Biomedical subjects

F Zonta

Publications and source records attributed to F Zonta.

At least 19 recordsLinked to original sources

PubMed1999

Liver ischemia modifies the concentration of plasmatic catecholamines after reperfusion in the rat.

Pulmonary hypertension is one of the most frequent and severe consequences of liver ischemia. The aim of this study is to evaluate the presence of humoral vasoactive mediators, generated during liver ischemia, which could be able to determine the onset of pulmonary hypertension. Thus, we evaluated the plasmatic concentration of catecholamines (adrenaline, noradrenaline, dopamine) during the immediate reperfusion period. Wistar rats were used. Animals (n = 89) were divided into four groups. Group 1 served as control (sham-operated). In group 2 animals underwent 60 min of left hepatic exclusion. In group 3 animals underwent to bilateral adrenectomy. In group 4 animals had both bilateral adrenectomy and liver ischemia. Ischemia in group 2 and 4 was induced by interrupting the vascular supply to the left and median lobes, so avoiding the use of a portal shunt. Blood samples were collected from the suprahepatic inferior caval vein immediately after reperfusion. Strips of the main pulmonary artery were put into an isolated organ bath and tested for the response to noradrenaline, adrenaline and plasma samples. Plasma samples collected after ischemia caused a significantly greater (p < 0.01) contraction of the pulmonary artery compared to controls. Plasma samples collected after adrenectomy caused a weak contraction which was not different from that obtained in the adrenectomy + ischemia group. Plasma concentrations of catecholamines after liver ischemia were significantly increased in the control group (p < 0. 01). In adrenectomized rats only the adrenaline level was greatly reduced. However ischemia did not increase plasma catecholamines as it occurred in sham-operated rats.

Animals↗

PubMed1998

Pharmacological characterization of alpha-adrenoceptors that mediate contraction in splenic artery strips from the pig.

The alpha-adrenoceptors that mediate contractions in strips of splenic artery from the pig were characterized by the use of selective agonists and subtype-selective antagonists. Noradrenaline, the alpha1-selective agonist phenylephrine and the alpha1-/alpha2-agonist oxymetazoline caused the preparations to contract with potency (pD2) values of 6.94, 6.14 and 7.27, respectively. Compared to noradrenaline, phenylephrine and oxymetazoline induced 93% and 78% of noradrenaline maximum effect. Conversely, the two alpha2-selective agonists clonidine and B-HT 920 induced only 31% and 13% of noradrenaline maximum effect. B-HT 920 only marginally contracted the tissue even when it was precontracted with phenylephrine. The alpha2-selective antagonist yohimbine antagonized oxymetazoline- and phenyleprine-induced contractions with affinity (pA2) values (6.80 and 6.74, respectively) consistent with alpha1-adrenoceptor interaction. This suggests that the pig splenic artery possesses only functional alpha1-adrenoceptors. The alpha1-adrenoceptor antagonists of varying subtype selectivities like WB-4101, 5-methylurapidil, benoxathian and BMY 7378 competitively antagonized phenylephrine-induced contractions with affinity values of 9.46, 8.26, 9.06 and 6.91, respectively. These values correlated highly with published affinity values for functional alpha1A-adrenoceptors (r=0.92) and alpha1a-clones (r=0.94) and less well with affinity values for functional alpha1B-adrenoceptors (r=0.84) and alpha1b-clones (r=0.87). Conversely, correlation with functional alpha1D-adrenoceptors (r=0.26) and alpha1d-clones (r=0.33) was poor. In addition the alpha1D-selective antagonist BMY 7378 had a low affinity value compared to that reported for alpha1D-adrenoceptors. Therefore, based on correlation studies, the plot that resembled the line of equal values most closely was that for the alpha1A-subtype. The alpha1A-selective antagonist RS-17053 antagonized phenylephrine-induced contractions in an apparently non-competitive manner and gave an apparent pA2 value of 7.06 which is similar to the "low" affinity values reported in other alpha1A-containing tissues. Exposure to the irreversible alpha1B/D-antagonist chloroethylclonidine slightly decreased maximum response to phenylephrine without significantly affecting its potency value, indicating that the phenylephrine response is substantially chloroethylclonidine-insensitive. It is concluded that splenic artery strips from the pig contract in response to phenylephrine through activation of alpha1-adrenoceptors which display the pharmacological profile of the alpha1A-subtype for which the recently reported alpha1A-selective antagonist RS-17053 shows low affinity. Evidence for contribution of the alpha1B-subtype in the overall contractile response is elusive while no evidence was obtained for the involvement of the alpha1D-subtype. The contribution of functional alpha2-adrenoceptors to the contractile response was ruled out.

