since hydrogen peroxide (HO) has recently been involved in the non-nitric oxide (NO) non-prostanoid relaxations of intrarenal arteries, the present study was sought to investigate whether NADPH oxidases may be functional sources of vasodilator HO in the kidney and to assess their role in the endothelium-dependent relaxations of human and rat intrarenal arteries. Renal interlobar arteries isolated from the kidney of renal tumor patients who underwent nephrectomy, and from the kidney of Wistar rats, were mounted in microvascular myographs to assess function. Superoxide (O) and HO production was measured by chemiluminescence and Amplex Red fluorescence, and Nox2 and Nox4 enzymes were detected by Western blotting and by double inmunolabeling along with eNOS. Nox2 and Nox4 proteins were expressed in the endothelium of renal arterioles and glomeruli co-localized with eNOS, levels of expression of both enzymes being higher in the cortex than in isolated arteries. Pharmacological inhibition of Nox with apocynin and of CYP 2C epoxygenases with sulfaphenazol, but not of the NO synthase (NOS), reduced renal NADPH-stimulated O and HO production. Under conditions of cyclooxygenase and NOS blockade, acetylcholine induced endothelium-dependent relaxations that were blunted by the non-selective Nox inhibitor apocynin and by the Nox2 or the Nox1/4 inhibitors gp91ds-tat and GKT136901, respectively. Acetylcholine stimulated HO production that was reduced by gp91ds-tat and by GKT136901. These results suggest the specific involvement of Nox4 and Nox2 subunits as physiologically relevant endothelial sources of HO generation that contribute to the endothelium-dependent vasodilatation of renal arteries and therefore have a protective role in kidney vasculature.
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http://dx.doi.org/10.1016/j.redox.2018.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105769PMC
October 2018

Comparison of intensive, pediatric-inspired therapy with non-intensive therapy in older adults aged 55-65 years with Philadelphia chromosome-negative acute lymphoblastic leukemia.

Leuk Res 2018 05 19;68:79-84. Epub 2018 Mar 19.

ICO Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute (IJC), Universitat Autònoma de Barcelona, Badalona, Spain.

Background And Objective: The standardization of treatment of older adults with Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) is challenging, especially in the age range of 55-65 years. This study aimed to compare intensive, pediatric-inspired therapy with non-intensive therapy in this population of patients.

Patients And Methods: The outcomes of 67 patients prospectively included in two consecutive pediatric-inspired intensive protocols (ALL-HR03 and ALL-HR11) from the Spanish PETHEMA Group were compared with those from 44 patients included in a contemporary semi-intensive protocol (ALL-OLD07).

Results: Baseline patient and ALL characteristics were similar in both groups, except for a younger median age in the intensive group (medians: 58 vs. 62 years). Patients treated intensively had a higher complete remission rate (85% vs. 64%, p = 0.005), a lower cumulative incidence of relapse (39% [95%CI, 25% to 52%] vs. 60% [95%CI, 38% to 77%], p = .003), a similar cumulative incidence of treatment-related mortality (28% [95% CI, 18%, 40%] vs. 21% [95% CI, 10%, 34%]) and superior event-free survival at 2 years (37% [95%CI, 25%-49%) vs. 21% [8%-34%], p = 0.002). On multivariable analysis the type of protocol was the only variable with independent significance for event-free survival (HR [95% CI]: 2 [1.3, 3], p = .002).

Conclusions: Compared with less intensive chemotherapy, pediatric-inspired intensive chemotherapy significantly improves the outcome of older adults with Ph-negative ALL in the age range of 55-65 years.
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http://dx.doi.org/10.1016/j.leukres.2018.03.010DOI Listing
May 2018

Phosphodiesterase type 4 inhibition enhances nitric oxide- and hydrogen sulfide-mediated bladder neck inhibitory neurotransmission.

Sci Rep 2018 03 16;8(1):4711. Epub 2018 Mar 16.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040, Madrid, Spain.

Nitric oxide (NO) and hydrogen sulfide (HS) play a pivotal role in nerve-mediated relaxation of the bladder outflow region. In the bladder neck, a marked phosphodiesterase type 4 (PDE4) expression has also been described and PDE4 inhibitors, as rolipram, produce smooth muscle relaxation. This study investigates the role of PDE4 isoenzyme in bladder neck gaseous inhibitory neurotransmission. We used Western blot and double immunohistochemical staining for the detection of NPP4 (PDE4) and PDE4A and organ baths for isometric force recording to roflumilast and tadalafil, PDE4 and PDE5, respectively, inhibitors in pig and human samples. Endogenous HS production measurement and electrical field stimulation (EFS) were also performed. A rich PDE4 and PDE4A expression was observed mainly limited to nerve fibers of the smooth muscle layer of both species. Moreover, roflumilast produced a much more potent smooth muscle relaxation than that induced by tadalafil. In porcine samples, HS generation was diminished by HS and NO synthase inhibition and augmented by roflumilast. Relaxations elicited by EFS were potentiated by roflumilast. These results suggest that PDE4, mainly PDE4A, is mostly located within nerve fibers of the pig and human bladder neck, where roflumilast produces a powerful smooth muscle relaxation. In pig, the fact that roflumilast increases endogenous HS production and EFS-induced relaxations suggests a modulation of PDE4 on NO- and HS-mediated inhibitory neurotransmission.
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http://dx.doi.org/10.1038/s41598-018-22934-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856743PMC
March 2018

