Search PubMed⌕ Search

Biomedical subjects

Pedro Cuevas

Publications and source records attributed to Pedro Cuevas.

At least 19 recordsLinked to original sources
PubMed2006

Enhanced thromboxane receptor-mediated responses and impaired endothelium-dependent relaxation in human corpus cavernosum from diabetic impotent men: role of protein kinase C activity.

We have evaluated the influence of protein kinase C (PKC) activity on penile smooth muscle tone in tissues from diabetic and nondiabetic men with erectile dysfunction. Human corpus cavernosum (HCC) strips were obtained from impotent diabetic and nondiabetic men at the time of penile prosthesis implantation and studied in organ chambers. Contractility responses to a prostanoid precursor, to prostanoids, and to the endothelium-dependent vasodilator acetylcholine were studied. Arachidonic acid (AA; 100 microM) caused cyclooxygenase-dependent relaxation of HCC. This relaxation was impaired in diabetic tissues and normalized by blocking thromboxane (TP) receptors with 20 nM [1S-[1alpha,2alpha(Z),3alpha,4alpha]]-7-[3-[[2-[(phenylamino)carbonyl]hydrazino]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (SQ29548). Diabetes did not affect prostaglandin (PG)E(1)-induced relaxation, but it reduced relaxation induced by the PGE(1) metabolite PGE(0). This effect was related to an interaction of PGE(0) with TP receptors. Diabetic tissues had reduced endothelium-dependent relaxation, which was partially improved by SQ29548 and completely normalized by the PKC inhibitor 3-[1-[3-(dimethylaminopropyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione monohydrochloride (GF109203X; 1 microM). In HCC from nondiabetic patients, treatment with the PKC activator phorbol-12,13-dibutyrate (0.3 microM) significantly attenuated endothelium-dependent relaxation, an effect prevented by coadministration of GF109203X. Tissues from diabetic patients had enhanced sensitivity to the contractile effects of the TP receptor agonist 9,11-dideoxy-9alpha,11alpha-epoxymethano PGF(2alpha) (U46619) (EC(50) = 0.65 +/- 0.42 and 6.01 +/- 2.28 nM in diabetic and nondiabetic patients, respectively). Inhibition of PKC with 1 microM GF109203X, prevented diabetes-induced hypersensitivity to U46619-induced contractions (EC(50) = 8.55 +/- 3.12 microM). Overactivity of PKC in diabetes is responsible for enhanced contraction and reduced endothelium-dependent relaxation of HCC smooth muscle. Such alterations can result in erectile dysfunction.

Alprostadil↗
PubMed2006

A new approach for bone marrow-derived stem cells intrapancreatic autotransplantation in diabetic rats.

PURPOSE: A new technique for stem cells intrapancreatic autotransplantation in rats. BASIC PROCEDURES: Section of a femoral diaphysis and aspirations of the bone marrow in both femoral segments were performed. A Kirschner needle was placed into the femur. Cells were isolated in Ficoll gradients and preserved at 4-6 degrees C. The second day, cells were injected, via aortic celiac trunk, into the pancreas of the same rat. RESULTS: Femoral surgery were well tolerated. Intrapancreatic homing of the injected cells was suggested with methylene blue injection that stained the pancreas, and proved by labeled cells in pancreas sections. Cell counts after Ficoll isolation were 1 x 10(6) +/- 2 x 10(5) ES. CONCLUSIONS: A technique is described for stem cell autotransplantation in rats. First we obtain autologous bone marrow-derived stem cells. Second, we inject the cells in the pancreas of the donor rat. This approach can be applied to experimental diabetes and other pancreatic processes.

Animals↗
PubMed2006

Antidepressant-induced inhibition of genital vascular responses is reversed by vardenafil in female rabbits.

