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Biomedical subjects

P Cuevas

Publications and source records attributed to P Cuevas.

At least 37 records · Page 2Linked to original sources
PubMed2000

Acidic fibroblast growth factor inhibits junctional communication of Schwann cells in culture.

The effect of acidic fibroblast growth factor (aFGF) was investigated on junctional communication of rat Schwann cells (SC) in culture. As measured by dye transfer, the incidence of coupling between SC was very low during the phase of proliferation and increased slowly and progressively with time under culture conditions that induced the myelinating phenotype. Treatment with aFGF alone or in combination with heparin decreased markedly coupling between SC in both culture stages. The coupling inhibition was rapid, the earliest effects being apparent 5-15 min after addition of growth factor, and was transient with a slower recovery of coupling at 1-3 h. The uncoupling effect of aFGF could be prevented by an inhibitor of protein-tyrosine kinase. Addition of heparin to cultures decreased the most effective aFGF concentration by 100-fold, from 100 ng ml-1 to 1 ng ml-1. The dose-response curves exhibited a characteristic window-shape. The results suggest that FGF might be involved in the regulation of the junctional communication between rat SC via tyrosine kinases.

Animals↗
PubMed2000

Fibroblast growth factor and hydrocephalus.

The immunohistochemical localization of basic fibroblast growth factor (bFGF) was studied in ventricular ependyma and choroid plexus of aged-matched normotensive and spontaneously hypertensive rats at different ages using a polyclonal antibody against bFGF. The bFGF-like immunoreactivity was observed in brain ependyma and choroid plexus of young and old normotensive rats. However, a progressive loss of immunoreactivity was observed with age in spontaneously hypertensive rats, that was associated with a progressive cerebroventricular dilation. These results show a new neuroendocrine anomaly to be added to the many others previously observed in this rat strain, when they develop hydrocephalus as they age.

Aging↗
PubMed2000

Fibroblast growth factor-1 inhibits medial smooth muscle cells apoptosis after balloon injury.

We performed balloon injury in the rat common carotid artery and identified apoptosis of vascular smooth muscle cells (VSMCs) by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, 2 h after injury. Balloon injury induces apoptosis and loss of bcl-X protein in the innermost layers of the media of the common carotid artery. Treatment with acidic fibroblast growth factor (aFGF, FGF-1) attenuated by 56% the balloon angioplasty-induced apoptosis. In addition, FGF-1 treatment also induces expression of the bcl-X anti-apoptotic protein in the same site of the media showing VSMC apoptosis. These data suggest that the anti-apoptotic effect of FGF in injured vascular wall was mediated by a bcl-X pathway and identified FGF as an important factor in vascular remodeling.

Animals↗
PubMed2000

Antiproteinuric effect of calcium antagonists on puromycin-induced experimental nephrosis.

Calcium antagonists have a potential for beneficial effects on kidney function unrelated to their antihypertensive action. In this study we have investigated the efficacy of calcium antagonists compounds (verapamil, nifedipine and diltiazem) on reversible acute renal insufficiency, proteinuria and interstitial nephritis induced by the puromycin ammonucleoside (PAN). An increase in blood pressure (BP) was detected on day 14, with no statistical differences in the response to calcium antagonists. Serum creatinine concentration increased to 1.2 mg/dL on day 7 after PAN and decreased to 0.7 mg/dL at 14 days, calcium antagonists shortened the time required to reach baseline or control levels. Calcium antagonists also reduced proteinuria in the PAN-treated animals, in both day 7 and day 14. Differential effects of the antagonists were observed. Verapamil caused a greater reduction (p < 0.01) in proteinuria than nifedipine or diltiazem in day 7. Moreover, verapamil (p < 0.01) and nifedipine (p < 0.01) reduced the total number of interstitial infiltrating leukocytes from 690 to 120 and 425 positive cells/20 high power fields (x63) respectively, by contrast, diltiazem had no effect. We conclude that in this model of PAN nephropathy verapamil is more effective in reducing both proteinuria and the severity of acute interstitial nephritis than either nifedipine or diltiazem. The possible clinical implications of these results remain to be elucidated.

Animals↗
PubMed2000

Rationale for the combination of PGE(1) and S-nitroso-glutathione to induce relaxation of human penile smooth muscle.

