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Biomedical subjects

E Ragazzi

Publications and source records attributed to E Ragazzi.

At least 73 records · Page 4Linked to original sources
PubMed1991

Properties of solubilized and reconstituted A1 adenosine receptors from bovine brain.

A simple method for solubilization and reconstitution of the A1 adenosine receptor from bovine brain is presented. Solubilization with CHAPS-phosphatidylcholine (CHAPS/PC) mixture did not alter the binding properties of the A1 adenosine receptor antagonist [3H]-DPCPX. The solubilized receptors were chromatographed on hydroxyapatite or DEAE-cellulose to remove native membrane lipids and part of non-receptor proteins. Elution of the receptor fractions was obtained from DEAE-cellulose column with a linear gradient of KCl (0-0.4 M). The fractions corresponding to the peak of [3H]-DPCPX binding activity were then reconstituted in phosphatidylcholine by dialysis. The reconstituted receptor retained all the binding characteristics and the same rank order of competition potency (R-PIA greater than S-PIA greater than NECA) as the native receptor, although its thermal stability was remarkably reduced. The binding of [3H]-DPCPX to A1 adenosine receptors was increased by GTP, probably as result of interactions with coeluted G-proteins.

Adenosine↗
PubMed1991

Effect of age on rabbit aortic responses to relaxant endothelium-dependent and endothelium-independent agents.

The aim of this study was to evaluate the effects of aging on endothelium-dependent and endothelium-independent relaxation of rabbit thoracic aorta from New Zealand white rabbits aged 4-6 and 7-12 months. The contractile response to noradrenaline (NA) decreased with increasing age, but NA [EC50] did not vary significantly. Acetylcholine (Ach)-induced relaxation of aortic rings precontracted with NA [EC50] did not change significantly with increasing age. The relaxation induced by ATP of aortic rings, precontracted with NA [EC50], was significantly greater in young than in adult rabbits. This difference between young and adult animals became more evident in aortic rings deprived of endothelium: in adult animals, the ATP-induced relaxation of aortic rings with endothelium was significantly greater than in the rings without endothelium. The endothelium-independent relaxation by sodium nitrite (NaNO2) at lower concentrations was significantly greater in young than in adult rabbit aortic rings precontracted with NA [EC50]. Concluding, the age-induced changes in vascular response in male New Zealand white rabbits are related to an impaired mechanism at smooth muscle level.

Adenosine Triphosphate↗
PubMed1991

Electrophysiological and receptor binding studies to assess activation of the cardiac adenosine receptor by adenine nucleotides.

Adenosine and adenine nucleotides shorten the action potential duration of atrial myocytes and activate a specific acetylcholine and adenosine receptor-operated potassium outward current referred to as IKACh,Ado. The objective of this study was to determine whether adenine nucleotides shorten the action potential duration and increase IKACh,Ado in guinea pig atrial myocytes by directly activating adenosine receptors. The potency and efficacy of AMP and adenosine in increasing IKACh,Ado and shortening atrial action potential duration were similar; the EC50 values for AMP and adenosine were 3.4 +/- 0.8 and 3.1 +/- 0.4 microM, respectively. Likewise, the maximum increases in IKACh,Ado caused by AMP and adenosine were similar (122 +/- 11% versus 123 +/- 9%). In comparison, ATP and the stable analogue of AMP, adenosine monophosphorothioate (AMPS), were significantly less potent and efficacious than adenosine and AMP, and adenosine receptor antagonist 8-(p-sulfophenyl)theophylline and abolished in the presence of adenosine deaminase and alpha, beta-methylene-ADP (APCP, an inhibitor of AMP degradation). Binding of the A1-adenosine antagonist [3H]8-cyclopentyl-1,3-dipropylxanthine (DPCPX) to guinea pig atrial membranes treated with adenosine deaminase and APCP was reduced up to 60% by 100 microM concentrations of AMP, AMPS, and adenosine. Inosine inhibited binding by 43 +/- 3% at 100 microM, whereas hypoxanthine and xanthine had little (5-10% inhibition) and uric acid had no effect. Only 3% of AMP and 35% of AMPS were recovered intact after a 90-minute incubation at 21 degrees C with preparations of guinea pig atrial membranes. Percent displacement of [3H]DPCPX binding to atrial membranes by 100 microM AMP was significantly less in the presence of nucleoside phosphorylase and xanthine oxidase (to degrade inosine, hypoxanthine, and xanthine to uric acid) than in their absence (12.4 +/- 3.1% versus 49.7 +/- 1.5%). The results suggest that the observed electrophysiological actions of adenine nucleotides in cardiomyocytes are mediated by adenosine and are consistent with activation of A1-adenosine receptors.