INTRODUCTION: Administration of serotonin reuptake inhibitors (SRI) or serotonin and norepinephrine reuptake inhibitors (SNRI) relieves depressive symptoms but may cause sexual dysfunction in women and men. AIM: The aim of the present study was to evaluate the effects of the phosphodiesterase type 5 (PDE5) inhibitor, vardenafil, on inhibition of genital vascular responses (GVR) induced by SRI or SNRI administration in female rabbits. METHODS: Vaginal and clitoral vasodilatory responses to pelvic nerve electrical stimulation were measured by laser Doppler flow needle probes. RESULTS: GVR were significantly potentiated by vardenafil even at the low dose of 0.1 mg/kg, in clitoris and vagina (181 +/- 22% and 180 +/- 31% of control, in vagina and clitoris, respectively, at 8 Hz). The selective SRI, paroxetine (5 mg/kg), significantly inhibited GVR in female rabbits (54 +/- 5% and 48 +/- 6% of control). GVR were also significantly inhibited by the SNRIs, venlafaxine (5 mg/kg) (57 +/- 3% and 32 +/- 11%) and duloxetine (1 mg/kg) (40 +/- 7% and 28 +/- 5%). Treatment with vardenafil (0.1 and 0.3 mg/kg) completely reversed the inhibition of GVR induced by paroxetine, venlafaxine, or duloxetine. CONCLUSIONS: Potentiation of the nitric oxide (NO) pathway by vardenafil improves vascular sexual responses in female rabbits and overcomes the inhibitory effects of acutely administered antidepressants on GVR, irrespective of the underlying pathophysiologic mechanism, i.e., disruption of the NO pathway or enhancement of alpha-adrenergic mechanisms. PDE5 inhibition may represent a reasonable approach to treat SRI- or SRNI-induced female sexual dysfunction, in particular, arousal disorders.

Animals↗
PubMed2005

Therapeutic response of rosacea to dobesilate.

Despite an incomplete understanding of the pathogenesis of rosacea, therapeutic modalities continue to expand. The principal subtype of rosacea includes erythematotelangiestatic rosacea, which is characterized by uncontrolled angiogenesis. Angiogenic growth factors such as fibroblast growth factors (FGF) and vascular endothelial growth factor (VEGF) are currently targets of intense effort to inhibit deregulated blood vessel formation in diseases such as cancer. Here we report a 33-years-old woman with erythematotelangestatic rosacea who responds to a daily treatment of topically applied dobesilate, an inhibitor of FGF, with an improvement in erythema and telangectasia after two weeks. Thus, dobesilate might be useful in the treatment of rosacea and other diseases that depend on pathologic angiogenesis.

Administration, Topical↗
PubMed2005

Dobesilate is an angiogenesis inhibitor.

Aberrant angiogenesis is essential for the progression of solid tumors and hematological malignancies. Antiangiogenic therapy is one of the most promising approaches to treat such diseases. Dobesilate is an oral agent for treatment of vascular complications of diabetic retinopathy. We have examined the possibility that this compound could interfere with the process of angiogenesis in a mouse gelatine sponge assay using acidic fibroblast growth factor (aFGF) as an inducer of neovascularization. According to the results reported here, dobesilate remarkably reduced vessel ingrowth in aFGF-containing subcutaneous sponges in mice. These findings suggest that dobesilate could be an effective agent in the treatment of angiogenesis-dependent diseases involving FGFs.

Angiogenesis Inhibitors↗
PubMed2005

Dobesilate in the treatment of plaque psoriasis.

Fibroblast growth factor (FGF)-mediated pathways participate in many of the cellular events implicated in the pathogenesis of psoriasis. Thus, targeting FGF signals may be potentially therapeutic in the treatment of psoriasis. We report for the first time on a 43-year-old man with chronic-type plaque psoriasis with a daily topical treatment of dobesilate, a new FGF inhibitor. As early as at day 14, the patient had cleared or achieved excellent improvement of psoriatic skin lesions. Topical dobesilate offers the potential for treatment of plaque psoriasis without atrophy or other local side effects associated with the use of topical corticosteroids.

Adult↗
PubMed2005

Synthesis of the blood circulating C-terminal fragment of insulin-like growth factor (IGF)-binding protein-4 in its native conformation. Crystallization, heparin and IGF binding, and osteogenic activity.

Insulin-like growth factor-binding proteins play a critical role in a wide variety of important physiological processes. It has been demonstrated that both an N-terminal and a C-terminal fragment of insulin-like growth factor-binding protein-4 exist and accumulate in the circulatory system, these fragments accounting for virtually the whole amino acid sequence of the protein. The circulating C-terminal fragment establishes three disulfide bridges, and the binding pattern of these has recently been defined. Here we show that the monodimensional 1H NMR spectrum of the C-terminal fragment is typical of a protein with a relatively close packed tertiary structure. This fragment can be produced in its native conformation in Escherichia coli, without the requirement of further refolding procedures, when synthesis is coupled to its secretion from the cell. The recombinant protein crystallizes with the unit cell parameters of a hexagonal system. Furthermore, it binds strongly to heparin, acquiring a well defined oligomeric structure that interacts with insulin-like growth factors, and promotes bone formation in cultures of murine calvariae.

Amino Acid Sequence↗
PubMed2005

Enhancement of both EDHF and NO/cGMP pathways is necessary to reverse erectile dysfunction in diabetic rats.

