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Biomedical subjects

G Folco

Publications and source records attributed to G Folco.

At least 55 records · Page 3Linked to original sources
PubMed1993

Formation of sulphidopeptide-leukotrienes by cell-cell interaction causes coronary vasoconstriction in isolated, cell-perfused heart of rabbit.

1. We have studied the transcellular biosynthesis of bioactive leukotrienes (LTs), generated upon blood cell-vascular wall interactions and their functional consequences, in the spontaneously beating, cell-perfused, heart of the rabbit. Rabbit isolated hearts were perfused under recirculating conditions (50 ml) with 5 x 10(6) cells of unpurified (buffy coat) or purified human neutrophils (PMNL), and challenged with 0.5 microM A23187 for 30 min. Coronary perfusion pressure (CPP), heart rate (HR), left ventricular end-diastolic pressure (LVEDP) and left ventricular pressure (LVP) were monitored continuously. Leukotriene formation was measured by specific enzyme-immunoassay and confirmed by reversed phase h.p.l.c. and u.v. spectral analysis. 2. Basal CPP values averaged 44 +/- 1.4 mmHg; A23187 triggered a marked increase in CPP both in the presence of buffy coat cells (+100% above basal) and PMNL (+270% above basal); the latter change in CPP was accompanied by a rise in LVEDP (+138% above basal). 3. The increase in CPP was preceded by a statistically significant rise in iLTC4-D4 concentration in the circulating buffer. Pretreatment with two structurally unrelated LTD4 receptor antagonists, LY171883 and SKF104353 (10 microM), fully prevented the increase in CPP and LVEDP. A similar protection was also observed when the rabbit heart was perfused with PMNL that had been pretreated with MK886 (1 microM), a potent inhibitor of leukotriene biosynthesis. 4. The increased coronary tone was accompanied by a marked release of lactate dehydrogenase (LDH), a marker of ischaemic damage; pretreatment of the heart with the LTD4 receptor antagonists as well as of the PMNL with MK886 resulted in a complete suppression of LDH activity release. 5. Positive identification of LTC4-D4 in the perfusates was obtained and a significant correlation observed between the CPP values and iLTC4-D4 concentrations.6. This study suggests that challenge of PMNL present within the coronary vasculature, causes a LTD4-dependent coronary vasoconstriction, favoured by an efficient uptake of PMNL-derived LTA4 by endothelial cells. The activation of the 5-lipoxygenase pathway in the context of tight interactions between blood cells and coronary vasculature, is suggested to have an important outcome in the alterations of coronary flow and cardiac contractility.

Animals↗
PubMed1992

CR 2039, a new bis-(1H-tetrazol-5-yl)phenylbenzamide derivative with potential for the topical treatment of asthma.

The pharmacological activity of CR 2039 (4-(1H-tetrazol-5-yl)-N-(4-[1H-tetrazol-5-yl]phenylbenzam ide)) a newly discovered antiallergic compound is described. CR 2039 administered i.m. or i.v. inhibited rat passive cutaneous anaphylaxis (PCA) with an ED50 of 0.1 mg/kg and a potency about 15 times higher than that of disodium cromoglycate (DSCG). CR 2039 i.m., by aerosol or as dry powder insufflation, gave dose-related significant protection against IgE-dependent bronchial anaphylaxis induced by aerosolized antigen in anesthetized guinea-pigs. In conscious guinea-pigs CR 2039 given i.m. delayed dose dependently (ED50, 17 mg/kg) the onset of bronchoconstriction induced by aerosolized antigen, while DSCG was ineffective up to 100 mg/kg. The protection was accompanied by significant inhibition of the vascular permeability provoked by antigen challenge in all airway segments except trachea. CR 2039 (10-100 mg/kg i.v.) inhibited the microvascular permeability changes in a model of allergic conjunctivitis in sensitized guinea-pigs. CR 2039 inhibited dose dependently guinea-pig lung cAMP-phosphodiesterase with an IC50 of 50 microM.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1990

Prostaglandins and gastric mucosal protection by esaprazole in rats.