Action Potentials↗
PubMed1991

Effects of two different kinds of silicium dioxide on release of drugs from suppositories: benzydamine hydrochloride.

Silica gel confirmed its function as viscosity agent for lipophylic excipients for suppositories, ensuring homogeneous drug distribution in the suppository mass. The influence on release rate of a water-soluble drug (benzydamine hydrochloride) was clearly different according to type of silica gel. With Aerosil 200 (hydrophylic), after a progressive decrease in release rate at the lowest concentrations, an increase was observed at the highest concentrations, until it reached that of the suppositories without silica gel. With Aerosil R972, release rate decreased progressively with increased silica gel concentration, until release was practically inhibited even at low concentrations.

Benzydamine↗
PubMed1990

Cholesterol diet followed by normal diet alters functional and metabolic responses in rabbit aorta.

Male New Zealand rabbits were fed a high cholesterol (1%) diet for 8 weeks followed by a normal diet for 8 additional weeks. Rabbits on normal diet were used as controls. Serum cholesterol, elevated at the end of the cholesterol feeding period, returned to normal at the time of observation. Aortic wall lesions were severe and vessel wall cholesterol in the thoracic aorta was approximately 10 times the level in control animals. In vitro, thoracic aortic rings were used to measure contractile response to noradrenaline (NOR); no difference in response was found between normal and treated rabbits. Rings pre-contracted with NOR, were exposed to acetylcholine (Ach), ATP and NaNO2. Proximal and distal rings from normal animals showed a dose-dependent relaxation response to all agents, though maximal dilation occurred at an intermediate concentration of Ach. The rings from treated rabbits relaxed normally in response to NaNO2, but ATP relaxation was reduced in proximal and distal rings and Ach induced a contractile response. HPLC analysis of tissue extracts from aortic arch and distal thoracic aorta showed reduced ATP, ADP, GTP and GDP, and increased AMP. These changes resulted in a reduced energy charge and a reduction in total adenine nucleotides. The data indicate that cholesterol feeding, followed by normal diet, causes severe alterations of aortic vessel wall and that at an advanced stage of the diet-induced experimental disease energy metabolism and endothelium dependent vasodilation remain impaired even in the presence of normal serum lipids.

Acetylcholine↗
PubMed1989

Endothelium-dependent relaxation, cholesterol content and high energy metabolite balance in Watanabe hyperlipemic rabbit aorta.

Functional and metabolic parameters of thoracic aorta from Watanabe heritable hyperlipemic (WHHL) rabbits (aged 11-14 months) were investigated in vitro. The aortic preparations, normally responsive to noradrenaline, showed a diminished response to the endothelium-dependent agent, acetylcholine, in comparison with control preparations from age-matched New Zealand rabbits (maximal relaxation: 33 +/- 4% in WHHL vs. 52 +/- 2% in controls: P less than 0.005). ATP relaxant effect (only partially endothelium-dependent) was unimpaired in WHHL aorta, and it was much higher than in controls (maximal response: 63 +/- 6% vs. 37 +/- 3%, respectively; P less than 0.005). The response to NaNO2, an endothelium-independent relaxant, was unchanged in WHHL aortas. Acetylcholine-induced response was found to be inversely related to the degree of total cholesterol infiltration in aorta (r = -0.62, P less than 0.05). No correlation was observed between either total serum cholesterol or triglycerides and ACh-induced response. Furthermore, the concentration of adenine nucleotides and nucleosides in the aortic tissue of WHHL rabbits was lower than in controls, indicating a loss of energy balance. The results indicate a functional damage induced by genetic hyperlipidemia on endothelium-dependent relaxation and an impairment of energy-rich phosphate metabolism of the aortic wall. The relationship between functional and metabolic parameters is not yet clarified.

Adenosine Triphosphate↗
PubMed1989

Effect of selective agonists and antagonists on atrial adenosine receptors and their interaction with Bay K 8644 and [3H]-nitrendipine.