AIMS AND METHODS: Phosphodiesterase 5 (PDE5) inhibitors are less effective in the treatment of erectile dysfunction (ED) in diabetic men than in nondiabetic patients. We have evaluated the effects of sildenafil, a PDE5 inhibitor that enhances the nitric oxide (NO)/cGMP pathway, calcium dobesilate (DOBE), which potentiates endothelium-derived hyperpolarizing factor (EDHF)-mediated responses and the combination of both on erectile responses elicited by cavernosal nerve electrical stimulation (CNES) in a rat model of ED after 8 weeks of streptozotocin-induced diabetes. RESULTS: After 8 weeks of diabetes, erectile responses to CNES were significantly decreased in diabetic animals compared with nondiabetic time controls. While intravenous administration of sildenafil (0.3 mg/kg) or DOBE (10 mg/kg), individually, enhanced erectile responses in nondiabetic rats (214.7 +/- 34.1% and 268.5 +/- 30.1% of control response at 1 Hz, respectively), each failed to significantly enhance erectile responses in diabetic rats. Only when administered in combination did DOBE and sildenafil markedly potentiate erectile responses in these animals (380.1 +/- 88.6% of control response at 1 Hz), completely restoring erectile function. CONCLUSIONS: These findings emphasize the importance of NO/cGMP and EDHF pathways for normal erectile function. They also give support to the in vitro observation that diabetes impairs NO and EDHF-dependent responses, precluding the complete recovery of erectile function with PDE5 inhibitors and explaining the relatively poor clinical response of diabetic men with ED to PDE5 inhibition. Finally, our study suggests that a pharmacological approach that combines enhancement of NO/cGMP and EDHF pathways could be necessary to treat ED in many diabetic men.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2005

Bone-like polyethelyne burr-hole cover.

OBJECTIVE: Several materials are available for covering burr holes but none of them are ideal with respect to biocompatibility, strength and morbidity. With these properties in mind, our objective was to design a porous polyethylene device, which looked like bone and provides protection and cosmesis while being quick and easy to apply. METHODS AND MATERIALS/RESULTS: A burr-hole cover was created to cover small cranial defects and craniostomies. Using high-density polyethylene, this cover was designed to resemble the bony structure of the skull. Its porous architecture allows for tissue ingrowth and bony integration. It consists of a cylinder which fits into the burr hole and a cap which can be sutured or anchored with titanium screws. CONCLUSIONS: The "bone-like" burr-hole cover provides adequate protection, biocompatibility and cosmesis and is simple to use. Alternative implants can be toxic to surrounding tissues, costly and time consuming to apply. This high-density polyethylene cover is compatible with surrounding tissue as well as being of a porous nature and the material it is made from offers high tensile strength for adequate protection.

Absorbable Implants↗
PubMed2004

Mechanisms for the inhibition of genital vascular responses by antidepressants in a female rabbit model.

Vaginal and clitoral vasodilator responses (genital vascular responses; GVRs) to pelvic nerve electrical stimulation in female rabbits were measured by laser Doppler flow needle probes. The intravenous administration of various treatments was evaluated. GVRs were attenuated by a nitric-oxide synthase inhibitor (48.5 and 51.8% of control at 8 Hz in the vagina and clitoris, respectively) and norepinephrine (NE) (78.5 and 61.5%), whereas serotonin (5-HT) had no inhibitory effect. The selective 5-HT reuptake inhibitor (SSRI) escitalopram did not modify GVRs, whereas the SSRI paroxetine dose-dependently inhibited GVRs in female rabbits (43.3 and 53.1% at 5 mg/kg). GVRs were also significantly inhibited by the 5-HT and NE reuptake inhibitors venlafaxine (53.4 and 52.6% at 5 mg/kg) and duloxetine (40.9 and 37.4% at 1 mg/kg). L-arginine prevented the inhibitory effects of paroxetine (105.5 and 115.3%) and partially prevented duloxetine-induced reduction of GVRs but had no effect on the inhibition of GVRs induced by venlafaxine. Conversely, the alpha-adrenergic receptor blocker phentolamine had no effect on paroxetine-induced reduction of GVRs, partially prevented the inhibitory effects of duloxetine, and fully prevented the effects of venlafaxine (93.0 and 96.7%). Duloxetine-induced inhibition of GVRs was completely prevented by combined administration of L-arginine and phentolamine (123.5 and 103.6%). Although 5-HT or the highly selective SRI escitalopram did not inhibit GVRs, NE or inhibition of nitric oxide (NO) synthesis did. Inhibition of the NO pathway by paroxetine and duloxetine or activation of alpha-adrenergic mechanisms by venlafaxine and duloxetine lead to antidepressant-induced inhibition of GVRs in female rabbits.