Adrenergic alpha-1 Receptor Agonists↗

PubMed1998

Quantitative changes in pharmacodynamic parameters of noradrenaline in different rat aorta preparations: influence of endogenous EDRF.

1. The aim of the present study was to assess the role of endothelial cells in the modulation of vasocontractile responses to noradrenaline in rat isolated aorta when cut as standard helical strips or as ring segments. 2. Noradrenaline-potency in helical strip preparations evaluated as -logEC50 was greater than that obtained in endothelium-intact ring preparations (9.45 +/- 0.28 versus 8.69 +/- 0.09, respectively) (P < 0.05). The maximum contractile response of helical strips was significantly higher than the response of ring preparations (P < 0.05). 3. Subsequent experiments were performed on helical strips and ring preparations where the endothelium was removed by rubbing the luminal surface of the aorta with filter paper. Removal of the endothelium potentiated the noradrenaline-induced contraction in ring preparations, but not in the helical strips. 4. The nitric oxide synthase inhibitors L-NAME (3 x 10(-5)-3 x 10(-4) M) or L-NNA (1 x 10(4)-3 x 10(-4) M) which were added to the tissue bath potentiated the noradrenaline-induced contraction in the endothelium-intact ring preparations, although only L-NNA induced a statistically significant potentiation. Both L-NAME and L-NNA had no effect on the noradrenaline-contraction induced in rings without endothelium, or in helical strips with or without endothelium. 5. Vascular acetylcholine-induced relaxation is dependent on endothelium derived relaxing factor (nitric oxide). Acetylcholine (10(-9)-10(-6) M) induced a concentration-dependent relaxation in noradrenaline preconstricted intact rings. The relaxant response was strongly reduced by L-NAME (3 x 10(-5)-1 x 10(-4) M). The relaxant response to acetylcholine was very weak in ring and helical strip preparations without endothelium, but also, surprisingly, in unrubbed standard helical strips. 6. The present results suggest that the endothelium of standard helical strip preparations may be greatly damaged, a view confirmed by morphological studies. The structural and functional damage of the endothelium induced very important changes in pharmacodynamic parameters such as in the potency and the maximal responses of vascular preparations to noradrenaline. Therefore, caution must be observed when the potency and intrinsic activity of agonists evaluated on different preparations are compared, even if these come from the same vascular segment.

Animals↗

PubMed1998

[The hemodynamic effects of the in-vivo administration of insulin-like growth-factor I].

BACKGROUND: Recent studies have demonstrated that IGF-I has several biological activities that correlate with the GH axis, by acting as a cell protecting factor and a promoting compound in different tissues and organs. Our latest findings have demonstrated a potential application of IGF-I in the treatment of postischemic renal injury, which frequently appears after a kidney transplant. The beneficial effect of the renal postoperative recovery probably correlates with the regulation of the vascular tone, in which IGF-I plays a role with other cytokines. However, this rises the question whether IGF-I has any effect on the general hemodynamic status. This study was designed to underline the intraoperative hemodynamic effect of exogenous IGF-I in an experimental setting of renal transplantation in swine. METHODS: Twelve female swine underwent a left renal autotransplantation. At the reperfusion the animals were separated in two groups. Group one served as control. Group two received 400 micrograms of IGF-I (added to the flushing solution). The animals were kept under complete hemodynamic monitoring over the operation. RESULTS: Among the different parameters studied (mean arterial pressure, mean pulmonary arterial pressure, pulmonary wedge pressure, central venous pressure, cardiac output, oxygen extraction ratio, systemic vascular resistance, oxygen delivery and oxygen consumption), any statistically significant difference between group one and two were observed. CONCLUSIONS: While the clinical administration of IGF-I requires further studies, the in vivo administration of this peptide is apparently well tolerated, and does not cause any hemodynamic instability to the operation.