Many men with erectile dysfunction have been successfully treated with intracavernosal injection of prostaglandin E(1) (PGE(1)) but this treatment is ineffective in 30 to 40% of patients. The goals of this study were to characterize PGE(1)-induced relaxation of isolated human penile smooth muscle (penile arteries and trabecular strips), correlating this in vitro response with the clinical response to this drug, and to evaluate the effects of the combination of PGE(1) with S-nitrosoglutathione (SNO-Glu) on relaxation of isolated human penile smooth muscle. Large variability in the EC(50) and maximal relaxation induced by PGE(1) was observed between tissues of different patients. Patients with poor clinical response to intracavernosal alprostadil (PGE(1)) had significantly larger EC(50) values and smaller maximal relaxation compared with patients with partial or complete clinical response to this drug. SNO-Glu consistently produced complete or near complete relaxation of human corpus cavernosum strips and penile arteries, even when the tissue responded poorly to PGE(1). In trabecular strips, the combination of PGE(1) and SNO-Glu in a 1:100 ratio demonstrated a synergistic relaxation effect. The combination of PGE(1) and SNO-Glu simultaneously increased the levels of both cAMP and cGMP in human corpus cavernosum tissue. Our results suggest that the clinical effectiveness of intracavernosal administration of PGE(1) is related to the variability of the relaxation responses of human trabecular tissue and penile arteries to this drug. The synergistic interaction of PGE(1) and SNO-Glu makes this combination an effective method to cause penile smooth muscle relaxation, a necessary step to initiate and maintain penile erection.

Alprostadil↗
PubMed1999

Cardioprotection from ischemia by fibroblast growth factor: role of inducible nitric oxide synthase.

Growing evidence from both animal experiments and clinical observations indicates that fibroblast growth factor (FGF) plays a protective role in myocardial reperfusion injury. The molecular and cellular mechanisms that lead to this postischemic myocardial protection, however, remain largely unexplored. We studied the cardioprotective effects of human recombinant acidic fibroblast growth factor (aFGF, FGF-1) in a rat model of myocardial reperfusion injury, induced by 20 minutes of left coronary artery occlusion followed by 24 hours of reperfusion. Intravenous FGF-1 administration at the onset of heart reperfusion attenuated both the functional impairment and the histological changes of ischemia/reperfusion injury. FGF-1 increases more than twice the left ventricular contractile function (p <0.005) compared to vehicle-treated rats. As shown by histology, myocardial tissue is better preserved with FGF-1 treatment. The infarct size, normalized for the area at risk, was significantly smaller in the FGF-1 group (p <0.01) than in the vehicle group. Furthermore, FGF-1 administration resulted in expression of inducible nitric oxide synthase (iNOS) in the area at risk. Since increased expression of iNOS could potentiate cardioprotection against myocardial reperfusion injury, our findings support a new non-mitogenic role for FGF and add a clinical interest for this protein in increasing myocardial ischemic tolerance.

Animals↗
PubMed1999

Apoptosis of glioma cells induced by the fibroblast growth factor inhibitor 1,3,6-naphthalenetrisulfonate.

Fibroblast growth factors (FGFs) are powerful angiogenic polypeptides that are involved in the autocrine growth stimulation of gliomas. We report here that addition to glioma cell cultures of 1,3,6-naphthalenetrisulfonate (NTS), an inhibitor of the mitogenic activity of FGFs, significantly enhanced apoptosis, as assessed by terminal deoxynucleotidyl transferase (TdT) assay. The pro-apoptotic effect of NTS was time-dependent. These findings suggest that FGF may play a pivotal role in the survival of glioma cells, and support a clinical interest of NTS as a leading compound for the development of new antitumorals.

Animals↗
PubMed1999

Fibroblast growth factor protects the kidney against ischemia-reperfusion injury.

