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P Cuevas

Publications and source records attributed to P Cuevas.

At least 55 records · Page 3Linked to original sources
PubMed1997

Fibroblast growth factor-1 prevents myocardial apoptosis triggered by ischemia reperfusion injury.

BACKGROUND: Apoptosis is a constant feature of reperfusion injury in ischemic cardiac myocytes, leading to late cell death. Since fibroblast growth factors (FGFs) inhibit apoptosis in differentiated cells, we hypothesized that FGF-1 (acidic FGF), in its native form, and a non-mitogenic isoform would attenuate myocardial ischemia-reperfusion- induced apoptosis. METHODS AND RESULTS: The effect of native and non-mitogenic fibroblast growth factor-1 mutein (FGF-1 and m-FGF-1) on apoptosis assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method was tested in a rat model of 20 min regional myocardial ischemia and 24h reperfusion. Myocardial ischemia followed by reperfusion resulted in a high myocardial apoptosis rate in the area at risk. When given as a systemic bolus inmediately after myocardial ischemia, both FGF-1 and m-FGF-1 significantly reduced apoptosis (by 60 and 61.2, respectively; p<0.0001). CONCLUSIONS: The programed myocyte cell death triggered by ischemia-reperfusion injury is attenuated by FGF-1 in its native or non mitogenic isoforms, suggesting that this effect does not depend on the mitogenic properties of this protein. FGF-1 would contribute to the functional preservation of the myocardium after acute myocardial infarction.

Animals↗
PubMed1997

Serum levels of basic fibroblast growth factor in acute myocardial infarction.

As it has been reported that basic fibroblast growth factor (bFGF) is a circulating peptide and bFGF gene expression is increased after myocardial ischemia, this study was designed to investigate the serum levels of bFGF in patients with acute myocardial infarction (AMI). Using a bFGF enzyme-linked immunoassay, bFGF levels were determined in venous blood of 15 patients with AMI on admission, at 10 days, and 30 days after infarction, and of 15 age-matched healthy volunteers who were used as controls. bFGF serum levels on admission were similar to normal values (7.48 +/- 2.3 vs 8.14 +/- 2.9 pg/ml). However, they significantly increased (16.82 +/- 3.4 pg/ml; p <0.05) 10 days after the onset of AMI, and at 30 days they returned to baseline (7.07 +/- 2.9 pg/ml). The increased bFGF levels at the second week post AMI suggest that bFGF plays an important role in mediating the development of coronary collateral circulation after myocardial ischemia in humans.

Female↗
PubMed1997

Kinins are implicated of the hypotensive effect of acidic fibroblast growth factor.

Acidic fibroblast growth factor causes an acute and transient nitric oxide-dependent hypotensive effect in experimental animals. However, this response is not found, or is very small, in vitro. We hypothesized that plasma mediators, such as kinins, are involved in aFGF-induced hypotension. We studied the hypotensive effect of intravenous aFGF (1 microg) in control Wistar rats, and compared this response to that in Wistar rats treated with a bradykinin receptor antagonist Na-adamantaneacetyl-D-Arg-(Hyp3,Thi5,8,D-Phe7]-brad yki nin), in kininogen-deficient Brown-Norway-Katholiek (BNK) rats, and in rats depleted of kininogen after repeated treatment with ellagic acid. FGF was administered in the jugular vein and mean arterial pressure was measured through a femoral artery catheter. Following treatment with the bradykinin receptor antagonist, the hypotensive effect of aFGF was reduced 38% with 58 microg of antagonist and by 60% with the 420 microg dose (9 +/- 1 vs 22 +/- 3mm Hg, p<0.01). Mean blood pressure decrease was 12 +/- 1 in BNK rats (p<0.01, vs control) and 10 +/- 2 mm Hg in kininogen-depleted ellagic acid-treated rats (p<0.05, vs control). These findings implicate kinins as necessary mediators for the hypotensive effect of aFGF in vivo. A full hypotensive effect of aFGF requires sufficient amounts of kininogens, the precursor molecules of kinins, as well as bradykinin receptors.

Adamantane↗
PubMed1997

A non-mitogenic form of acidic fibroblast growth factor reduces neutrophil infiltration in rat ischemic reperfused heart.

