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Biomedical subjects

G C Folco

Publications and source records attributed to G C Folco.

At least 37 records · Page 2Linked to original sources
PubMed1988

Mediators and allergic inflammation of human airways.

Local antigen challenge in patients with respiratory allergy is associated with histamine and arachidonic acid metabolites release, both in upper and in lower respiratory airways. Raised histamine levels can be detected in nasal secretions 5 min after allergen stimulation. Increased leukotriene C4 and prostaglandin D2 concentrations persist for a longer period (respectively 20 and 30 min). Endobronchial antigen stimulation is also followed by release of histamine, leukotriene C4 and prostaglandin D2, which can be detected in bronchial lavage fluid. Elevated concentrations of these mediators can be found 5 and 15 min after challenge. Moreover, endobronchial antigen stimulation is associated with an increase in the number of bronchial epithelial cells recovered in bronchial lavage fluids.

Adult↗
PubMed1988

(5Z)-carbacyclin displays agonist-antagonist properties on prostacyclin-receptors in platelets and vascular myocytes.

(5E)- and (5Z)-carbacyclin are chemically stable analogues of prostacyclin (PGI2), which mimic PGI2 actions. In particular, they inhibit platelet aggregation and relax vascular smooth muscle, through the activation of adenylate cyclase (AC) being, however, less potent than PGI2. The characteristics of AC activity modulation by the two isomeric carbacyclins in membranes of human platelets and of myocytes cultured from rabbit mesenteric artery have been investigated. In human platelet membranes, both carbacyclins stimulated AC activity with the same efficacy as PGE1 and PGI2; in addition, these two prostaglandins inhibited the aggregation of human and rabbit platelets to the same extent as PGE1. On the contrary, in myocytes (5Z)-carbacyclin fails to produce the same degree of stimulation of AC elicited by PGI2, (5E)-carbacyclin and PGE1, nor does it induce the maximal relaxation of rabbit mesenteric artery attained with the other prostaglandins. (5Z)-carbacyclin is also able to antagonize the activation of AC by PGE1, PGI2 or (5E)-carbacyclin, acting therefore as a partial agonist. In conclusion, (5Z)-carbacyclin is a full agonist at the platelet level both in human and rabbit, thus excluding possible interspecies differences, but it is a partial agonist on myocytes. Therefore, (5Z)-carbacyclin appears to discriminate between PGI2 -receptors in the two target cells.

Adenylyl Cyclases↗
PubMed1988

Prostaglandin synthetase inhibition and formation of lipoxygenase products in immunologically challenged normal human lung parenchyma.

Normal human lung parenchyma, passively sensitized with an hyperimmune serum, releases eicosanoids from the cyclo-oxygenase pathway and from different lipoxygenases (5-, 12-, 15-HETE) upon anti-IgE challenge. Prostaglandin D2 represents almost 50% of the total arachidonate metabolites whereas, among sulphidopeptide leukotrienes, LTE4 is the one present in larger amounts. Pretreatment of the passively sensitized tissue with indomethacin (1.5 X 10(-5) M) inhibits cyclo-oxygenase by more than 90% without a concomitant shift of arachidonate metabolism towards leukotriene formation.

Biological Assay↗
PubMed1987

(5Z)-carbacyclin discriminates between prostacyclin-receptors coupled to adenylate cyclase in vascular smooth muscle and platelets.

(5E)- and (5Z)-carbacyclin are prostacyclin (PGI2) analogues endowed with antiaggregating and vasodilator properties, which stimulate adenylate cyclase activity in membranes from human platelets and cultured myocytes from rabbit mesenteric artery. In platelets they display the same efficacy as prostaglandin E1 (PGE1), and hence PGI2 both as activators of adenylate cyclase and as inhibitors of aggregation. In contrast, in vascular smooth muscle cells (5Z)-carbacyclin fails to produce the same degree of stimulation of the enzyme as PGI2, (5E)-carbacyclin and PGE1, nor does it induce the maximal relaxation of the mesenteric artery as do the other prostaglandins. (5Z)-carbacyclin is also able to antagonize the activation of adenylate cyclase and the relaxation elicited by PGE1 or PGI2 in the mesenteric artery, and therefore it displays partial agonist properties in these cells. We conclude that the receptors for PGI2 coupled to adenylate cyclase in platelets and vascular smooth muscle cells are different from each other, because (5Z)-carbacyclin can discriminate between them, being a partial agonist at myocyte but not at platelet level.

Adenylyl Cyclases↗
PubMed1987

Study of mediators of anaphylaxis in nasal wash fluids after aspirin and sodium metabisulfite nasal provocation in intolerant rhinitic patients.

