Vicente Felipo

Publications (254) View all

• Article: Sildenafil citrate improves perinatal outcome in fetuses from pre-eclamptic rats.

  S Herraiz, B Pellicer, V Serra, O Cauli, J Cortijo, V Felipo, A Pellicer
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  ABSTRACT: Please cite this paper as: Herraiz S, Pellicer B., Serra V, Cauli O, Cortijo J, Felipo V, Pellicer A. Sildenafil citrate improves perinatal outcome in fetuses from pre-eclamptic rats. BJOG 2012;119:1394-1402. Objective  To evaluate perinatal outcome after sildenafil citrate (SC) administration at the onset of pregnancy in a rat pre-eclampsia model. Design  In vivo animal experimental study. Setting  Fundación IVI-Instituto Universitario IVI, Valencia, Spain. Sample Control and pre-eclampsia-induced pregnant Wistar rats exposed to chronic SC administration. Methods  We evaluated the use of SC, which was tested as a potential therapeutic tool to maintain vasodilatation in complicated pregnancies. We have demonstrated previously that SC shows a hypotensive selective effect in normal rat pregnancies when compared with nonpregnant animals. Main outcome measures  Maternal blood pressure, weight and mortality during pre- and postnatal development, maternal blood cellularity and haemodynamic changes with maternal and fetal Doppler quantitative indices. Results  SC restores normal values of blood pressure, cell count and proteinuria for maternal syndrome. In offspring, SC improves weight gain and increases survival rates without fetotoxic effects. According to the haemodynamic results, SC has a significant effect on the resistance index in the uterine artery in pre-eclamptic animals, as it restores normal values to correlate with an increase in fetal perfusion through the ductus venosus. Conclusions  These results suggest that SC administration during pregnancy may have a potential benefit for the treatment of hypertension during pregnancy by reversing the maternal effects of pre-eclampsia and by improving uteroplacental and fetal perfusion.
  BJOG An International Journal of Obstetrics & Gynaecology 07/2012; 119(11):1394-402. · 3.41 Impact Factor
• Article: Progressive reduction of sleep time and quality in rats with hepatic encephalopathy caused by portacaval shunts.

  M Llansola, J L Cantero, E Hita-Yañez, M J Mirones-Maldonado, B Piedrafita, H Ahabrach, M Errami, A Agusti, V Felipo
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  ABSTRACT: Patients with liver cirrhosis show sleep disturbances. Insight into their relationship with hepatic encephalopathy (HE) can be obtained using animal models of HE. The aims of this work were to assess (1) whether rats with portacaval shunts (PCS), a model of HE, show alterations in sleep and if they are similar to those in patients with HE; (2) Whether hyperammonemia plays a role in these sleep alterations; and (3) the time course of sleep alterations in these animal models. Rats were subjected to PCS to induce HE. Another group of rats was fed an ammonium-containing diet to induce hyperammonemia. Polysomnographic recordings were acquired for 24 h and sleep architecture was analyzed in control, PCS, and hyperammonemic rats at 4, 7, and 11 weeks after surgery or diet, respectively. PCS rats show a significant reduction in rapid eye movement (REM) and non-rapid eye movement (NREM) sleep time and increased sleep fragmentation, whereas reduced sleep occurs at 4 weeks and worsens at 7 and 11 weeks, sleep fragmentation appears at 7 weeks and worsens at 11 weeks. Hyperammonemic rats show decreased REM sleep, starting at 7 weeks and worsening at 11 weeks, with no changes in NREM sleep or sleep fragmentation. Therefore, PCS rats are a good model to study sleep alterations in HE, their mechanisms, and potential treatment. Mild hyperammonemia mainly impacts mechanisms involved in REM generation and/or maintenance but does not seem to be involved in sleep fragmentation.
  Neuroscience 11/2011; 201:199-208. · 3.38 Impact Factor
• Article: Differential modulation of the glutamate-nitric oxide-cyclic GMP pathway by distinct neurosteroids in cerebellum in vivo.