Esaprazole, N-cyclohexyl-1-piperazineacetamide monohydrochloride, was studied for its activity to prevent gastric mucosal damage induced by several necrotizing agents in the rat. Its effects on acid gastric secretion and the role of gastric mucosal prostaglandin generation were also investigated. Esaprazole, given orally, dose dependently prevented the formation of mucosal damage induced by absolute ethanol, 0.2 N NaOH or 0.6 N HCl. This activity occurred at doses lower than the antisecretory doses. Esaprazole was also found to increase the gastric mucosal prostaglandin content but at doses that exceeded the cytoprotective doses. The failure of indomethacin to impair the gastric mucosal protection provided by esaprazole suggests that mechanisms other than mobilization of endogenous prostaglandins may be involved.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Mediator release after endobronchial antigen challenge in patients with respiratory allergy.

The aim of the present study was to evaluate the release of some potential mediators of allergic reactions, such as histamine, peptide leukotrienes (LTs), LTB4 and prostaglandin D2 (PGD2), in bronchoalveolar lavage (BAL) fluids from 11 patients with respiratory allergy (eight with bronchial asthma and three with allergic rhinitis), who underwent specific endobronchial challenge. Histamine, peptide LT, and PGD2 levels in BAL fluids increased significantly after antigen stimulation both in patients with asthma and in patients with rhinitis. By contrast, LTB4 concentration was always below the limits of detection of the radioimmunoassay. In patients with asthma, histamine concentration increased from 5.3 +/- 0.6 ng/ml in lavages obtained before provocation to 20.2 +/- 5.8 ng/ml (mean +/- SEM; p less than 0.04) 5 minutes after bronchoprovocation. Peptide LTs increased from 0.32 +/- 0.08 to 0.82 +/- 0.21 ng/ml (p less than 0.02) and PGD2 from 0.06 +/- 0.01 ng/ml to 0.36 +/- 0.09 ng/ml (p less than 0.02). Elevated histamine, peptide LT, and PGD2 concentrations were also found in the 15-minute postchallenge BAL fluids. Similar results were obtained in patients with rhinitis. Histamine concentration was 3.4 +/- 0.6 ng/ml in prechallenge bronchial lavages and 11.3 +/- 1.7 ng/ml in postchallenge lavages; peptide LTs increased from 0.13 +/- 0.008 ng/ml to 0.73 +/- 0.21 ng/ml, and PGD2 from 0.05 +/- 0.01 ng/ml to 0.26 +/- 0.06 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Inhibition by lipoxygenase products of TXA2-like responses of platelets and vascular smooth muscle. 14-Hydroxy from 22:6n-3 is more potent than 12-HETE.

Lipoxygenase products, which are formed in great amounts in platelets during their activation, have been prepared from arachidonic acid (20:4n-6), the main polyunsaturated fatty acid (PUFA) esterified in platelet phospholipids, and from two major PUFAs of fish fat, eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) acids. These compounds have been synthesized using platelet suspension as enzymic source, purified by high performance liquid chromatography, and their structure were checked by gas chromatography-mass spectrometry. Their effects were investigated in vitro upon human platelet aggregation induced by 11,9-epoxy-methano-analogue of PGH2 (U-46619) and upon thromboxane A2-induced vasoconstriction of rabbit aorta. All hydroxylated fatty acids inhibited U-46619-induced aggregation in a concentration-dependent fashion. Compounds issued from 22:6n-3 were the most potent inhibitors and their IC50 differed significantly from that of 12-hydroxy-eicosatetraenoic acid (12-HETE). Among them, 14-hydroxy-docosahexaenoic acid (14-OH-22:6) was the most effective anti-aggregating molecule (IC50:0.45 microM). 10 microM 12-HETE and 14-OH-22:6 inhibited 60% and 75% of smooth muscle contraction induced by TXA2-like material, respectively. At 1 microM, solely 14-OH-22:6 had an inhibitory effect on adrenaline-, angiotensine- or histamine-induced contraction. Since thromboxane receptors in platelets and vascular smooth muscle cells present strong similarities, it is concluded that hydroxylated fatty acids can antagonize prostanoid action probably by interfering with their receptor sites.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1987

Defibrotide, an antithrombotic substance which prevents myocardial contracture in ischemic rabbit heart.