Real life experience with frontline azacitidine in a large series of older adults with acute myeloid leukemia stratified by MRC/LRF score: results from the expanded international E-ALMA series (E-ALMA+).

Leuk Lymphoma 2018 05 24;59(5):1113-1120. Epub 2017 Aug 24.

h Department of Hematology , University Hospital , León , Spain.

Azacitidine (AZA) prolonged overall survival (OS) in the AZA-AML-001 trial. However, few subjects were randomized to AZA or intensive chemotherapy (IC). The Medical Research Council (MRC) and the Leukemia Research Foundation (LRF) developed a score for older AML patients receiving IC or non-intensive regimens, whereas the E-ALMA study validated a score for survival and response in elderly patients receiving AZA in daily practice. Both identified three groups with different risk estimates. This analysis evaluates the efficacy of frontline AZA in older AML patients (N = 710) unfit for IC from different national registries (E-ALMA + series) stratified by the MRC/LRF risk score. Median OS of patients categorized as good, standard and poor-risk groups by the MRC/LRF score was 13.4 (95% CI, 10.8-16), 12.4 (95% CI, 9.9-14.8), and 8.1 months (95% CI, 7-9.1), respectively (p = .0001). In conclusion, this is the largest retrospective cohort of older AML patients treated with AZA.
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http://dx.doi.org/10.1080/10428194.2017.1365854DOI Listing
May 2018

Clinical characteristics of patients with central nervous system relapse in BCR-ABL1-positive acute lymphoblastic leukemia: the importance of characterizing ABL1 mutations in cerebrospinal fluid.

Ann Hematol 2017 Jul 27;96(7):1069-1075. Epub 2017 Apr 27.

Instituto de Investigación Hospital 12 de Octubre (i+12), Servicio de Hematología, Hematología Traslacional, Hospital Universitario 12 de Octubre, Avda de Andalucía s/n, 28041, Madrid, Spain.

We investigated the frequency, predictors, and evolution of acute lymphoblastic leukemia (ALL) in patients with CNS relapse and introduced a novel method for studying BCR-ABL1 protein variants in cDNA from bone marrow (BM) and cerebrospinal fluid (CSF) blast cells. A total of 128 patients were analyzed in two PETHEMA clinical trials. All achieved complete remission after imatinib treatment. Of these, 30 (23%) experienced a relapse after achieving complete remission, and 13 (10%) had an isolated CNS relapse or combined CNS and BM relapses. We compared the characteristics of patients with and without CNS relapse and further analyzed CSF and BM samples from two of the 13 patients with CNS relapse. In both patients, classical sequencing analysis of the kinase domain of BCR-ABL1 from the cDNA of CSF blasts revealed the pathogenic variant p.L387M. We also performed ultra-deep next-generation sequencing (NGS) in three samples from one of the relapsed patients. We did not find the mutation in the BM sample, but we did find it in CSF blasts with 45% of reads at the time of relapse. These data demonstrate the feasibility of detecting BCR-ABL1 mutations in CSF blasts by NGS and highlight the importance of monitoring clonal evolution over time.
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http://dx.doi.org/10.1007/s00277-017-3002-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486784PMC
July 2017

CYP epoxygenase-derived HO is involved in the endothelium-derived hyperpolarization (EDH) and relaxation of intrarenal arteries.

Free Radic Biol Med 2017 05 14;106:168-183. Epub 2017 Feb 14.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid, Spain. Electronic address:

Reactive oxygen species (ROS) like hydrogen peroxide (HO) are involved in the in endothelium-derived hyperpolarization (EDH)-type relaxant responses of coronary and mesenteric arterioles. The role of ROS in kidney vascular function has mainly been investigated in the context of harmful ROS generation associated to kidney disease. The present study was sought to investigate whether HO is involved in the endothelium-dependent relaxations of intrarenal arteries as well the possible endothelial sources of ROS generation involved in these responses. Under conditions of cyclooxygenase (COX) and nitric oxide (NO) synthase inhibition, acetylcholine (ACh) induced relaxations and stimulated HO release that were reduced by catalase and by the glutathione peroxidase (GPx) mimetic ebselen in rat renal interlobar arteries, suggesting the involvement of HO in the endothelium-dependent responses. ACh relaxations were also blunted by the CYP2C inhibitor sulfaphenazole and by the NADPH oxidase inhibitor apocynin. Acetylcholine stimulated both superoxide (O) and HO production that were reduced by sulfaphenazole and apocynin. Expression of the antioxidant enzyme CuZnSOD and of the HO reducing enzymes catalase and GPx-1 was found in both intrarenal arteries and renal cortex. On the other hand, exogenous HO relaxed renal arteries by decreasing vascular smooth muscle (VSM) intracellular calcium concentration [Ca] and markedly enhanced endothelial K currents in freshly isolated renal endothelial cells. CYP2C11 and CYP2C23 epoxygenases were highly expressed in interlobar renal arteries and renal cortex, respectively, and were co-localized with eNOS in renal endothelial cells. These results demonstrate that HO is involved in the EDH-type relaxant responses of renal arteries and that CYP 2C epoxygenases are physiologically relevant endothelial sources of vasodilator HO in the kidney.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.02.031DOI Listing
May 2017

Effects of chronic lead exposure on bone mineral properties in femurs of growing rats.

Toxicology 2017 02 30;377:64-72. Epub 2016 Nov 30.

Universidad de Buenos Aires, Facultad de Odontología, Cátedra de Fisiología, Buenos Aires, Argentina.

Lead exposure has been associated with several defective skeletal growth processes and bone mineral alterations. The aim of the present study is to make a more detailed description of the toxic effects of lead intoxication on bone intrinsic material properties as mineral composition, morphology and microstructural characteristics. For this purpose, Wistar rats were exposed (n=12) to 1000ppm lead acetate in drinking water for 90days while control group (n=8) were treated with sodium acetate. Femurs were examined using inductively coupled plasma optical emission spectrometry (ICP-OES), Attenuated Total Reflection Fourier transform infrared spectroscopy (ATR-FTIR), X-ray diffraction (XRD), and micro-Computed Tomography (μCT). Results showed that femur from the lead-exposed rats had higher carbonate content in bone mineral and (Ca+Mg+ Na)/P ratio values, although no variations were observed in crystal maturity and crystallite size. From morphological analyses, lead exposure rats showed a decreased in trabecular bone surface and distribution while trabecular thickness and cortical area increased. These overall effects indicate a similar mechanism of bone maturation normally associated to age-related processes. These responses are correlated with the adverse actions induced by lead on the processes regulating bone turnover mechanism. This information may explain the osteoporosis diseases associated to lead intoxication as well as the risk of fracture observed in populations exposed to this toxicant.
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http://dx.doi.org/10.1016/j.tox.2016.11.017DOI Listing
February 2017

Deleterious effect of chronic continuous hypoxia on oral health.

Arch Oral Biol 2016 Dec 5;72:1-7. Epub 2016 Aug 5.

Department of Physiology, Faculty of Dentistry, University of Buenos Aires, Argentina. Electronic address:

Objective: To evaluate the effect of chronic continuous hypoxia (CCH) in alveolar bone and its correlation with the inflammatory markers which play a key role in the development of periodontitis.

Material And Methods: Wistar rats were exposed to CCH (600mbar, 3 months). Macroscopic and histological analyses of alveolar bone were performed, together with measurement of oxidative stress and inflammatory parameters in gums and submandibular glands (SMG).

Results: HCC induced cortical alveolar bone loss, decreased interradicular bone volume and increased the periodontal ligament height compared to control rats (p<0.05). CCH enhanced iNOS activity in gums (from 2735,04±662,96 nmol/min/mg proteins to 4289,58±915,63 p<0.05) and in SMG (from 56,71±12,05 nmol/min/mg proteins to 90,15±21,78 p<0.05). PGE did not change in gums or in SMG by means of CCH, while TNFα decreased in gums (p<0.05). Regarding oxidative stress, thiobarbituric acid reactive species concentration in CCH animals was higher both in gums as in SMG, and catalase activity was decreased in SMG.

Conclusion: Higher iNOS activity both in gums and SMG under CCH could be associated with the alveolar bone loss observed. The increase in oxidative stress occurring in SMG and gums, together with a lower antioxidant capacity might indicate a deleterious effect of HX in oral health.
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http://dx.doi.org/10.1016/j.archoralbio.2016.08.006DOI Listing
December 2016

Augmented oxidative stress and preserved vasoconstriction induced by hydrogen peroxide in coronary arteries in obesity: role of COX-2.

Br J Pharmacol 2016 11 7;173(22):3176-3195. Epub 2016 Oct 7.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.

Background And Purpose: Oxidative stress plays a key role in the vascular and metabolic abnormalities associated with obesity. Herein, we assessed whether obesity can increase coronary vasoconstriction induced by hydrogen peroxide (H O ) and the signalling pathways involving COX-2 and superoxide (O ) generation.

