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F Ledda

Publications and source records attributed to F Ledda.

118 records · Page 7Linked to original sources
PubMedDate not supplied

Enhancement of the vasoconstrictor response to KCL by nitric oxide synthesis inhibition: a comparison with noradrenaline.

The role of the vascular endothelium in the response to a vasoconstrictor agent acting through a non-receptorial mechanism, such as KCl, was tested in the isolated mesenteric vascular bed of the rat. It was confirmed that the vasoconstrictor response evoked by stimulation of sympathetic terminals was unaffected by 100 microM NG-nitro-D-arginine methyl ester (D-NAME), but was significantly potentiated by 100 microM NG-nitro-L-arginine methyl ester (L-NAME) and by removal of endothelium. Responses to exogenous noradrenaline (1-100 microM) were also enhanced by treatment with 100 microM NG-monomethyl-L-arginine (L-NMMA) and with L-NAME, but not with D-NAME. The potentiating effect of NO synthesis inhibitors was reversed by 1 mM L-arginine. Moreover, the noradrenaline-induced vasoconstriction was significantly increased by endothelium-deprivation. Potassium chloride (80 mM) induced a vasoconstrictor response which was not modified by pretreatment with prazosin (0.1 microM) and yohimbine (0.1 microM). The response to KCl was unaffected by D-NAME (100 microM) but the L-stereoisomer induced a significant increase in the perfusion pressure. In endothelium-denuded preparations the vasoconstrictor response to KCl was greater than in control conditions and was quantitatively similar to that observed in L-NAME-treated preparations. The responses to electrical field stimulation, noradrenaline and KCl in endothelium-denuded preparations were not modified by L-NAME. The results suggest that an increase in vascular tone, per se, may represent a trigger for the release of endothelium-derived relaxing factor from endothelial cells.

Amino Acid Oxidoreductases↗
PubMedDate not supplied

Different efficacy of in vivo herpes simplex virus thymidine kinase gene transduction and ganciclovir treatment on the inhibition of tumor growth of murine and human melanoma cells and rat glioblastoma cells.

Initial studies have demonstrated the therapeutic efficacy for cancer treatment of in vivo transfer of the herpes simplex virus thymidine kinase gene followed by ganciclovir (GCV) treatment. However, recent studies have questioned the validity of this approach. Using retroviral vector-producing cells (VPC) as a source for in vivo gene transfer, we evaluated the efficacy of in vivo transduction of malignant cells using three different tumor cell models: B16 murine and IIB-MEL-LES human melanomas and a C6 rat glioblastoma. In vitro studies showed a bystander effect only in C6 cells. In vivo studies showed an inhibition of tumor growth in the two melanoma models when tumor cells were coinjected with VPC-producing retroviral vectors carrying the herpes simplex virus thymidine kinase gene, followed by GCV treatment; however, 100% of mice developed tumors in both models. Under similar experimental conditions, 70% (7 of 10) of syngeneic rats completely rejected stereotactically transferred C6 tumor cells; most of them (5 of 10) showed a prolonged survival. Treating established C6 tumors with VPC-producing retroviral vectors carrying the herpes simplex virus thymidine kinase gene and GCV led to the cure of 33% (4 of 12) of the animals. Rats that rejected tumor growth developed an antitumor immune memory, leading to a rejection of a stereotactic contralateral challenge with parental cells. The immune infiltrate, which showed the presence of T lymphocytes, macrophages, and polymorphonuclear cells at the site of the first injection and mainly T lymphocytes and macrophages at the site of tumor challenge, strengthened the importance of the immune system in achieving complete tumor rejection.

Animals↗
PubMedDate not supplied

Induction by histamine of oscillatory activity in sheep Purkinje fibers and suppression by verapamil or lidocaine.

Histamine (1--2 x 10(-5) M) induced or enhanced oscillatory activity in four of five sheep Purkinje fibers depolarized by a low-potassium medium. These effects of histamine were readily antagonized by 2 x 10(-5) M burimamide but were unaffected by 10(-5) M practolol. Oscillatory activity was consistently induced or enhanced by 5 x 10(-6) M adrenaline in five preparations. Oscillatory activity, whether induced by histamine or adrenaline, was always abolished by verapamil (0.22--2.2 x 10(-6 M) but in only one of five experiments by lidocaine (4.2 x 10(-5) M). We conclude that induction of oscillatory responses may be added to the other arrhythmogenic mechanisms produced by histamine through the stimulation of H2 receptors. We confirmed that oscillatory activity is very effectively suppressed by verapamil.