Defibrotide, a polydeoxyribonucleotide obtained from mammalian lungs, reduced in a dose-dependent fashion the ischemic contracture due to low perfusion (0.2 ml/min) of isovolumic left heart of rabbit and abolished the irregular rhythm of the heart, thereby restoring the cardiomechanical activity upon reperfusion (20 ml/min). Defibrotide stimulated the release of PG-like material from the heart in a dose-dependent manner without modifying the basal contractility. Both PGE2 and PGI2 (10 ng/ml) have an antiischemic activity on this preparation as shown by the partial reduction of the ischemic contracture and by the improvement of heart contractility upon reperfusion. Indomethacin infusion (1 microgram/ml) completely removed both the antiischemic activity of Defibrotide (400 micrograms/ml) and its ability to increase the generation of prostaglandins in the rabbit heart. These results suggest that Defibrotide has a beneficial influence on ischemic rabbit heart through an increase in prostaglandin synthesis. However other mechanisms not necessarily related to prostaglandin generation, such as a direct effect on membrane function deactivation and mitochondrial Ca2+ overload, should be considered in explaining the antiischemic activity of Defibrotide in the rabbit heart.

Animals↗
PubMed1987

Effect of baclofen on different models of bronchial hyperreactivity in the guinea-pig.

In this paper we report an inhibitory effect of (-)-baclofen on many models of bronchial hyperreactivity both in vivo and in vitro. (-)-Baclofen protects guinea-pigs from the anaphylactic bronchospasm induced in sensitized animals by an ovalbumin aerosol and from that induced by aerosols of histamine and PGF2 alpha. Moreover (-)-baclofen reduces the TXA2 and TXB2 output induced by ovalbumin from isolated sensitized guinea-pig lungs. On the other hand (-)-baclofen does not show antihistaminic, anticholinergic or antiprostaglandinic action on isolated tracheal preparations. It is concluded that baclofen can provide protection from bronchial hyperreactivity possibly through a modulation of autonomic nervous system activity.

Acetylcholine↗
PubMed1987

Behavior and clinical relevance of histamine and leukotrienes C4 and B4 in grass pollen-induced rhinitis.

The release kinetics of histamine and leukotrienes C4 (LTC4) and B4 (LTB4) were investigated in nasal secretions of 10 patients with hay fever after antigen challenge. High levels of biologically active histamine were found in nasal washes from asymptomatic allergic and normal subjects. With repeated lavages, the amount of histamine recovered dropped markedly. Grass pollen challenge was followed by a significant (p less than 0.05) dose-dependent and time-limited (5 min) increase in histamine level in 7 of 10 patients; these values, however, were lower than those found in basal conditions. In 8 of 10 patients with hay fever, antigen challenge induced a significant (p less than 0.05) dose-dependent increase in LTC4 level, which persisted for 30 min. The LTC4 generation was well correlated with the appearance of allergic symptoms; LTB4 production was found in 2 patients only. A different pattern of symptoms was observed after in vivo nasal stimulation with histamine and LTC4. Histamine caused sneezing, itching, rhinorrhea, and nasal obstruction; conversely, the main symptom induced by LTC4 was a more pronounced and longer lasting nasal obstruction.

Adult↗
PubMed1986

Stimulus-related difference in the formation of leukotrienes and PGD2 after immunological and non-immunological challenge of human lung parenchyma "in vitro".