Ischemia-reperfusion injury, a common source of renal dysfunction in adults, is associated with tubular epithelial cell damage. Since fibroblast growth factors (FGF) attenuated tissue injury after transient myocardial ischemia, we hypothesized that acidic fibroblast growth factor (aFGF; FGF-1) would attenuate renal ischemia-reperfusion injury. We studied the effects of FGF-1 in a rat model of acute renal failure induced by bilateral renal ischemia (60 min) and 1, 2 or 7 days reperfusion. After FGF-1 administration at the onset of renal reperfusion, there was less functional impairment of the kidneys. The histological changes were not as severe as in controls. Increases in serum creatinine and blood urea nitrogen 24 h after reperfusion were attenuated by 35% (p< 0.01) and by 53% (p< 0.001), respectively, in FGF-1-treated animals compared to vehicle-treated rats. The ischemia/reperfusion-induced increase in tissue myeloperoxidase, a marker of neutrophil infiltration, was mitigated (67% reduction, p< 0.05) with FGF-1 treatment. As shown by histology, neutrophil infiltration and tubular cell necrosis in medulla were less pronounced (p< 0.0001 and p< 0.05, respectively) in animals receiving FGF-1. Furthermore, ischemia-induced apoptosis, prevalent in tubular cells of the cortex, was also attenuated by FGF-1-treatment (83% reduction, p< 0.0001). Pretreatment of animals with Nw-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide synthase, abolished the attenuating effects of FGF-1 on neutrophil infiltration, suggesting that nitric oxide might participate in the anti-inflammatory effects of FGF-1 in this experimental design. Our data support a role for FGF-1 in attenuation of renal damage or failure after ischemia-reperfusion injury of the kidney, in part at least by inhibition of neutrophil infiltration.

Animals↗
PubMed1999

Enhanced contractility of rabbit corpus cavernosum smooth muscle by oxidized low density lipoproteins.

We have investigated the effect of oxidatively-modified low density lipoproteins (ox-LDL) on the contractility of rabbit trabecular smooth muscle. Low density lipoproteins (LDL) were isolated from fresh human plasma pooled from multiple donors and oxidized by exposure to copper. Corpus cavernosum strips from New Zealand White rabbits were studied in organ chambers for isometric tension measurement. Corporeal strips in which moderate tone was induced by phenylephrine, contracted when exposed to ox-LDL, but not when exposed to either native LDL (nLDL) or LDL protected from oxidation by butylated hydroxytoleune (BHT-LDL). Removal of the endothelium, or treatment of the corporeal strips with N(omega)-nitro-L-arginine (nitric oxide synthase inhibitor), methylene blue of LY83583 (guanylate cyclase inhibitors/superoxide producing agents), did not prevent ox-LDL-induced contraction. ox-LDL, dose-dependently, enhanced the contractile response of corporeal strips to low and moderate concentrations by phenylephrine. nLDL had no significant effect on phenylephrine-induced contraction of corporeal strips. ox-LDL, nLDL or BHT-LDL had no effect on relaxation induced by the endothelium-dependent dilator, acetylcholine, or the nitric oxide donor, nitroprusside. In conclusion, this present study demonstrates significant pro-contractile effects of ox-LDL on corporeal smooth muscle, this effect is independent of the endothelium or the nitric oxide/cGMP pathway. The pro-contractile effect of ox-LDL may interfere with penile smooth muscle relaxation, necessary for the initiation and maintenance of penile erection.

Aminoquinolines↗
PubMed1999

Suppression of acidic fibroblast growth factor-dependent angiogenesis by the antigrowth activity of 1,3,6-naphthalenetrisulfonate.

Growth factor-induced angiogenesis was studied using subcutaneously implanted gelatin sponges loaded with 10 mg ml-1 of acidic fibroblast growth factor (aFGF) in 20 micrograms ml-1 PBS heparin. The administration of 1,3,6-naphthalenetrisulfonate (NTS) directly into the sponge (20 mg ml-1) or intraperitoneally (200 mg kg-1) blocks invasion of the sponge by vasculature. Since angiogenesis is essential for tumor progression, the findings of the present study that NTS is an efficient inhibitor of neovascularization warrant further investigation of the potential clinical utility of this angiostatic agent for treating tumor growth and metastasis.

Animals↗
PubMed1999

Design and evaluation of nitrosylated alpha-adrenergic receptor antagonists as potential agents for the treatment of impotence.