Adrenergic Uptake Inhibitors↗
PubMed2004

Bone marrow stromal cell implantation for peripheral nerve repair.

Cell therapy using bone marrow stromal cells is a new promising therapy for regenerative medicine. Previous studies demonstrated that local bone marrow stromal cells implantation in the distal stump of transected sciatic nerve of rats promotes early functional recovery. The purpose of this study was to expand on the preliminary research by investigating the long-term efficacy of bone marrow stromal cells using the same experimental setting. Functional test and histological studies demonstrate that bone marrow stromal cell-treated rats exhibit significant improvement on a walking tract test at day 180 after surgery compared with control rats. Taken together, these data suggest that bone marrow stromal cell therapy is a safe and effective strategy for peripheral nerve injuries.

Animals↗
PubMed2004

Neomycin inhibits glioma cell migration.

Blocking migration is an attractive strategy to inhibit glioma tumorigenesis. Previous studies have indicated that neomycin inhibits glioma cells proliferation. The purpose of this study was to expand on the preliminary research by investigating the antimigratory effect of neomycin. We used glioma C6 cells to investigate the role of neomycin in cell migration in vitro. Cell wounding assay showed that neomycin inhibits in a dose-dependent manner glioma cells migration into the wound. Taken together, these results suggest that neomycin is an attractive candidate for the development of novel antimigratory molecules useful for the treatment of gliomas.

Animals↗
PubMed2004

Differentiation-inducing activity of neomycin in cultured rat glioma cells.

Induction of cellular differentiation is an attractive therapeutic strategy against glioma cell proliferation and tumorigenicity. Preliminary in vitro studies have indicated that neomycin inhibits the proliferation of cultured glioma cells and induces changes in cellular morphology, making it potentially useful as a therapeutic agent for gliomas. The purpose of this work was to expand on the preliminary research by investigating the differentiation effect of neomycin in rat C6 glioma cells, using glial fibrillary acidic protein (GFAP) staining as a reliable marker of differentiation for normal astrocytes and for tumors of astrocytic lineage. Cell cultures were grown in the absence or presence of 10 mM neomycin sulfate for 48 hours. Neomycin treatment produced changes in cell morphology and GFAP expression indicative of cellular differentiation. These results suggest that neomycin is an attractive differentiation agent for the treatment of gliomas.

Animals↗
PubMed2004

Perivascular delivery of neomycin inhibits the activation of NF-kappaB and MAPK pathways, and prevents neointimal hyperplasia and stenosis after arterial injury.

The nuclear transcription factor kappaB (NF-kappaB) is a cytoplasmic dimer that, as the family of mitogen-activated protein kinase (MAPK), can directly regulate the expression of early genes and genes involved in the stress response, following a variety of physiological or pathological stimuli. Both of them stimulate the transcription of many proteins, which are considered important during inflammation. A crucial role has been assigned to these factors in cellular proliferation and in neointimal hyperplasia secondary to the endothelial lesion of arterial vessels. On the other hand, it has been described that neomycin can have an inhibitory function on tumor cell proliferation, through the inhibition of different intracellular pathways of signaling, among them the NF-kappaB and MAPK pathways. Rat common carotid artery was subjected to balloon angioplasty. Neomycin sulfate (18 mg) was applied using pluronic acid gel on the adventitial surface of the injured vessel. MAPK and NF-kappaB activation was quantified after 24 hours with immunohistochemical staining. Neointimal formation was quantified after 14 days with morphometry. Immunohistochemistry results demonstrating MAPK and NF-kappaB activation reveal that both transcription factors are activated in the media of the control vessel wall. In contrast, the immunoreactivity for MAPK and NF-kappaB in the sections obtained from arteries treated with neomycin over 24 hours was insufficient or nonexistent. Treatment with neomycin on adventitia over 14 days in arteries on which angioplasty was performed shows a neointimal index (intimal area/medial area) decrease of 71% in comparison with arteries that were not treated. The adventitial neomycin treatment over 14 days produces a very significant increase (287.5%; p<0.0001) in the arterial luminal circumference in comparison with arteries treated with vehicle. These results support the theory that neomycin plays an important role against neointimal hyperplasia through the inhibition of MAPK and NF-kappaB activation.

Animals↗
PubMed2003

Diabetes impairs endothelium-dependent relaxation of human penile vascular tissues mediated by NO and EDHF.