We studied the effects of a non-mitogenic form of acidic fibroblast growth factor (aFGF) on neutrophil infiltration in a rat model of myocardial ischemia (20 min) and reperfusion (24 hr). Neutrophil infiltration, as assessed by measurement of myeloperoxidase (MPO) activity was compared in homogenates of the infarcted left ventricle and the non-infarcted septum which was used as a reference of normal tissue. Myocardial ischemia followed by reperfusion resulted in severe myocardial injury and high cardiac MPO activity indicative of neutrophil accumulation in the ischemic myocardium. A systemic bolus (i.v.) of aFGF (2.6 microg) administered immediately after myocardial ischemia, significantly reduced (p<0.001) the MPO activity in the ischemic reperfused left ventricle compared to vehicle-treated rats. Furthermore, aFGF significantly attenuated tissue damage and neutrophil accumulation in the area at risk after myocardial ischemia and reperfusion as assessed by conventional histology. The mechanism of this protective effect appears to be related to inhibition of neutrophil extravasation, a critical step in neutrophil-induced myocardial reperfusion injury. Thus, non-mitogenic aFGF appears as an effective cardioprotective treatment for myocardial infarction.

Animals↗
PubMed1997

Osteopromotion for cranioplasty: an experimental study in rats using acidic fibroblast growth factor.

BACKGROUND: Many growth factors influence the bone healing cascade. Furthermore, the occasional failure of bone repair may in part be due to perturbation in the activation of local growth factors. Local activation of fibroblast growth factors (FGFs) at the fracture site may serve to increase neovascularization, and induce early granulation formation that can affect bone healing. METHODS: We have performed a rat parietal (6 x 3 mm) critical size defect (CSD). Human recombinant acidic fibroblast growth factor (hraFGF) imbided in agarose was topically administered at the craniectomy site. Control animals received agarose alone in the same manner. Three weeks after surgery, osteopromotion was histologically evaluated. RESULTS: hraFGF-treated animals show a continuous bridge of regenerated bone extending from one edge of the defect to the other. None of the parietal defects that had been treated with agarose contained new bone in the central portion. CONCLUSION: Our results suggest an important role of FGFs to promote large cranioplasty repair and support the use of these proteins as an alternative choice for bone grafts and bone substitutes.

Animals↗
PubMed1997

Role of fibroblast growth factors in neural trauma.

Following a traumatic insult to the adult mammalian central nervous system (CNS), a complex of molecular and cellular responses ensues. Several peptide growth factors seem implicated in the CNS traumatic response. Furthermore, several of them, like some of the members of the fibroblast growth factor family of polypeptides seem to have a protective role. The purpose of this article is to point toward some basic aspects of FGFs neuroprotective activity against traumatic CNS injuries for the development of novel therapeutic strategies in neural trauma.

Adult↗
PubMed1997

Protection of rat myocardium by mitogenic and non-mitogenic fibroblast growth factor during post-ischemic reperfusion.

The effects of acidic fibroblast growth factor (FGF-1) and basic fibroblast growth factor (FGF-2) and a non mitogenic form of FGF1 on myocardial ischemia and reperfusion were assessed. Rats underwent 10 minutes of coronary artery occlusion followed by 24 hours of reperfusion. Creatinine kinase content of the affected myocardium showed that both fibroblast growth factors 1 and 2 effectively protected against ischemia reperfusion injury (p < 0.01), and that the vasoactive but nonmitogenic form of the FGF1 was equally protective (p < 0.01 versus control + vehicle). The results were confirmed by light and electron-microscopy histological studies. Histological evaluations after treatment with the non-mitogenic fibroblast growth factor 1 showed that it did not generate the severe hyperplasia and connective tissue disorganization observed with the native mitogenic proteins. The possibility of using a non-mitogenic form of fibroblast growth factor for cardio-protection circumvents many of the potentially undesirable effects that may derive from systemically introducing broad spectrum acting fibroblast growth factors in vivo. This myocardial protection observed 24 hours after the treatment with fibroblast growth factors, and the efficacy of the non-mitogenic form of the protein, also suggest that the protective effect of fibroblast growth factors may be due to the increased blood flow rather than to angiogenesis.

Animals↗
PubMed1997

Protective effects of acidic fibroblast growth factor against cardiac arrhythmias induced by ischemia and reperfusion in rats.

An in vivo study has been conducted to evaluate the effect of acidic fibroblast growth factor (aFGF) on cardiac arrhythmias which occur in transient myocardial ischemia followed by reperfusion. In a rat model of myocardial ischemia and reperfusion, cardiac arrhythmias were assessed during the first three minutes of reperfusion. Systemic administration of 2.6 micrograms aFGF just before coronary recirculation resulted in a significant reduction in incidence and severity of ventricular extra beats (VEBs), ventricular tachycardia (VT) and ventricular fibrillation (VF), compared with control rats (VT incidence: 30% vs 80%, VF incidence: 10% vs 40%; episodes of VT: 4.1 +/- 0.34 vs 8.8 +/- 0.95; episodes of VF: 4.8 +/- 0.32 vs 11.5 +/- 1.47). Our results suggest a novel role for FGFs as potential antiarrhythmic agents.