Nasal histamine (H), leukotriene C4 (I-LTC4) and SRS-A activity were studied in seven aspirin-(ASA)-intolerant patients (AIR) with rhinitis and in five ASA-tolerant control patients with chronic rhinitis after nasal provocation (NP) with a lysine acetylsalicylate solution. The same parameters were also studied after metabisulfite (MBS) NP in four sulfite-intolerant patients with rhinitis and in six control patients with chronic rhinitis. In six ASA-intolerant subjects and in four controls, we studied the PGD2 levels in nasal washes after ASA NP 0.2 mL of lysine acetylsalicylate solution (10 mg/mL) was sprayed intranasally in ASA-intolerant patients and controls and a 25-mg/mL MBS solution in sulfite intolerant patients and controls. Nasal wash fluids were obtained using 5 mL of 0.15 M saline before and 7 1/2, 15, 30, and 60 minutes after nasal provocation. The nasal provocation with ASA induced itching and sneezing in four out of seven intolerant subjects. In this subgroup histamine values in nasal wash fluids were significantly higher versus the remaining ASA-intolerant patients at 30 and 60 minutes (P less than .05 and P less than .01, respectively) and versus controls at 60 minutes (P less than .01). We found significantly higher I-LTC4 (P less than .01) and SRS-A levels in nasal washes collected from ASA-intolerant subjects versus controls at 60 minutes after nasal provocation. There was no significant increase in the mean PGD2 values in either the ASA-intolerant or control groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspirin↗
PubMed1986

Effect of the beta-2 adrenergic agonist fenoterol on the release of leukotrienes and prostaglandin D2 from human lung parenchyma.

Ca++-ionophore and antigen challenge of human lung fragments caused a massive release of leukotrienes, whose relative proportions varied considerably and were dependent on the experimental conditions. A broncho-selective beta 2-adrenoceptor agonist fenoterol was able to prevent the antigen-induced leukotriene release completely, whereas the Ca++-ionophore induced leukotriene release was only moderately inhibited. The HPLC data were confirmed by SRS-A bioassay.

Arachidonic Acid↗
PubMed1985

Identification of specific binding sites for leukotriene C4 in membranes from human lung.

Leukotriene C4 (LTC4), one of the major components of the slow-reacting substance of anaphylaxis (SRS-A), is a potent constrictor of bronchial smooth muscle in many species including humans. Here we report the identification and characterization of specific binding sites for LTC4 in membranes from human lung parenchyma. At 4 degrees, 3H-LTC4 binding is specific, saturable (Bmax = 32-41 pmoles/mg prot.), rapid (equilibrium being attained within 15 min), reversible and of high affinity (Kd = 3.6-7 X 10(-8) M). The binding sites are sensitive to heat and probably possess a protein moiety, being inactivated upon trypsinization. CaCl2 affects both the association and the dissociation rate and dose-dependently enhances the binding of 3H-LTC4 at equilibrium; maximal enhancement (4-fold) occurred at 10(-2)M CaCl2. Unlabelled LTC4 is able to complete with 3H-LTC4 for its binding sites with an IC50 of 7.8 X 10(-8) M. The addition of 10(-2) M CaCl2 increases the potency of LTC4 in inhibiting the binding (2.2-fold); both the competition curves are monophasic, indicating the existence of a homogeneous class of binding sites. In the presence of CaCl2, LTD4, LTE4 and the SRS-A antagonist FPL 55712 can inhibit 3H-LTC4 specific binding, being, however, less potent than LTC4 (IC50 S = 2.2 X 10(-6), 2.4 X 10(-5) M, for LTD4, LTE4 and FPL 55712, respectively). FPL 55712 displayed a competitive mechanism; its affinity, however, was lower if absorption to glass was not prevented. The present studies indicate that specific binding sites for 3H-LTC4 exist in human lung parenchyma, and that a receptor-mediated process might be involved in the bronchoconstriction induced by LTC4.

Calcium Chloride↗
PubMed1984

Intima-related vasodilatation of the perfused rat caudal artery.

We examined the endothelial dependence of responses to ACh and some vasodilator drugs by using the central tail artery of the rat perfused with Krebs buffer. Perfusion with ACh (100 nM-100 microM) produced dose-dependent vasodilatation of arteries preconstricted with norepinephrine and antagonized pressor responses to periarterial electrical stimulation. Endothelium was removed by introducing a fine catheter through the lumen or a stream of gas (O2 95%-CO2 5%) intraluminally. Both procedures prevented the vasodilator effect of ACh. Gassing also abolished the vasodilatation in response to hydralazine 334 nM but not to equidilator amounts of papaverine 13 microM, or nitroglycerin 50 nM. These results indicating endothelial dependence of hydralazine and ACh responses are in accord with our previous studies on vascular rings.

Acetylcholine↗
PubMed1984

Gastroprotective effects of morniflumate, an esterified anti-inflammatory drug.