Analysis of Variance↗

PubMed1997

Insulin-like growth factor-I ameliorates delayed kidney graft function and the acute nephrotoxic effects of cyclosporine.

BACKGROUND: Delayed graft function (DGF) is a relatively common complication after cadaveric renal transplantation. The adverse effect of DGF on long-term graft survival has lead to intensive efforts to reduce ischemic graft injury. In this study we examined the effects of a new protective treatment based on insulin growth factor (IGF)-I. We evaluated the impact of the treatment on renal recovery and on the nephrotoxicity that is a common side effect of mainstream immunosuppressants. Because therapy with IGF-I or the analog des(1-3)IGF-I is effective in treating experimental ischemic renal failure, these peptides may be useful as perspective clinical treatments. METHODS: We have addressed three areas relating to the potential use of IGF-I and its analog des(1-3)IGF-I. First, because of the immunogenic properties of IGF-I, we assessed the effect of des(1-3)IGF-I on the rejection of skin allografts in Lewis rats. Next we determined whether treatment with des(1-3)IGF-I influences the early function of transplanted kidneys in a model of DGF induced by a combination of warm and cold ischemia. Finally we tested whether IGF-I protects against acute cyclosporine nephrotoxicity. RESULTS: Des(1-3)IGF-I did not accelerate the rejection of the skin grafts (P=0.57). The administration of this peptide in a model of syngenic renal transplant improved the early function of the graft. Postoperative values of creatinine and blood urea nitrogen were significantly better (P<0.05) in treated animals. IGF-I also ameliorated the nephrotoxicity of cyclosporine, with better values of creatinine and blood urea nitrogen (P<0.05). CONCLUSIONS: In evaluating this study it should be recognized that the animal models studied, although widely used, differ from the human condition. However, IGF-I and des(1-3)IGF-I exhibit properties that strongly suggest their value in preventing clinical DGF, and they deserve further studies.

Animals↗

PubMed1996

Evaluation of the reperfusion syndrome after liver ischemia in the rat.

Hepatic surgery in man often requires a transient interruption of the blood flow to the liver. After the vascular declamping the hepatic reperfusion induces a group of phenomena commonly called "reperfusion injuries." The aim of this study was to evaluate the presence and effect of vasoactive agents that could induce the acute pulmonary arterial hypertension which contributes to reperfusion injury. Wistar rats were used. The hepatic ischemia was induced by crossclamping the whole hepatic hilus for 20, 40, and 60 min. In control experiments a sham operation was performed. Blood samples were collected from the suprahepatic inferior vena cava. Strips of the main pulmonary artery were set up in an isolated organ bath and tested for the response to noradrenaline, adrenaline, KCl, and plasma samples. Plasma levels of catecholamines were determined by high-performance liquid chromatography. Plasma concentration of noradrenaline significantly increased from 1.6 +/- 0.4 (control) to 10.8 +/- 2.9 ng.ml-1 and adrenaline concentration rose from 2.7 +/- 0.7 to 38.7 +/- 7.6 ng.ml-1 after ischemia. Noradrenaline potency, compared to control values, significantly increased after prolonged liver ischemia. The plasma samples collected after prolonged liver ischemia caused a greater contraction of the pulmonary artery than from control plasma. This contraction is partially inhibited by phentolamine. We conclude that hepatic ischemia modifies the response of the pulmonary artery to exogenous noradrenaline. At the same time it induces an increase in the plasma levels of adrenaline and noradrenaline. The resulting combined effect may cause the pulmonary hypertension which has been observed in reperfusion injury.