Experimental Approach: Contractile responses to H O and O generation were measured in coronary arteries from genetically obese Zucker rats (OZR) and compared to lean Zucker rats (LZR).

Key Results: Both basal and H O -stimulated O production were enhanced in coronary arteries from OZR, but H O -induced vasoconstriction was unchanged. The selective COX-2 inhibitor NS398 significantly reduced H O -induced contractions in endothelium-denuded arteries from LZR and OZR, but only in endothelium-intact arteries from LZR. PGI (IP) receptor antagonism modestly reduced the vasoconstrictor action of H O while antagonism of the PGE receptor 4 (EP ) enhanced H O contractions in arteries from OZR but not LZR. Basal release of COX-2-derived PGE was higher in coronary arteries from OZR where the selective agonist of EP receptors TCS 2519 evoked potent relaxations. COX-2 was up-regulated after acute exposure to H O in coronary endothelium and vascular smooth muscle (VSM) and inhibition of COX-2 markedly reduced H O -elicited O generation in coronary arteries and myocardium. Expression of Nox subunits in VSM and NADPH-stimulated O generation was enhanced and contributed to H O vasoconstriction in arteries from obese rats.

Conclusion And Implications: COX-2 contributes to cardiac oxidative stress and to the endothelium-independent O -mediated coronary vasoconstriction induced by H O in obesity, which is offset by the release of COX-2-derived endothelial PGE acting on EP vasodilator receptors.
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http://dx.doi.org/10.1111/bph.13579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071563PMC
November 2016

Role of endogenous hydrogen sulfide in nerve-evoked relaxation of pig terminal bronchioles.

Pulm Pharmacol Ther 2016 12 4;41:1-10. Epub 2016 Sep 4.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain. Electronic address:

Hydrogen sulfide (HS) is a gasotransmitter employed for intra- and inter-cellular communication in almost all organ systems. This study investigates the role of endogenous HS in nerve-evoked relaxation of pig terminal bronchioles with 260 μm medium internal lumen diameter. High expression of the HS synthesis enzyme cystathionine γ-lyase (CSE) in the bronchiolar muscle layer and strong CSE-immunoreactivity within nerve fibers distributed along smooth muscle bundles were observed. Further, endogenous HS generated in bronchiolar membranes was reduced by CSE inhibition. In contrast, cystathionine β-synthase expression, another HS synthesis enzyme, however was not consistently detected in the bronchiolar smooth muscle layer. Electrical field stimulation (EFS) and the HS donor P-(4-methoxyphenyl)-P-4-morpholinylphosphinodithioic acid (GYY4137) evoked smooth muscle relaxation. Inhibition of CSE, nitric oxide (NO) synthase, soluble guanylyl cyclase (sGC) and of ATP-dependent K, transient receptor potential A1 (TRPA) and transient receptor potential vanilloid 1 (TRPV) channels reduced the EFS relaxation but failed to modify the GYY4137 response. Raising extracellular K concentration inhibited the GYY4137 relaxation. Large conductance Ca-activated K channel blockade reduced both EFS and GYY4137 responses. GYY4137 inhibited the contractions induced by histamine and reduced to a lesser extent the histamine-induced increases in intracellular [Ca]. These results suggest that relaxation induced by EFS in the pig terminal bronchioles partly involves the HS/CSE pathway. HS response is produced via NO/sGC-independent mechanisms involving K channels and intracellular Ca desensitization-dependent pathways. Thus, based on our current results HS donors might be useful as bronchodilator agents for the treatment of lung diseases with persistent airflow limitation, such as asthma and chronic obstructive lung disease.
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http://dx.doi.org/10.1016/j.pupt.2016.09.003DOI Listing
December 2016

Impaired Excitatory Neurotransmission in the Urinary Bladder from the Obese Zucker Rat: Role of Cannabinoid Receptors.

PLoS One 2016 10;11(6):e0157424. Epub 2016 Jun 10.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040-Madrid.

Metabolic syndrome (MS) is a known risk factor for lower urinary tract symptoms. This study investigates whether functional and expression changes of cannabinoid CB1 and CB2 receptors are involved in the bladder dysfunction in an obese rat model with insulin resistance. Bladder samples from obese Zucker rat (OZR) and their respective controls lean Zucker rat (LZR) were processed for immunohistochemistry and western blot for studying the cannabinoid receptors expression. Detrusor smooth muscle (DSM) strips from LZR and OZR were also mounted in myographs for isometric force recordings. Neuronal and smooth muscle CB1 and CB2 receptor expression and the nerve fiber density was diminished in the OZR bladder. Electrical field stimulation (EFS) and acetylcholine (ACh) induced frequency- and concentration-dependent contractions of LZR and OZR DSM. ACh contractile responses were similar in LZR and OZR. EFS-elicited contractions, however, were reduced in OZR bladder. Cannabinoid receptor agonists and antagonists failed to modify the DSM basal tension in LZR and OZR In LZR bladder, EFS responses were inhibited by ACEA and SER-601, CB1 and CB2 receptor agonists, respectively, these effects being reversed by ACEA plus the CB1 antagonist, AM-251 or SER-601 plus the CB2 antagonist, AM-630. In OZR bladder, the inhibitory action of ACEA on nerve-evoked contractions was diminished, whereas that SER-601 did not change EFS responses. These results suggest that a diminished function and expression of neuronal cannabinoid CB1 and CB2 receptors, as well as a lower nerve fiber density is involved in the impaired excitatory neurotransmission of the urinary bladder from the OZR.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157424PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902197PMC
July 2017