An experimental study on morniflumate, the beta-morpholinoethyl ester of niflumic acid, was undertaken in the rat to test its gastroprotective and "cytoprotective" properties and to assess its effects on gastric secretion and on the prostaglandin contents in the stomach wall. Morniflumate induced intense and usually dose-dependent inhibition of the gastric hemorrhagic lesions caused by acetylsalicylic acid, indomethacin, diclofenac, ketoprofen, naproxen and phenylbutazone and of the gastric necrotic lesions caused by absolute ethanol, HCl 0.6 mol l-1, NaOH 0.2 mol l-1 and NaCl 25%. Morniflumate also exerted marked inhibition of gastric acid secretion both in normal and in pylorus-ligated rats. The compound raised the concentration of "cytoprotective" prostaglandins in the glandular portion of the stomach but did not reverse the synthesis-block effect of the ulcerogenic nonsteroidal anti-inflammatory drugs whose gastric effects it inhibited.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Bronchodilating activity of mequitazine.

The bronchodilating activity of mequitazine (MQ) (10-[3- quinuclidynilmethyl ]-phenothiazine) has been investigated in the guinea-pig using various spasmogens such as acetylcholine, histamine and leukotriene-C4 (LTC4). Mequitazine showed a potent protecting activity versus bronchoconstriction induced by the above agonists and was also able to prevent their capacity to trigger activation of arachidonic acid metabolism and preferential formation of TXA2. The results obtained with the "in vivo" experiments correlate well with those obtained "in vitro" using guinea-pig perfused lungs, where LTC4 and histamine stimulate TXA2 formation and release in the pulmonary effluent. MQ demonstrated its efficacy in protecting passively sensitized guinea-pigs from antigen challenge; this protection is accompanied by a substantial reduction of circulating TXA2. The bronchodilating and antiallergic activity of MQ is likely due to a direct control of histamine and muscarinic receptors and to a diminished bioamplification via eicosanoid activation. In addition, the capacity of MQ to counteract the "in vitro" and "in vivo" effects of LTC4 adds interest to its therapeutic potential.

Acetylcholine↗
PubMed1983

New pharmacological aspects of the bronchodilating activity of procaterol.

The selectivity of procaterol for beta 2-adrenoceptors vs beta 1-adrenoceptors in animals has been already described. In these studies the ability of procaterol to protect guinea-pig against bronchoconstriction induced by various spasmogens such as histamine, LTC4 and acetylcholine is demonstrated. The results obtained both in anaesthetized animals and in perfused lungs clearly show that procaterol antagonizes not only the direct effect of the bronchoconstrictors quoted above but also their ability to activate arachidonic acid metabolism and to augment the generation of TXA2. Procaterol (0, 3-3 micrograms/Kg i.v.) is more potent than salbutamol in protecting passively sensitized guinea-pig from massive bronchoconstriction following antigen challenge: a phenomenon which is paralleled by an increment of the circulating TXA2. The possibility that the adenylate-cyclase-stimulating properties of procaterol may explain its antiasthmatic activity is discussed.

Animals↗
PubMed1983

Beta 2-adrenoceptor blockade is the basis of guinea-pig bronchial hyper-responsiveness to leukotriene C4 and other agonists.

Four beta-adrenoceptor antagonists, namely (-)-propranolol, (+)-propranolol, ICI-118551 and (+/-)-practolol, were investigated for their effects on leukotriene C4 (LTC4)-induced bronchoconstriction in the anesthetized guinea-pig. (-)-Propranolol was also investigated for its effects on acetylcholine and histamine bronchospasm in the anaesthetized guinea-pig, and on LTC4-induced contractions of guinea-pig isolated trachea and lung parenchyma. The various beta-adrenoceptor antagonists potentiated, dose-dependently, the bronchoconstriction induced by threshold doses of LTC4 and the intensity of the potentiation correlated with the beta 2-blocking capacity possessed by the drugs. (-)-Propranolol potentiated the bronchospasm induced by threshold doses of acetylcholine and histamine but to a lesser degree than the LTC4-induced bronchospasm. The airway hyper-responsiveness induced by (-)-propranolol was unaffected by pretreatment with mepyramine, cyproheptadine, phenoxybenzamine, atropine or indomethacin. The airway hyper-responsiveness induced by (-)-propranolol persisted even in adrenalectomized or reserpine-treated guinea-pigs, although adrenalectomy induced some increase in airway responsiveness. (-)-Propranolol had no effect on LTC4, histamine and acetylcholine-induced contractions of isolated trachea and lung parenchyma. The results show that the airway hyper-responsiveness induced by beta-adrenoceptor antagonists generally correlates with their beta 2-blocking activity. The possibility remains that some other unknown mechanism(s) may also be implicated.

Adrenalectomy↗