We designed and evaluated a new class of molecules, nitrosylated alpha-adrenergic receptor antagonists, as potential agents for the treatment of impotence. In in vitro studies with human and rabbit corpus cavernosum strips in organ chambers, the alpha-adrenergic receptor antagonists (alpha-ARAs) moxisylyte and yohimbine and their corresponding nitrosylated compounds, SNO-moxisylyte (NMI-221) and SNO-yohimbine (NMI-187), concentration-dependently relaxed endothelin-induced contraction. The nitrosylated compounds were significantly more potent than the parent alpha-ARA. In human tissues, the specific phosphodiesterase type 5 inhibitor zaprinast potentiated the relaxing effects of the nitrosylated compounds. Only nitrosylated compounds induced accumulation of cyclic GMP in rabbit corpus cavernosum strips. Yohimbine and NMI-187 demonstrated a potent alpha2-blocking activity, with no significant differences in pA2 values (8.9 versus 8.2, respectively). Moxisylyte and NMI-221 showed moderate potency in antagonizing phenylephrine contraction, with comparable pA2 values for both molecules (6.5 versus 6.6, respectively). alpha-Adrenergic receptor-binding studies showed similar binding affinities for the alpha-ARA and their corresponding nitrosylated compounds. In vivo, intracavernosal injection of nitrosylated molecules caused greater increases in intracavernosal pressure (NMI-221 versus moxisylyte) that were more long lasting than those of moxisylyte or yohimbine. There were no significant differences between nitrosylated and non-nitrosylated compounds in the magnitude of systemic mean arterial pressure decrease after intracavernosal injection. alpha-ARA and the nitrosylated compounds showed no pain-inducing activity as evaluated with the paw-lick model in mice. In summary, nitrosylated alpha-ARA have the dual functionalities of nitric oxide donors and alpha-ARA. These drugs induced penile erection in animals, suggesting their possible therapeutic value as agents for the local pharmacological treatment of impotence.

Adrenergic alpha-Antagonists↗
PubMed1999

Inhibition of intra-tumoral angiogenesis and glioma growth by the fibroblast growth factor inhibitor 1,3,6-naphthalenetrisulfonate.

1,3,6-naphthalenetrisulfonate (NTS) can inhibit the proliferation in vitro of cells of various origin including glioma. We have studied the effects of NTS on intra-tumoral angiogenesis and tumor growth in the rabbit cornea after implantation of C6 rat glioma cells. It was found that neovascularization and glioma growth were abolished by topical administration of NTS. This effect could be mediated by both induction of programmed cell death and inhibition of growth, in endothelium and in tumor cells, most likely as a consequence of the disruption of the autocrine and paracrine effects of FGF released from endothelial and tumor cells. The results suggest that NTS is a promising candidate to lead the development of new angiogenesis inhibitors for the treatment of cancer and other diseases whose progression is dependent upon the development of new blood vessels.

Animals↗
PubMed1998

Systemic administration of acidic fibroblast growth factor ameliorates the ischemic injury of the retina in rats.

The central neuroprotective effects against ischemic injury of fibroblast growth factor (FGF), administered either directly into the central nervous system or systemically, is well documented. Here we show in a rat model of transient retinal ischemia that the neuroprotective effect of systemically administered acidic fibroblast growth factor (aFGF, FGF-1) extends to the retina. Histological findings show a lower decrease of retinal ganglion cells and inner nuclear layer cells (P < 0.0001) in animals receiving FGF-1. These results suggest that FGF may function as a natural protection agent during transient retinal ischemia and further document that an efficient neuroprotection of central nervous tissues can be obtained by systemic administration of this protein. Our data may, thus, contribute to the development of novel and safe therapeutic approach for the treatment of the ischemic injury of the retina.

Animals↗
PubMed1998

Spasmolytic effect of acidic fibroblast growth factor in early cerebral vasospasm in the rat.

BACKGROUND: In animal models of subarachnoid hemorrhage (SAH), basilar artery spasm has been described. Since fibroblast growth factors (FGFs) dilate rat basilar artery in vivo, we tested whether systemic administration of acidic fibroblast growth factor (aFGF) can reverse the basilar artery spasm following rat SAH. METHODS: SAH was mimicked by injecting autologous blood into the cisterna magna. We used a digital substraction angiography system in order to evaluate the spasmolytic effect of aFGF administered via the axillary artery 7 minutes after the injection of the autologous blood. Control animals received vehicle solution in the same manner. RESULTS: Intraarterial bolus injection of 2.6 micrograms aFGF, but not the solvent, reverses the acute basilar artery narrowing caused by SAH (23.05% of the baseline value at 5 minutes post-SAH). CONCLUSIONS: Our results suggest an important role for FGFs in the cerebral tone regulation and support a clinical interest of FGFs in preventing cerebral ischemia following SAH, particularly if these vasoactive effects are added to the known neuroprotective effects of FGFs.