Animals↗

PubMed1995

High-performance liquid chromatographic profiles of aloe constituents and determination of aloin in beverages, with reference to the EEC regulation for flavouring substances.

Characteristic HPLC profiles of fresh and aged aloe solutions, detected at 360 and 220 nm, are presented and compared. Several aloe constituents (aloesin, aloeresin A, hydroxyaloin, aloin A and B and aloinoside A and B) were simultaneously separated and identified. The determination of aloin is described (detection limit 0.15 ppm) and discussed. In aloe-based alcoholic beverages, the aloins could not be detected, owing to their instability and degradation in solution; this is discussed in relation to the EEC Council Directive 88/388, which fixed the values of maximum allowable concentrations for aloin in food and beverages. Instead of aloin, other aloe compounds (e.g., aloeresin A or aloesin) should perhaps be used as an index of the presence of aloe in alcoholic beverages.

Alcoholic Beverages↗

PubMed1994

Selectivity of LG50643 for postjunctional muscarinic-receptor subtype in the guinea-pig trachea.

The effects of (+/-)-LG50643, a new N-quaternary tropinic ester of phenylcyclohexene carboxylic acid, endowed with a potent antimuscarinic activity, have been investigated on muscarinic receptor-mediated responses of the guinea-pig trachea to electrical field stimulation. An isolated preparation which allows the simultaneous measurement of tritiated acetylcholine release (prejunctional effect) and smooth muscle contraction (postjunctional effect) was used. The guinea-pig epithelium-deprived trachea was stimulated with 500 pulses (20 Hz, 1 ms, 9 V for 5 s, 30 s apart) in the presence of indomethacin (1 microM). Three successive pre- and postjunctional responses were observed. The potencies (-logEC50) of (+/-)-LG50643 for pre- and postjunctional muscarinic receptors were determined and compared with those of selective muscarinic antagonists. In addition, the affinity values of (+/-)-LG50643 for muscarinic-receptor subtypes were determined in radioligand binding experiments in cerebral cortex, heart and salivary glands of rat as target tissues for M1, M2 and M3 receptors, respectively. The results obtained in both functional and binding assays indicate (+/-)-LG50643 is a potent and selective antagonist for the M3-receptor subtype.

Acetylcholine↗

PubMed1993

Synthesis and muscarinic activity of some muscarone analogs.

The synthesis of some muscarone analogs has been accomplished and their muscarinic activity has been assayed in three in vitro functional tests. The results of such an investigation put in evidence the active role played by the methylene moiety, placed exocyclic to the pentaatomic ring, on the interaction of the ligands with the different muscarinic receptor subtypes. Worth noting is the ileum-atria selectivity displayed by methylene derivative 7.

Animals↗

PubMed1992

Synthesis and pharmacological investigation of the enantiomers of muscarone and allomuscarone.

A strategy based on the use of (R)- and (S)-lactic ester as starting materials allowed the synthesis of the two enantiomers of muscarone [(-)-1 and (+)-1] and allomuscarone [(-)-5 and (+)-5] in greater than 98% enantiomeric excess. The compounds were examined for their ability to bind to membranes from cerebral cortex (M1), heart (M2), and salivary glands (M3) and to recognize affinity agonist states of the muscarinic receptors. The two pairs of enantiomers were also tested in five functional assays, and their muscarinic potency was determined. In both binding and functional tests, (-)-1 (2S,5S) and (-)-5 (2R,5S) were the eutomers of muscarone and allomuscarone, respectively. The eudismic ratio of muscarone, evaluated in the functional tests, spanned a range of 280-440. These values are substantially different from ones (2.4-10.1) reported in the literature. From a stereochemical point of view, muscarone behaves as muscarine and all other major muscarinic agonists; as a consequence, the hypotheses advanced to account for the anomalies of muscarone no longer have reason to exist.

Animals↗

PubMed1992

Synthesis and pharmacological investigation of stereoisomeric muscarines.