Animals↗
PubMed1996

Loss of basic fibroblast growth factor in the subcommissural organ of old spontaneously hypertensive rats.

The immunocytochemical localization of basic fibroblast growth factor (bFGF) was studied in subcommissural organ (SCO) of aged-matched normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats at 10, 14 and 18 months of age using a polyclonal antibody against bFGF. The bFGF-like immunoreactivity (bFGF-ir) was observed in SCO ependymal cells of young and old normotensive rats. However, a progressive loss of bFGF-immunopositive ependymal SCO cells was observed with age in SH rats (27.24, 57.5 and 96.9% in 10, 14 and 18 months old respectively) compared with aged-matched WKY normotensive rats. Considering the potential role of the SCO in sleep regulation and sodium homeostasis, which are altered in essential hypertension, these data show a new neuroendocrine anomaly to be added to the many others previously observed in this rat strain, when they develop hypertension as they get old.

Aging↗
PubMed1996

Correction of hypertension by normalization of endothelial levels of fibroblast growth factor and nitric oxide synthase in spontaneously hypertensive rats.

Acidic and basic fibroblast growth factors (FGFs) share a wide range of diverse biological activities. To date, low levels of FGF have not been correlated with a pathophysiologic state. We report that blood vessels of spontaneously hypertensive rats are shown to be associated with a marked decrement in endothelial basic FGF content. This decrement correlates both with hypertension and with a decrease in the endothelial content of nitric oxide synthase. Restoration of FGF to physiological levels in the vascular wall, either by systemic administration or by in vivo gene transfer, significantly augmented the number of endothelial cells with positive immunostaining for nitric oxide synthase, corrected hypertension, and ameliorated endothelial-dependent responses to vasoconstrictors. These results suggest an important role for FGFs in blood pressure homeostasis and open new avenues for the understanding of the etiology and treatment of hypertension.

Animals↗
PubMed1996

Analgesic effects of fibroblast growth factor in the rat.

Intraperitoneal (i.p.) injection of acidic fibroblast growth factor (aFGF) to Sprague-Dawley rats induced short-lasting analgesia as measured by tail-flick latency (TFL) test. The maximum effect, a 26% increase in tail-flick latency, was obtained 15 min following 1 microgram i.p. aFGF. By 30 min the effect was considerably reduced, and was no longer present by 45 min after treatment. Administration of heat-inactivated aFGF or a hybrid form of aFGF (CLYT/aFGF) that, although active, is unable to cross the blood-brain barrier (BBB), caused no analgesia. Furthermore, the analgesic effects of aFGF were prevented by pretreatment with the nitric oxide synthase inhibitor, L-NG-nitroarginine methyl ester (L-NAME). Our findings demonstrate an analgesic effect of FGF, which requires crossing of BBB and implicates the nitric oxide pathway.

Analgesics↗
PubMed1996

The effect of depressing glial function in rat brain in situ on ion homeostasis, synaptic transmission, and neuron survival.

The supporting role of glial cells in maintaining neurons and in ion homeostasis has been studied in situ by perfusing the gliotoxin fluorocitrate (FC) through a microdialysis fiber in the CA1 area of urethane-anesthetized rats. Extracellular direct current potential, extracellular potassium concentration ([K+]o) and amino acid levels, extracellular pH (pHo), and evoked field activity were studied. Histology verified the swelling of glial cells after 4 hr of FC treatment. Massive neuron damage was evident after 8 hr. FC dialysis caused the rapid decrease of glutamine, pHo became progressively more acid, and [K+]o moderately elevated. Orthodromic transmission was variably blocked within 30 min to 4 hr. After 4 hr, spreading depression (SD) waves that originated from the neocortex invaded hippocampal CA1, [K+]o increased to higher levels, pHo became very acid, and there were steep increases in taurine, glutamate, and GABA levels. Simultaneously, the antidromic population spike (a-PS) became depressed and eventually disappeared. When a shorter dialysis probe that spared cortex was used to sample CA1, no SD was seen, a-PS was not abolished, and ion homeostasis was altered less markedly. Repeated SD provoked in hippocampus in the absence of FC caused only mild depression of a-PS. Dialysis of high-K+ solution in healthy neocortex or hippocampus caused only slight elevation of [K+]o at distances of 200-400 microns from the dialysis membrane. After treatment with FC, similar high-K+ dialysis raised [K+]o much more. We conclude the following: (1) recurrent SD waves injure neurons if and only if glial function has failed; (2) neurons can regulate [K+]o, albeit imperfectly; (3) glia is required for the normal fine tuning of [K+]o and particularly for the recovery of pathologically elevated [K+]o; and (4) glia are required for the regulation of pHo. The similarities between glial poisoning by FC and the reported changes in the penumbra of ischemic infarcts suggest that the extension of neuron loss into the penumbral region might depend on failure of glial protection.