The stimulation of human lung parenchymal fragments with A-23187 induces formation of leukotrienes as well as of PGD2: LTE4 is the compound found in larger amount and independently of the intensity of the stimulus the % of metabolized precursor which is converted to leukotrienes or PGD2 is remarkably similar. However, under conditions of IgE-Anti IgE challenge the predominant conversion of arachidonic acid occurs to PGD2, LTB4 is almost negligible and LTD4 and E4 together represent less than 30% of the oxidative products of arachidonic acid. Whether PGD2 and leukotrienes derive from the same or different subset of cells is unresolved.

Antibodies↗
PubMed1986

Arachidonate metabolites and vasospasm after subarachnoid haemorrhage.

A wide literature exists about the pathogenesis of cerebral arterial spasm following subarachnoid haemorrhage: several compounds have been identified in human cerebrospinal fluid as possible vasoactive agents involved in the biochemical mechanism of vasospasm onset. Many experimental evidences exist for a major involvement of arachidonate metabolites. The present work represents a review of experimental data supporting the hypothesis of cerebral arterial spasm as a result of an imbalanced vascular regulatory mechanism involving arachidonate metabolites. The authors have also monitored, in 25 cases of aneurysmal subarachnoid haemorrhage, lumbar and cisternal CSF levels of prostacyclin and PGD2, as representative of vasodilating and, respectively, vasoconstrictor compounds. In all cases CSF arachidonate metabolite levels after SAH were significantly higher than in control cases. Ten patients presented with symptomatic vasospasm: lumbar CSF PGD2 levels show fluctuations with superimposed peaks related to the neurological deterioration due to vasospasm, while lumbar CSF prostacyclin concentration-trend suggest a decreasing synthesis. In 15 patients presenting without vasospasm, lumbar CSF concentration of arachidonate metabolites are in a 'steady-state'. These data confirm the existence of an imbalanced biochemical situation promoting vasospasm, markedly in cisterns near to the ruptured aneurysmal wall. The evaluation of cisternal CSF levels of arachidonate metabolites supports the hypothesis of the clotting phenomenon around the ruptured aneurysm as an important predictive pattern of vasospasm, as shown in CT findings.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Non-steroidal antiinflammatory drug therapy: advantages and disadvantages of long half-life drugs versus slow-release formulations.

A single daily administration of non-steroidal antiinflammatory drugs is widely recognized as the best dose regimen in chronic diseases such as degenerative osteoarthropathy, in inflammatory affections of the skeletal muscles, etc. Biomedical research has therefore developed drugs characterized either by a long half-life or available in a slow-release formulation. Isoxicam, piroxicam and benoxaprofen, which possess long half-lives, were compared with diclofenac sodium, indomethacin and ketoprofen, in their slow-release formulations, in terms of pharmacodynamics, pharmacokinetics and toxicity. Isoxicam, piroxicam and diclofenac showed excellent long lasting antiinflammatory properties: however the evidence showed that in cases of mild or severe renal pathology, drugs in their slow-release formulations are to be preferred.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1985

Cisternal and lumbar CSF concentration of arachidonate metabolites in vasospasm following subarachnoid hemorrhage from ruptured aneurysm: biochemical and clinical considerations.

Two representative cases of subarachnoid hemorrhage in which prostaglandin D2 (PGD2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), stable metabolite of prostacyclin (PGI2), were monitored with serial lumbar punctures and detected in cisternal CSF during operations for aneurysm, are reported. In the case with demonstrated arterial vasospasm, prostaglandin D2 has a concentration trend with characteristic peak related to vasospasm; the synthesis of prostacyclin appears inhibited after the hemorrhage. In the patient without radiologic evidence of vasospasm, arachidonate metabolite concentration trend appears in a steady-state. Cisternal prostaglandin D2 concentration in the patient with demonstrated vasospasm is two times the highest lumbar CSF concentration, while 6-keto-prostaglandin F1 alpha concentration is very low. This suggests the role of the clotting phenomenon and likely confirms the importance of arachidonate metabolites in the genesis of cerebral arterial spasm following subarachnoid hemorrhage.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Release of leukotrienes, induced by the Ca++ ionophore A23187, from human lung parenchyma in vitro.