Mature solid tubal teratoma producing β-HCG simulating a ruptured tubal ectopic pregnancy.

Eur J Obstet Gynecol Reprod Biol 2016 Mar 2;198:165-166. Epub 2015 Dec 2.

Department of Histopathology, Hospital de A Coruña, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain.

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http://dx.doi.org/10.1016/j.ejogrb.2015.11.006DOI Listing
March 2016

Feasibility and results of subtype-oriented protocols in older adults and fit elderly patients with acute lymphoblastic leukemia: Results of three prospective parallel trials from the PETHEMA group.

Leuk Res 2016 Feb 2;41:12-20. Epub 2015 Dec 2.

Hematology Department of Institut Català d'Oncologia-Hospital Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Universitat Autònoma de Barcelona, Spain.

Background And Objective: The prognosis of acute lymphoblastic leukemia (ALL) is poor in older adults and elderly patients, and subtype-oriented prospective trials are scarce in these patients. We present the results of three prospective parallel subtype-oriented protocols in fit patients older than 55 years.

Patients And Methods: In 2008, three prospective phase II trials in patients older than 55 years were activated: ALLOLD07 for Philadephia (Ph) chromosome-negative ALL, ALLOPH07 for Ph-positive ALL, and BURKIMAB08 for mature B-ALL. Early death (ED), complete remission (CR), disease-free survival (DFS), overall survival (OS) and toxicity were analyzed.

Results: 56, 53 and 21 patients from the ALLOLD07, ALLOPH07 and BURKIMAB08 trials, respectively, were evaluable. CR was 74%, 87% and 70%, with an ED rate of 13%, 11% and 15%, respectively. The medians of DFS were 8 and 38 months for ALLOLD07 and ALLOPH07 protocols, not being achieved in the BURKIMAB08 trial (p=0.001), and the median OS was 12, 37 and 25 months, respectively (p=0.030). Neutropenia, thrombocytopenia and infections were less frequent in the ALLOPH07 trial vs. ALLOLD07 and BURKIMAB trials, and renal toxicity and mucositis were more frequent in the BURKIMAB08 trial vs. the ALLOLD07 and ALLOPH07 trials. ECOG score and WBC count had prognostic significance for OS in ALLOPH07 and BURKIMAB08 trials, whereas no prognostic factors were identified in ALLOLD07 protocol.

Conclusion: Subtype-oriented treatment had an impact in the outcome of older adults with ALL. The poorest outcome was observed in Ph-negative non-Mature B-cell ALL patients, for whom improvements in therapy are clearly needed.
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http://dx.doi.org/10.1016/j.leukres.2015.11.012DOI Listing
February 2016

Chronic lead poisoning magnifies bone detrimental effects in an ovariectomized rat model of postmenopausal osteoporosis.

Exp Toxicol Pathol 2016 Jan 28;68(1):47-53. Epub 2015 Sep 28.

Department of Physiology, Faculty of Dentistry, University of Buenos Aires, Argentina. Electronic address:

Lead (Pb) is a persistent environmental contaminant that is mainly stored in bones being an important source of endogenous lead exposure during periods of increased bone resorption as occurs in menopause. As no evidence exists of which bone biomechanical properties are impaired in those elderly women who had been exposed to Pb during their lifetime, the aim of the present study is to discern whether chronic lead poisoning magnifies the deterioration of bone biology that occurs in later stages of life. We investigated the effect of Pb in the femora of ovariectomized (OVX) female Wistar rats who had been intoxicated with 1000 ppm of Pb acetate in drinking water for 8 months. Structural properties were determined using a three-point bending mechanical test, and geometrical and material properties were evaluated after obtaining the load/deformation curve. Areal Bone Mineral Density (BMD) was estimated using a bone densitometer. Femoral histomorphometry was carried out on slices dyed with H&E (Hematoxylin and Eosin). Pb and OVX decreased all structural properties with a higher effect when both treatments were applied together. Medullar and cortical area of femurs under OVX increased, allowing the bone to accommodate its architecture, which was not observed under Pb intoxication. Pb and OVX significantly decreased BMD, showing lead treated ovariectomized rats (PbOVX) animals the lowest BMD levels. Trabecular bone volume per total volume (BV/TV%) was decreased in OVX and PbOVX animals in 54% compared to the control animals (p<0.001). Pb femurs also showed 28% less trabeculae than the control (p<0.05). We demonstrated that Pb intoxication magnifies the impairment in bone biomechanics of OVX rats with a consequent enhancement of the risk of fracture. These results enable the discussion of the detrimental effects of lead intoxication in bone biology in elderly women.
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http://dx.doi.org/10.1016/j.etp.2015.09.007DOI Listing
January 2016

Incidence, clinical and biological characteristics and outcome of secondary acute lymphoblastic leukemia after solid organ or hematologic malignancy.