Standard treatments for erectile dysfunction (ED) (i.e., PDE5 inhibitors) are less effective in diabetic patients for unknown reasons. Endothelium-dependent relaxation (EDR) of human corpus cavernosum (HCC) depends on nitric oxide (NO), while in human penile resistance arteries (HPRA) endothelium-derived hyperpolarizing factor (EDHF) and NO participate. Here we show that diabetes significantly reduced EDR induced by acetylcholine (ACh) in HCC and HPRA. Relaxation attributed to EDHF was also impaired in HPRA from diabetic patients. The PDE5 inhibitor, sildenafil (10nM), reversed diabetes-induced endothelial dysfunction in HCC, but not in HPRA. Calcium dobesilate (DOBE; 10 microM) fully reversed diabetes-induced endothelial dysfunction in HPRA by specifically potentiating the EDHF-mediated component of EDR. Impairment by diabetes of NO and EDHF-dependent responses precluded the complete recovery of endothelial function in HPRA by sildenafil. This could explain the poor clinical response to PDE5 inhibitors of diabetic men with ED and suggests that a pharmacological approach that combines enhancement of NO/cGMP and EDHF pathways could be necessary to treat ED in many diabetic men.

Acetylcholine↗
PubMed2003

Leads for development of new naphthalenesulfonate derivatives with enhanced antiangiogenic activity: crystal structure of acidic fibroblast growth factor in complex with 5-amino-2-naphthalene sulfonate.

Inhibition of angiogenesis-promoting factors such as fibroblast growth factors is considered to be a potential procedure for inhibiting solid tumor growth. Although several peptide-based inhibitors are currently under study, the development of antiangiogenic compounds of small molecular size is a pharmacological goal of considerable interest. We have already shown that certain naphthalene sulfonates constitute minimal functional substitutes of the antiangiogenic compounds of the suramin and suradista family. Using those data as a lead, we have carried out a rational search for new angiogenesis inhibitors that could provide new pharmacological insights for the development of antiangiogenic treatments. The results of the study strongly underline the relevance of the stereochemistry for an efficient inhibition of acidic fibroblast growth factor mitogenic activity by the naphthalene sulfonate family and allow us to formulate rules to aid in searching for new inhibitors and pharmaceutical developments. To provide further leads for such developments and acquire a detailed insight into the basis of the inhibitory activity of the naphthalene sulfonate derivatives, we solved the three-dimensional structure of acidic fibroblast growth factor complexed to 5-amino-2-naphthalenesulfonate, the most pharmacologically promising of the identified inhibitors. The structure shows that binding of this compound would hamper the interaction of acidic fibroblast growth factor with the different components of the cell membrane mitogenesis-triggering complex.

Angiogenesis Inhibitors↗
PubMed2003

Activation and potentiation of the NO/cGMP pathway by NG-hydroxyl-L-arginine in rabbit corpus cavernosum under normoxic and hypoxic conditions and ageing.

1 When nitric oxide synthase (NOS) produces NO from N(G)-hydroxy-L-arginine (OH-arginine) instead of L-arginine, the total requirement of molecular oxygen and NADPH to form NO is reduced. The aim of this work was to evaluate the effects of OH-arginine on the contractility of rabbit corpus cavernosum (RCC) and to compare the capacities of L-arginine and OH-arginine to enhance NO-mediated responses under normoxic and hypoxic conditions and in ageing, as models of defective NO production. 2 OH-arginine, but not L-arginine, was able to relax phenylephrine-contracted rabbit trabecular smooth muscle. OH-arginine-induced relaxation was inhibited by the NOS-inhibitor, L-NNA (300 microM), and by the guanylyl cyclase inhibitor, ODQ (20 microM), while it was not affected by the cytochrome P450 oxygenase inhibitor, miconazole (0.1 mM). Administration of OH-arginine, but not L-arginine, produced a significant increment of cGMP accumulation in RCC tissue. 3 Relaxation elicited by OH-arginine (300 microM) was still observed at low oxygen tension. The increase of cGMP levels induced by ACh (30 microM) in RCC was significantly enhanced by addition of OH-arginine (300 microM) in normoxic conditions, as well as under hypoxia, while L-arginine did not alter the effects of ACh on cGMP accumulation. 4 Endothelium-dependent and nitrergic nerve-mediated relaxations were both significantly reduced in RCC from aged animals (>20-months-old) when compared with young adult rabbits (5-months-old). Treatment with OH-arginine (300 microM) significantly potentiated endothelium-dependent and neurogenic relaxation in corpus cavernosum from aged rabbits, while L-arginine (300 microM) did not have significant effects. 5 Results show that OH-arginine promotes NO-mediated relaxation of RCC and potentiates the NO-mediated responses induced by stimulation of endogenous NO generation in hypoxic and aged tissues. We propose that the use of OH-arginine could be of interest in the treatment of erectile dysfunction, at least in those secondary to defective NO production.

Aging↗