When chopped human lung is stimulated with the Ca++ ionophore A23187 (0.25-10 microM) leukotriene (LT) B4, LTD4 and LTE4 are found in the incubation medium according to different patterns. LTD4 is released promptly and its levels increase up to 45 min after the stimulus (A23187, 10 microM) and decline later (120 min); LTE4 formation follows a sigmoidal shape and continues to accumulate even 2 hr after the challenge; LTB4 levels reach a plateau at 45 min. LTC4 was undetectable in most experiments but it was found to accumulate when reduced glutathione (10 mM) was added. Addition of exogenous LTC4 to unstimulated fragments of human lung shows that an effective interconversion to LTD4 and LTE4 takes place: A23187 stimulates formation of LT and cyclo-oxygenase products dose dependently; a statistically significant formation of LT occurs at A23187 concentration of 1 microM whereas thromboxane B2 (TXB2) and 6-K-prostaglandin F1 alpha levels increased significantly only at 2.5 microM A23187. Pretreatment with U-60257 (100 microM) prevented formation of LT without a concomitant increase of TXB2 levels. Indomethacin (1.5 microM) blocked the release of 6-K-prostaglandin F1 alpha and TXB2 without a shift of arachidonic acid towards LT-like activity. Addition of exogenous LTC4 did not trigger synthesis of TXB2 or 6-K-prostaglandin F1 alpha. Our results indicate that reduced glutathione levels and the activity of the enzymes involved in LT biosynthesis and/or metabolism play an important role in controlling the pattern of LT release from human lung.

Arachidonic Acid↗
PubMed1984

Beta-adrenoceptor and cyclo-oxygenase block as a tool for evoking the direct bronchoconstrictor effect of leukotriene C4 in the guinea-pig.

The intravenous administration of LTC4 to anaesthetized guinea-pigs induced dose-dependent bronchoconstriction, which was maximal at the dose of 1.6 nmol kg-1. The response was abolished by indomethacin. The maximal dose of LTC4, preceded by both (-)-propranolol and indomethacin, induced maximal, slow in onset and reversible broncho-constriction. This direct effect of LTC4 was markedly and long-lastingly antagonized by FPL-55712. The beta-blocker did not appreciably affect the systemic blood pressure changes induced by LTC4. The procedure described is suggested as a suitable tool for investigating the per se effect of leukotrienes on the guinea-pig airways in vivo, as well as the efficacy of their receptor antagonists.

Adrenergic beta-Antagonists↗
PubMed1982

Anticholinergic agents prevent guinea-pig airway constriction induced by histamine, bradykinin and leukotriene C4: Relationship to circulating TXA2.

Various doses of histamine, bradykinin and leukotriene C4 caused bronchoconstriction in anaesthetized guinea-pigs which were breathing spontaneously or artificially ventilated; there was a simultaneous, dose-related increase in circulating TXA2. The animals were prepared for continuous recording of extracorporeal circulation in order to detect the appearance in the blood of bioassayable levels of TXA2 -like substance. Furthermore, a TXA2 derivative, the mono-O-Me-TXB2, was radioimmunoassayed. Atropine, oxytropium bromide and ipratropium bromide given in mumol doses prevented both the increased airway resistance and the release of TXA2-like substance in the blood Pirenzepine dihydrochloride was the least active of the drugs tested. The protecting activity of anticholinergics and the relationship with their ability to affect TXA2-like substance generation suggest a new site of action for these drugs besides the blockade of muscarinic receptors.

Airway Resistance↗