Leuk Lymphoma 2016 12;57(1):86-91. Epub 2015 May 12.

b Hematology Department of Institut Català d'Oncologia-Hospital Germans Trias i Pujol . Jose Carreras Research Institute , Badalona , Universitat Autònoma de Barcelona, Spain.

Acute lymphoblastic leukemia (ALL) following solid organ or hematologic malignancy (secondary ALL, s-ALL) is not well characterized. We analyzed the characteristics and outcome of patients with s-ALL and compared them with those of patients with de novo- ALL. Of 448 patients, 24 (5%) had previous neoplasia. Sixteen patients had received previous cytotoxic therapy (therapy-associated ALL, t-ALL), and eight had not (antecedent-malignancy ALL, am-ALL). Except for more advanced age in patients with s-ALL, no statistically significant differences were observed in WBC count, CNS involvement, immunophenotype or cytogenetics between the groups, nor in complete remission (t-ALL: 94%; am-ALL: 75%; de novo-ALL: 85%), 3-year remission duration (58%; 50%; 72%), overall survival (71%; 38%; 60%) or event-free survival (53%, 38%; 53%). Our study did not show poor clinical or cytogenetic features or inferior outcome in ALL patients with antecedent neoplastic disease, irrespective of the type of treatment received for the neoplasia.
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http://dx.doi.org/10.3109/10428194.2015.1040013DOI Listing
October 2016

COX-2 is involved in vascular oxidative stress and endothelial dysfunction of renal interlobar arteries from obese Zucker rats.

Free Radic Biol Med 2015 Jul 1;84:77-90. Epub 2015 Apr 1.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid 28040, Spain. Electronic address:

Obesity is related to vascular dysfunction through inflammation and oxidative stress and it has been identified as a risk factor for chronic renal disease. In the present study, we assessed the specific relationships among reactive oxygen species (ROS), cyclooxygenase 2 (COX-2), and endothelial dysfunction in renal interlobar arteries from a genetic model of obesity/insulin resistance, the obese Zucker rats (OZR). Relaxations to acetylcholine (ACh) were significantly reduced in renal arteries from OZR compared to their counterpart, the lean Zucker rat (LZR), suggesting endothelial dysfunction. Blockade of COX with indomethacin and with the selective blocker of COX-2 restored the relaxations to ACh in obese rats. Selective blockade of the TXA2/PGH2 (TP) receptor enhanced ACh relaxations only in OZR, while inhibition of the prostacyclin (PGI2) receptor (IP) enhanced basal tone and inhibited ACh vasodilator responses only in LZR. Basal production of superoxide was increased in arteries of OZR and involved NADPH and xanthine oxidase activation and NOS uncoupling. Under conditions of NOS blockade, ACh induced vasoconstriction and increased ROS generation that were augmented in arteries from OZR and blunted by COX-2 inhibition and by the ROS scavenger tempol. Hydrogen peroxide (H2O2) evoked both endothelium- and vascular smooth muscle (VSM)-dependent contractions, as well as ROS generation that was reduced by COX-2 inhibition. In addition, COX-2 expression was enhanced in both VSM and endothelium of renal arteries from OZR. These results suggest that increased COX-2-dependent vasoconstriction contributes to renal endothelial dysfunction through enhanced (ROS) generation in obesity. COX-2 activity is in turn upregulated by ROS.
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http://dx.doi.org/10.1016/j.freeradbiomed.2015.03.024DOI Listing
July 2015

[Impact of female genital mutilation on the millennium goals].

Rev Gaucha Enferm 2015 ;36 Spec No:254-61

Facultad de Enfermería, Universidad de Murcia, Murcia, España.

Objective: To relate the Female Genital Mutilation as a negative factor for the achievement of the Millennium Development Goals 1, 3, 4, 5 and 6.

Method: Data collection was through review literature review between in the years 2014 and 2015 in the databases Medline/PubMed, Web of Science, LILACS, SCIELO, Tesis Doctorales TESEO and in the webs of WOK, UNICEF, UNAF and WHO using the descriptors: female circumcision, millennium development goals, rights of women. Articles published between years 2010 y 2015, were included and finally 24 articles were selected.