The synthesis of the eight stereoisomers of muscarine has been efficiently accomplished by utilizing the two enantiomers of lactic esters as starting material. The synthetic strategy is based on a SnCl4-catalyzed addition of allyltrimethylsilane to O-protected lactic aldehydes followed by an iodocyclization process. All the final derivatives possess an enantiomeric excess higher than 98%. The four pairs of enantiomers bound to M1, M2, and M3 muscarinic receptor subtypes in membranes from cerebral cortex, heart, and salivary glands, respectively, and recognized heterogeneous states of the receptors. Of the eight isomers, only natural muscarine (+)-1 recognized three affinity states of the M2 receptor. The compound was also the only one to show selectivity in the binding study, demonstrating 37- to 44-fold higher affinity for the M2 than for the M1 or M3 receptors. In addition, the compounds were tested in functional assays on isolated guinea pig atria (M2 receptors) and ileum (mixed population of M2 and M3 receptors) and their muscarinic potencies were determined. Among the eight isomers, again only (+)-1 enantiomer was found to be very active on both tissues. Its potency was more than two orders of magnitude higher than that of its enantiomer (-)-1 as well as the other six isomers. The eudismic ratios (E.R.) deduced from the two functional tests were 324 and 331.

Animals↗

PubMed1992

A novel class of cholinergic agents structurally related to 2-morpholinol.

A series of esters and ethers of N-alkylmorpholin-2-ols, and their methiodides, which can be considered cyclic analogues of acetylcholine, were synthesized. The amines were obtained by acylation or etherification of morpholinols with the appropriate acyl chlorides and alcohols. All compounds were tested for their ability to interact with the muscarinic receptor M2 (guinea-pig atria) or M3 (rat ileum and urinary bladder) subtype. Some compounds, although endowed with relatively low potency, proved interesting for their organ selectivity. Some considerations on the structure-activity relationship are made and the results obtained with reference agonists and antagonists are also shown.

Animals↗

PubMed1991

Inhibition by glibenclamide of the effects of cromakalim on responses of rat vas deferens to naphazoline.

Cromakalim has been shown to inhibit naphazoline-induced contractions and spontaneous activity induced by exposure to naphazoline in the rat isolated vas deferens. Glibenclamide 10(-6) M blocked both these effects of cromakalim. Our data add to the list of data derived mainly from experiments on vascular smooth muscle; they suggest that the same glibenclamide-sensitive K+ channel is present in vascular and non-vascular smooth muscle and that it may be involved in the relaxant actions of cromakalim.

Animals↗

PubMed1991

Effects of cromakalim (BRL 34915) on mechanical responses of rat vas deferens to noradrenaline and naphazoline.

The contractile responses produced by noradrenaline were compared to those produced by naphazoline in the rat isolated vas deferens, a preparation which is usually quiescent. The responses to noradrenaline were biphasic: prominent spontaneous contractile activity was superimposed on contractions produced by naphazoline. After removal of naphazoline the rat vas deferens displayed periodic spontaneous activity. The effects of cromakalim and verapamil were compared on contractions induced by noradrenaline and naphazoline and on spontaneous activity induced by exposure to naphazoline. Cromakalim (1-10 x 10(-7) M) shifted to the right the cumulative concentration-response curve of naphazoline but not that of noradrenaline; at the same range of concentrations, cromakalim inhibited naphazoline-induced periodic spontaneous activity. Verapamil (3-30 x 10(-8) M) flattened in a dose-dependent manner the concentration-response curves of noradrenaline and naphazoline; higher concentrations of verapamil (3-30 x 10(-6) M) were required to modify periodic spontaneous activity. It was concluded that naphazoline but not noradrenaline can block K+ channel(s) and that this property can represent an important difference between imidazolines and phenethylamines.

Animals↗

PubMed1991

Potentiating actions of tranylcypromine and moclobemide on the sympathomimetic activity of dopamine.