Action Potentials↗
PubMedDate not supplied

Electrophysiological and antiarrhythmic properties of propafenon in isolated cardiac preparations.

Propafenon, a new antiarrhythmic drug, caused a 30% decrease in maximal driving frequency and a 65 ms net increase in functional refractory period of isolated guinea pig atria at a concentration as low as 0.5 microgram/ml. The spontaneous rate of isolated atria and the contractility of electrically driven ventricular strips were reduced after treatment with propafenon 1 microgram/ml. Propafenon 0.5 microgram/ml also altered action potentials of sheep Purkinje fiber. It reduced the action potential and overshoot amplitudes, decreased the maximum rate of depolarization of the action potential upstroke in a frequency-dependent fashion, shortened the action potential and effective refractory period, and depressed the membrane responsiveness. Moreover, propafenon antagonized the chronotropic and inotropic effects of isoprenaline in isolated guinea pig heart preparations; the pA2 value was about 6.4. Finally, propafenon possessed very weak calcium antagonist properties, being about 100 times less potent than verapamil in this respect. We conclude that propafenon is an antiarrhythmic drug with beta-adrenoceptor blocking and "membrane stabilizing" activities in the same range of concentrations and that it has a calcium antagonistic activity only at much higher concentrations.

Action Potentials↗
PubMedDate not supplied

Endostatin: a promising drug for antiangiogenic therapy.

Angiogenesis, the formation of new blood vessels from existing capillaries, is critical for tumors to grow beyond a few in size. Tumor cells produce one or more angiogenic factors including fibroblast growth factor and vascular endothelial growth factor. Surprisingly, antiangiogenic factors or angiogenesis inhibitors have been isolated from tumors. Some angiogenesis inhibitors, such as angiostatin, are associated with tumors while others, such as platelet-factor 4 and interferon-alpha are not. Endostatin, a C-terminal product of collagen XVIII, is a specific inhibitor of endothelial cell proliferation, migration and angiogenesis. The mechanism by which endostatin inhibits endothelial cell proliferation and migration is unknown. Endostatin was originally expressed in a prokaryotic system and, late, in a yeast system, thanks to which it is possible to obtain a sufficient quantity of the protein in a soluble and refolded form to be used in preclinical and clinical trials.

Angiogenesis Inhibitors↗
PubMedDate not supplied

The potent relaxant effect of adenosine in rabbit corpora cavernosa is nitric oxide independent and mediated by A2 receptors.

In the present study the effect of adenosine and adenosine analogues on rabbit isolated cavernosal smooth muscle has been evaluated in comparison with the effect of acetylcholine and electrical field stimulation. In the presence of guanethidine and indomethacin, acetylcholine and electrical field stimulation relaxed the rabbit corpus cavernosum, which was precontracted with phenylephrine. The nitric oxide synthesis inhibitor, N omega-nitro-L-arginine-methylester (L-NAME), greatly reduced the relaxation induced by electrical stimulation and completely abolished the relaxant effect of acetylcholine. A concentration-dependent relaxation of the rabbit corpus cavernosum was produced by adenosine; this effect was not modified by L-NAME, but was reduced by adenosine deaminase. On the other hand, the adenosine-induced relaxation was potentiated by the inhibitor of adenosine deaminase, erythro-9-(2-hydroxy-3-nonyl)adenine and by the adenosine uptake inhibitor dipyridamole. Moreover, the effect of adenosine was antagonized by the unspecific adenosine receptor antagonist 8-phenyltheophylline. The receptor subtypes involved in cavernosal relaxation were characterized by using selective receptor antagonists: 1,3-dipropyl-8-cyclopentylxanthine, a blocker of A, receptors, did not modify adenosine-induced relaxation. This effect was, however, antagonized by the A2-receptor antagonist CGS15943. A relaxant effect was also obtained with nanomolar concentrations of two synthetic adenosine analogues, the preferential A2 receptor agonist 5'-N-ethylcarboxamidoadenosine and the A2a selective agonist CGS21680. These results demonstrated that adenosine has potent relaxant activity on the corpus cavernosum, acting through a mechanism different from the nitric oxide pathway, and that receptors involved in the effect of adenosine belong to the A2a subtype.

Acetylcholine↗