Results: The Female Genital Mutilation is based on gender discrimination, and reinforces and encourages the circle of poverty. This practice causes physical complications that may affect the infant mortality and morbidity, complications in pregnancy and childbirth and there is a relationship between the practice and the transmission of human immunodeficiency virus.

Conclusion: The fight against Female Genital Mutilation contributes to the achievement of five of the eight Millennium Goals.
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http://dx.doi.org/10.1590/1983-1447.2015.esp.56724DOI Listing
September 2016

Pre- and post-junctional bradykinin B2 receptors regulate smooth muscle tension to the pig intravesical ureter.

Neurourol Urodyn 2016 Jan 18;35(1):115-21. Epub 2014 Oct 18.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.

Aims: Neuronal and non-neuronal bradykinin (BK) receptors regulate the contractility of the bladder urine outflow region. The current study investigates the role of BK receptors in the regulation of the smooth muscle contractility of the pig intravesical ureter.

Methods: Western blot and immunohistochemistry were used to show the expression of BK B1 and B2 receptors and myographs for isometric force recordings.

Results: B2 receptor expression was consistently detected in the intravesical ureter urothelium and smooth muscle layer, B1 expression was not detected where a strong B2 immunoreactivity was observed within nerve fibers among smooth muscle bundles. On ureteral strips basal tone, BK induced concentration-dependent contractions, were potently reduced by extracellular Ca(2+) removal and by B2 receptor and voltage-gated Ca(2+) (VOC) channel blockade. BK contraction did not change as a consequence of urothelium mechanical removal or cyclooxygenase and Rho-associated protein kinase inhibition. On 9,11-dideoxy-9a,11a-methanoepoxy prostaglandin F2α (U46619)-precontracted samples, under non-adrenergic non-cholinergic (NANC) and nitric oxide (NO)-independent NANC conditions, electrical field stimulation-elicited frequency-dependent relaxations which were reduced by B2 receptor blockade. Kallidin, a B1 receptor agonist, failed to increase preparation basal tension or to induce relaxation on U46619-induced tone.

Conclusions: The present results suggest that BK produces contraction of pig intravesical ureter via smooth muscle B2 receptors coupled to extracellular Ca(2+) entry mainly via VOC (L-type) channels. Facilitatory neuronal B2 receptors modulating NO-dependent or independent NANC inhibitory neurotransmission are also demonstrated.
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http://dx.doi.org/10.1002/nau.22685DOI Listing
January 2016

Lead intoxication under environmental hypoxia impairs oral health.

J Toxicol Environ Health A 2014 ;77(21):1304-10

a Department of Physiology, School of Dentistry , University of Buenos Aires , Buenos Aires , Argentina.

We have reported that chronic lead intoxication under hypoxic environment induces alveolar bone loss that can lead to periodontal damage with the subsequent loss of teeth. The aim of the present study was to assess the modification of oral inflammatory parameters involved in the pathogenesis of periodontitis in the same experimental model. In gingival tissue, hypoxia increased inducible nitric oxid synthase (iNOS) activity (p < .01) and meanwhile lead decreased prostaglandin E2 (PGE2) content (p < .05). In submandibular gland (SMG), iNOS activity was enhanced by lead and PGE2 content was increased by both lead and hypoxia (p < .01) and even more by combined treatments (p < .001). In the SMG, hypoxia stimulated angiogenesis (p < .01) with blood extravasation. Adrenal glands were 22% bigger in those animals exposed to lead under hypoxic conditions. Results suggest a wide participation of inflammatory markers that mediate alveolar bone loss induced by these environmental conditions. The lack of information regarding oral health in lead-contaminated populations that coexist with hypoxia induced us to evaluate the alteration of inflammatory parameters in rat oral tissues to elucidate the link between periodontal damage and these environmental conditions.
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http://dx.doi.org/10.1080/15287394.2014.938209DOI Listing
November 2014

Diminished neurogenic femoral artery vasoconstrictor response in a Zucker obese rat model: differential regulation of NOS and COX derivatives.

PLoS One 2014 12;9(9):e106372. Epub 2014 Sep 12.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.

Objective: Peripheral arterial disease is one of the macrovascular complications of type 2 diabetes mellitus. This study addresses femoral artery regulation in a prediabetic model of obese Zucker rats (OZR) by examining cross-talk between endothelial and neural factors.

Methods And Results: Arterial preparations from lean (LZR) and OZR were subjected to electrical field stimulation (EFS) on basal tone. Nitric oxide synthase (NOS) and cyclooxygenase (COX) isoform expression patterns were determined by immunohistochemical labelling and Western blotting. Results indicate significantly reduced noradrenergic contractions in preparations from OZR compared with those of LZR. Functional inhibition of endothelial NOS (eNOS) indicated a predominant role of this isoform in LZR and its modified activity in OZR. Neural (nNOS) and inducible NOS (iNOS) were activated and their expression was higher in femoral arteries from OZR. Neurotransmission modulated by large-conductance Ca2+-activated (BKCa) or voltage-dependent (KV) K+ channels did not seem compromised in the obese animals. Endothelial COX-1 and COX-2 were expressed in LZR and an additional adventitial location of COX-2 was also observed in OZR, explaining the higher COX-2 protein levels detected in this group. Prostanoids derived from both isoforms helped maintain vasoconstriction in LZR while in OZR only COX-2 was active. Superoxide anion inhibition reduced contractions in endothelium-intact arteries from OZR.