Ex vivo investigations were carried out to study the potentiating actions of the MAOIs moclobemide and tranylcypromine on peripheral alpha- and beta-adrenergic effects of dopamine. Isolated rat vas deferens and atria were used. Preliminary experiments showed that both moclobemide and tranylcypromine did not affect the response to noradrenaline, while they enhanced the response to tyramine. By comparison of the responses to dopamine in control and reserpinized rats, it was shown that dopamine acts in a direct and indirect manner on both the tissues tested. Two concentrations (20, 40 mg/kg, i.p.) of moclobemide were tested and administered at different time periods (2, 5 or 24 h) before the animals were sacrificed. Two concentrations (2, 20 mg/kg, i.p.) of tranylcypromine were tested at different intervals of time (2, 24 h). The results obtained pointed out that: (1) Moclobemide 20 mg/kg potentiated the alpha-adrenergic response to dopamine only 2 h after administration while 40 mg/kg exerted a potentiation which was evident not only 2 but also 5 h after administration. Both doses were ineffective 24 h after administration. (2) Moclobemide 20 and 40 mg/kg potentiated the beta-adrenergic response to dopamine. The effect was present 2 and 5 h after administration but it was absent 24 h after. (3) Tranylcypromine 20 mg/kg potentiated the alpha-adrenergic response to dopamine: this effect was present after 2 h from pretreatment and was still evident after 24 h. The lower concentration of tranylcypromine (2 mg/kg) enhanced the response to dopamine only after 24 h from pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Nitrile oxides in medicinal chemistry. 3. Synthesis and bioenantioselectivity of (+)- and (-)-2-methyl-5-[(dimethylamino)-methyl]-3-oxo-isoxazolidine methiodide.

The two enantiomers of the potent muscarinic ligand 2-methyl-5[(dimethylamino)methyl]-3-oxo-isoxazolidine methiodide [(+/-)-V] were synthesized in a very high enantiomeric excess (98.8 and greater than 99%). The muscarinic activity of the two enantiomers was assayed on the isolated guinea pig ileum and atria, and on rat jejunum and urinary bladder and the nicotinic activity was evaluated on the frog rectus abdominis muscle. (R)-(-)-V, the most potent enantiomer in the muscarinic tests, has the same absolute configuration as [2R,5R]-muscarone and, like muscarone, has a low eudismic ratio (ER: 2.5-10.4). In the nicotinic assay, (S)-(+)-V was found to be the eutomer (ER: 3.5).

Animals↗

PubMed1988

High-performance liquid chromatography of carotenoids from some marine shellfish.

The chromatographic profiles of carotenoids from some marine shellfish are reported. The analyses were performed both by gradient elution reversed-phase and isocratic direct phase high-performance liquid chromatography (HPLC), and the results obtained are compared and discussed. The six main carotenoids extracted from three shellfish species (Chlamys opercularis, L., Cardium tuberculatum, L., Pecten jacobaeus, L.) were isolated in highly pure form by means of semi-preparative HPLC. They were characterized by means of spectroscopic methods (visible absorption and infrared spectroscopy), and chemical tests: the identification of fucoxanthin and alloxanthin was possible while a tentative identification of two other carotenoids (fucoxanthinol and diatoxanthin) was suggested. Carotenoids in clams and scallops were present both in esterified and free form, while in cardia only carotenoid esters were detected.

Animals↗

PubMed1987

Simultaneous high-performance liquid chromatographic analysis of free carotenoids and carotenoid esters.

High-performance liquid chromatography using a non-aqueous reversed phase with gradient elution on C18 columns is a powerful tool for investigating the carotenoid composition of natural samples, e.g., flower petals, and for the simultaneous detection of carotenoids of the widest possible polarity range (xanthophylls, diones, hydrocarbons and carotenoid esters). The comparison of sample extracts submitted or not to saponification allows the presence of carotenoid esters to be revealed through the appearance of the corresponding free hydroxycarotenoids. The gas chromatographic analysis of the fatty acids after alkaline hydrolysis of esters provides further confirmation. In most cases, peaks of various carotenoids were identified by comparison with standards. The wavelengths of the visible absorbance maxima of the chromatographed carotenoids as obtained on-line by the stop-flow method in the eluent system and off-line in carbon disulphide are reported. The esters appear to constitute the main carotenoid fraction in flower petals.

Carotenoids↗