Animals↗
PubMed1996

Antiepileptic effects of acidic fibroblast growth factor examined in kainic acid-mediated seizures in the rat.

The possibility that exogenous recombinant human acidic fibroblast growth factor (rhaFGF) may have anticonvulsant properties was investigated in a model of temporal lobe epilepsy in awake rats. We found that after intraperitoneal injection of rhaFGF in kainic acid-treated rats, tonic-clonic convulsions and mortality were decreased by 74% and 77%, respectively. These results are consistent with previous studies showing a neuroprotective effect of FGF against insults to the brain and support a possible therapeutic role for FGF in the treatment of excitotoxic processes.

Analysis of Variance↗
PubMed1996

Fibroblast growth factor decreases locomotor activity in rats.

The spontaneous locomotor behavior of rats receiving subcutaneous administration of either acidic or basic fibroblast growth factors was recorded in an activity cage. We report that doses between 1 and 100 micrograms/kg significantly decreased the horizontal and vertical activity, as well as the exploratory and stereotypy behavior of the rats. These effects of fibroblast growth factors seem to be specific since (i) they were cancelled by protein hydrolysis and anti-fibroblast growth factor antibodies, (ii) they were unrelated to their hypotensive activity and (iii) they were not attributable to their high structural similarity with the cytokine interleukin-1. Thus fibroblast growth factors did not show any thermogenic activity, did not affect the hypothalamic output of corticotropin-releasing factor and did not change the plasma levels of corticosterone. Pretreatment of the rats with a specific inhibitor of brain nitric oxide synthase prevented the effects of fibroblast growth factors, suggesting the involvement of nitric oxide in these behavioral modifications. Our results contribute to the accumulating evidence describing non-mitogenic activities of fibroblast growth factors.

Animals↗
PubMed1996

Central nervous system distribution of fibroblast growth factor injected into the blood stream.

It has been shown that fibroblast growth factors (FGFs) protect hypocampal CAI cells from the effects of transient ischemia when injected either intraventrically or intravenously. The effectiveness of the systemic treatment seems to suggest that FGFs cross the blood-brain barrier to some extent. The appearance of basic fibroblast growth factor (bFGF) in the rat central nervous system after systemic administration have been autoradiographically examined using a 14C uniformly labeled preparation. Our results show that, two hours after a systemic bolus administration, bFGF spots in several populations of neuronal and in non-neural cells except in glial cells. Label accumulation was imperceptible when either 14C-bFGF was heated previously to the systemic injection or was co-administered with an excess of unlabeled bFGF. Our results indicate the existence of a saturable transport system of FGFs across the blood-brain barrier.

Animals↗
PubMed1996

Is glia disfunction the initial cause of neuronal death in ischemic penumbra?

The supportive role of glial cells on neuronal function and survival has been studied in anesthetized rats by using the selective gliotoxin fluorocitrate. Disabling glia operation reproduced many features of ischemic penumbra. An initial mild acidosis and increased interstitial potassium but not glutamate was followed after 3-4 h by repetitive spreading depression waves. These gradually provoked higher levels of acidosis, potassium and glutamate, gradual neuronal function decay and finally, neuron death. We conclude that neurons become highly vulnerable to spreading depression waves only in absence of normal glia operation. Our findings directly associate early glial disfunction to neuronal loss and lead to new insights for the understanding of ischemic pathology.

Animals↗
PubMed1996

Sleep promoting effects of intravenously administered acidic fibroblast growth factor.

The influence of acidic fibroblast growth factor (aFGF) on sleep was studied in conscious rabbits. An intravenous (i.v.) bolus injection of aFGF induced a significant increase in sleep duration in comparison with animals that received vehicle solution. Somnogenic effects were obtained 30 min following i.v. aFGF administration and lasted about 75 min. Furthermore, the somnogenic effects of aFGF were prevented by pretreatment with the nitric oxide synthase inhibitor L-NAME. Our findings demonstrate a somnogenic effect of aFGF which requires crossing the blood-brain barrier (BBB) and implicate that nitric oxide sleep pathway may be involved in this biological effect.

Animals↗