Conclusions: Endothelial dysfunction led to reduced neurogenic vasoconstriction in femoral arteries from OZR. In a setting of obesity, NO-dependent nNOS and iNOS dilation activity could be an alternative mechanism to offset COX-2- and reactive oxygen species-mediated vasoconstriction, along with impaired endothelial NO relaxation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106372PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162543PMC
May 2015

Neuronal and non-neuronal bradykinin receptors are involved in the contraction and/or relaxation to the pig bladder neck smooth muscle.

Neurourol Urodyn 2014 Jun 12;33(5):558-65. Epub 2013 Jul 12.

Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.

Aims: The current study investigates the role played by bradykinin (BK) receptors in the contractility to the pig bladder neck smooth muscle.

Methods: Bladder neck strips were mounted in myographs for isometric force recordings and BK receptors expression was also determined by immunohistochemistry.

Results: B2 receptor expression was observed in the muscular layer and urothelium whereas B1 expression was consistent detected in urothelium. A strong B2 immunoreactivity was also observed within nerve fibers among smooth muscle bundles. On urothelium-denuded preparations basal tone, BK induced concentration-dependent contractions which were reduced in urothelium-intact samples, by extracellular Ca(2+) removal and by blockade of B2 receptors and voltage-gated Ca(2+) (VOC) and non-VOC channels, and increased by cyclooxygenase (COX) inhibition. On phenylephrine-precontracted denuded strips, under non-adrenergic non-cholinergic (NANC) conditions, electrical field stimulation-elicited frequency-dependent relaxations which were reduced by B2 receptor blockade. In urothelium-intact samples, the B1 receptor agonist kallidin promoted concentration-dependent relaxations which were reduced by blockade of B1 receptors, COX, COX-1 and large-conductance Ca(2+) -activated K(+) (BKCa ) channels and abolished in urothelium-denuded samples and in K(+) -enriched physiological saline solution-precontracted strips.

Conclusions: These results suggest that BK produces contraction of pig bladder neck via smooth muscle B2 receptors coupled to extracellular Ca(2+) entry via VOC and non-VOC channels with a minor role for intracellular Ca(2+) mobilization. Facilitatory neuronal B2 receptors modulating NANC inhibitory neurotransmission and urothelial B1 receptors producing relaxation via the COX-1 pathway and BKCa channel opening are also demonstrated. Neurourol. Urodynam. 33:558-565, 2014. © 2013 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/nau.22434DOI Listing
June 2014

Alveolar bone loss associated to periodontal disease in lead intoxicated rats under environmental hypoxia.

Arch Oral Biol 2013 Oct 9;58(10):1407-14. Epub 2013 Jul 9.

Department of Physiology, Faculty of Dentistry, University of Buenos Aires, Argentina.

Previously reported studies from this laboratory revealed that rats chronically intoxicated with lead (Pb) under hypoxic conditions (HX) impaired growth parameters and induced damages on femoral and mandibular bones predisposing to fractures. We also described periodontal inflammatory processes under such experimental conditions. Periodontitis is characterised by inflammation of supporting tissues of the teeth that result in alveolar bone loss. The existence of populations living at high altitudes and exposed to lead contamination aimed us to establish the macroscopic, biochemical and histological parameters consistent with a periodontal disease in the same rat model with or without experimental periodontitis (EP). Sixty female rats were divided into: Control; Pb (1000ppm of lead acetate in drinking water); HX (506mbar) and PbHX (both treatments simultaneously). EP was induced by placing ligatures around the molars of half of the rats during the 14 days previous to the autopsy. Hemi-mandibles were extracted to evaluate bone loss by histomorphometrical techniques. TNFα plasmatic concentration was greater (p<0.01) in Pb and HX animals. TBA-RS content was significantly higher in gums of rats with or without EP only by means of Pb. The SMG PGE2 content increased by Pb or HX was higher in PbHX rats (p<0.01). Pb and HX increased EP induced alveolar bone loss, while Pb showed spontaneous bone loss also. In conclusion, these results show that lead intoxication under hypoxic environment enhanced not only alveolar bone loss but also systemic and oral tissues inflammatory parameters, which could aggravate the physiopathological alterations produced by periodontal disease.
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http://dx.doi.org/10.1016/j.archoralbio.2013.06.010DOI Listing
October 2013
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