  O Cauli, A González-Usano, A Agustí, V Felipo
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  ABSTRACT: The glutamate-nitric oxide (NO)-cGMP pathway mediates many responses to activation of N-methyl-d-aspartate (NMDA) receptors, including modulation of some types of learning and memory. The glutamate-NO-cGMP pathway is modulated by GABAergic neurotransmission. Activation of GABA(A) receptors reduces the function of the pathway. Several neurosteroids modulate the activity of GABA(A) and/or NMDA receptors, suggesting that they could modulate the function of the glutamate-NO-cGMP pathway. The aim of this work was to assess, by in vivo microdialysis, the effects of several neurosteroids with different effects on GABA(A) and NMDA receptors on the function of the glutamate-NO-cGMP pathway in cerebellum in vivo. To assess the effects of the neurosteroids on the glutamate-NO-cGMP pathway, they were administered through the microdialysis probe before administration of NMDA and the effects on NMDA-induced increase in extracellular cGMP were analyzed. We also assessed the effects of the neurosteroids on basal levels of extracellular cGMP. To assess the effects of neurosteroids on nitric oxide synthase (NOS) activity and on NMDA-induced activation of NOS, we also measured the effects of the neurosteroids on extracellular citrulline. Pregnanolone and tetrahydrodeoxy-corticosterone (THDOC) behave as agonists of GABA(A) receptors and completely block NMDA-induced increase in cGMP. Pregnanolone but not THDOC also reduced basal levels of extracellular cGMP. Pregnenolone did not affect extracellular cGMP or its increase by NMDA administration. Pregnenolone sulfate increased basal extracellular cGMP and potentiated NMDA-induced increase in cGMP, behaving as an enhancer of NMDA receptors activation. Allopregnanolone and dehydroepiandrosterone sulphate behave as antagonists of NMDA receptors, increasing basal cGMP and blocking completely NMDA-induced increase in cGMP. Dehydroepiandrosterone sulphate seems to do this by activating sigma receptors. These data support the concept that, at physiological concentrations, different neurosteroids may rapidly modulate, in different ways and by different mechanisms, the function of the glutamate-NO-cGMP pathway and, likely, some forms of learning and memory modulated by this pathway.
  Neuroscience 06/2011; 190:27-36. · 3.38 Impact Factor
• Article: Haemodynamic effects of long-term administration of sildenafil in normotensive pregnant and non-pregnant rats.

  B Pellicer, S Herraiz, O Cauli, R Rodrigo, M Asensi, J Cortijo, V Serra, E Morcillo, V Felipo, C Simón, A Pellicer
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  ABSTRACT: To determine the effects of chronic administration of sildenafil citrate on healthy pregnant rats. In vivo animal experimental study. Fundación IVI-Instituto Universitario IVI, Valencia, Spain. Pregnant and non-pregnant Wistar rats exposed to chronic administration of sildenafil. Placental cross-barrier and feto-maternal relationship levels, maternal blood pressure, and haemodymamic effects on uterine arteries were evaluated. The effect of growth on weight and fetal tissues, and on perinatal outcome, was investigated. Maternal blood pressure, blood viscosity, vascular indices of uterine arteries and fetal ductus venosus, plasmatic levels of sildenafil, embryo/fetal and litter weights, perinatal/postnatal survival rates. Sildenafil citrate crossed the placenta. The maternal and fetal levels of sildenafil, and its metabolite desmethyl-sildenafil, demonstrated a positive linear correlation in treated pregnant animals versus controls; a selective maternal hypotensive effect without changes in uterine vascular resistance was noted on days E8 and E11 (embryonic day). The lower pulsatility index of the ductus venosus on day E18 suggests fetal overflow at the end of the pregnancy. Effects on offspring were placental and liver enlargement, and increased fetal weight gain in the second half of pregnancy (irrespective of liver enlargement) and at birth. Perinatal and postnatal survival rates in the sildenafil group remained unaltered. No haemodynamic effects were evident in non-pregnant animals. In normotensive rats, sildenafil appears to have a selective effect at the onset of pregnancy, implying increased fetal blood supply, and increased fetal weight, and placental and liver enlargement, but no increased perinatal mortality.
  BJOG An International Journal of Obstetrics & Gynaecology 01/2011; 118(5):615-23. · 3.41 Impact Factor
• Article: Treatment with sildenafil prevents impairment of learning in rats born to pre-eclamptic mothers.

  O Cauli, S Herraiz, B Pellicer, A Pellicer, V Felipo
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  ABSTRACT: Pre-eclampsia is an important hypertensive pregnancy disorder and a main cause of maternal and fetal morbidity and mortality. Children born from mothers with pre-eclampsia may present cognitive deficits. The mechanisms leading to this cognitive impairment remain unclear and no treatments to improve it have been tested. Pre-eclampsia is associated with impaired regulation of the nitric oxide-3'-5'guanosine monophosphate cyclic (cGMP) pathway, which modulates some cognitive functions. We hypothesized that alterations in the NO-cGMP pathway would be involved in the mechanisms leading to cognitive impairment in rats born to pre-eclamptic mothers and that treatment with sildenafil, an inhibitor of the phosphodiesterase that degrades cGMP, could restore their cognitive function. To test these hypotheses, we used an animal model of pre-eclampsia in rats: pregnant rats treated with l-nitro-arginine methyl ester, an inhibitor of nitric oxide synthase. Using this model, we assessed: (1) whether rats born to pre-eclamptic mothers show reduced learning ability and/or altered motor activity or coordination when they are 2 months-old; (2) whether cognitive impairment is associated with reduced function of the glutamate-NO-cGMP pathway in brain in vivo; and (3) whether treatment of the mothers with sildenafil prevents this cognitive and motor alterations. The results reported show that the ability to learn a conditional discrimination task in a Y maze is reduced in rats born to pre-eclamptic mothers. This impairment was associated with reduced function of the glutamate-NO-cGMP pathway in brain in vivo, as assessed by microdialysis in freely moving rats. Treatment with sildenafil restores the function of this pathway and learning ability.
  Neuroscience 12/2010; 171(2):506-12. · 3.38 Impact Factor