Angiography, Digital Subtraction↗
PubMed1998

Intravenous fibroblast growth factor penetrates the blood-brain barrier and protects hippocampal neurons against ischemia-reperfusion injury.

BACKGROUND: Fibroblast growth factors (FGFs) play a role in neuronal survival after brain ischemia when administered intrace-rebrally. However, the clinical problems that chronic intracerebral infusion of FGFs involves may restrict its use. The purpose of this study was to analyze if FGFs administered intravenously might afford neuroprotection against transient brain ischemia in the light of new published data that suggest that these polypeptides cross the blood brain-barrier (BBB). METHODS: The efficacy of acidic fibroblast growth factor (aFGF) treatment was analyzed in a gerbil model of 5 min forebrain ischemia followed by 7 days of reperfusion. Native and nonmitogenic aFGF was injected in gerbils as a bolus through a jugular vein at the onset of reperfusion. Control animals received in the same manner vehicle solution alone. Seven days later, neuroprotection was evaluated histologically. Penetration of the FGF across the BBB was assessed by autoradiographic studies in rats. For that purpose, we injected through the jugular vein 0.1 microgram of uniformly labeled native 14C-basic fibroblast growth factor (bFGF), 0.1 microgram of heat-denatured 14C-bFGF, or a coinjection of 14C-bFGF with a 900-fold excess of unlabeled bFGF. Two hours later, animals were killed for morphological studies. RESULTS: We report that a venous injection of either native or nonmitogenic form of aFGF after 5 min forebrain ischemia in the gerbil significantly reduced the occurrence of delayed neuronal death (DND) in the CA1 sector of the hippocampus. We also confirmed that blood-borne 14C-bFGF accumulates in CA1 pyramidal neurons.

Animals↗
PubMed1998

Acidic fibroblast growth factor rescues gerbil hippocampal neurons from ischemic apoptotic death.

Neurotrophic factors have been shown to support the survival of injured neurons and promote their recovery. Here, we investigated whether acidic fibroblast growth factor (aFGF) could modify programmed cell death caused by transient forebrain ischemia in the gerbil. The data show that systemic administration of 2.6 microg aFGF after 5 min ischemia followed by 7 days of brain reperfusion significantly (p < 0.05) reduced the occurrence of apoptotic cell death in CA1 neurons. These data suggest that aFGF would contribute to brain protection after acute stroke.

Animals↗
PubMed1998

The effects of fibroblast growth factors on ischemic kidney, liver and gut injuries.

OBJECTIVE: To explore the possibility of reducing reperfusion injuries of internal organ with acidic and basic fibroblast growth factors (aFGF and bFGF). METHODS: Two kinds of ischemia and reperfusion animal models were used in this study. In rat model of superior mesenteric artery (SMA) occlusion, microvascular clamp was placed on the root of SMA to cut off the blood flow for 45 minutes, and then the clamp was removed. In rat model of bilateral renal ischemia and reperfusion, both renal arteries were clipped to get complete cessation of blood flow for 60 minutes, then the blood flow was allowed to return. At the onset of reperfusion, the doses of 4.0 micrograms/rat of bFGF in SMA occluded rats or 2.6 micrograms/rat of aFGF in rats with acute renal injury were administered through the jugular vein. The liver and renal function examination, tissue bacterial study and histopathological evaluation were done to evaluate the treatment results. RESULTS: The functional impairment of ischemic liver, gut and kidney were reduced with venous administration of aFGF or bFGF at the onset of reperfusion. The results of pathological and tissue bacterial examination supported the assertion of significant protective effects of FGFs. CONCLUSIONS: The protective effects of FGFs may come from the non-mitogenic effects of FGFs at the early and the mitogenic effects at the late stage of tissue repair. These results indicate a potential for clinical use of FGFs as a therapeutic modality in ischemic visceral organ injuries in the future.

Animals↗