1. (-)-N6-phenylisopropyladenosine (R-PIA) and N6-cyclohexyladenosine (CHA), highly selective agonists at A1-adenosine receptors, 5'-N-ethyl-carboxamidoadenosine (NECA), a non-selective agonist at A1 and A2 receptors, and 2-phenylaminoadenosine (CV-1808), a selective A2 agonist, were compared in spontaneously beating and electrically driven atria. R-PIA, CHA and NECA inhibited contraction in both preparations. CV-1808 was not effective up to 500 nM. 2. 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX), a new selective A1 receptor antagonist, competitively inhibited the effects of the adenosine agonists, at low concentrations (IC50 less than 1 nM). 3. CHA and NECA were able to inhibit the positive inotropic effect of Bay K 8644 both in spontaneously beating and in electrically driven atria. 4. R-PIA, CHA and NECA (agonists), 8-phenyltheophylline (PT) and DPCPX (antagonists), failed to influence [3H]-nitrendipine binding on microsomal membranes from guinea-pig atria and ventricles in a range of concentrations from 1 nM to 100 microM. 5. The data support the existence of A1 receptors in atrial tissue. No evidence for a direct interaction between adenosine analogues and Bay K 8644 was found at the level of slow calcium channels. Adenosine analogues appear to antagonize the effects of Bay K 8644 indirectly by activation of A1 receptors.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Potassium channel blockers differentially affect carbachol and (-)-N6-phenylisopropyladenosine on guinea-pig atria.

1. The effect of three different potassium channel blockers (tetraethylammonium, TEA; 4-aminopyridine, 4-AP; and apamin) and of variations in the concentration of K+ and Ca2+ in the medium, have been studied on the responses of guinea-pig isolated atria to (-)-N6-phenylisopropyladenosine (R-PIA), a stable adenosine A1-receptor agonist, and to carbachol, a muscarinic agonist. R-PIA and carbachol showed the same negative inotropic effects over a similar range of concentrations (3-300 microM), both in spontaneously beating and in electrically driven atria. 2. TEA (0.1 to 20 mM) and 4-AP (0.3 to 3 mM), both antagonized the negative inotropic and chronotropic effects of carbachol in a concentration-dependent manner. In contrast, these compounds failed to inhibit the effects induced by R-PIA. Apamin, a specific blocker of a low conductance Ca2+-activated K+ channel, was ineffective in accordance with the absence of these channels in atrial tissue. 3. TEA (0.1 to 20mM) inhibited the negative inotropic effect of carbachol, but not that of R-PIA, in atria paced and depolarized by a high K+ medium (22 mM). In this preparation Na+ current is abolished and the contraction induced by noradrenaline and electrical stimulation is solely dependent on Ca2+ influx currents. 4. Stepwise addition of Ca2+ to a calcium-depleted perfusing medium of electrically driven atria, induced a positive inotropic effect which was inhibited by R-PIA. In contrast, carbachol had no effect. 5. In agreement with our previous study, the data suggest that R-PIA acts on isolated atria by inhibiting Ca2+ influx through L-channels.

4-Aminopyridine↗
PubMed1989

Segmental impairment of endothelium-mediated relaxation in thoracic aortas from atherosclerotic rabbits. Comparison to cholesterol infiltration and energy metabolism.

Three sets of parameters, (i) relaxation to acetylcholine (Ach), ATP and NaNO2, (ii) cholesterol content in aortic tissue, and (iii) energy metabolism were compared in normal and atherosclerotic rabbits, fed 1% cholesterol for eight weeks. A special protocol was envisaged to permit a strict comparison between Ach, ATP and NaN O2 at different levels of thoracic aorta, in each rabbit. A gradual impairment of the endothelium-dependent relaxation to Ach and ATP was found at different levels of the thoracic aorta from hypercholesteromic rabbits. By contrast, NaNO2--endothelium-independent--maintained its relaxing power quite normally at all aortic levels. A close correlation was evident between the impairment of aorta relaxation to Ach and the cholesterol infiltration in the vessel wall, being the correlation coefficient -0.85 (P less than 0.001). A correlation was also evident for ATP, but to a lower degree, being the correlation coefficient -0.61 (P less than 0.01). Energy metabolism and related parameters (ATP, ADP, AMP, adenosine, inosine, GTP, GDP, guanosine, NAD, NADP, total adenylate nucleotides and adenylate energy charge) were not modified by the cholesterol diet. These data show that the gradual impairment of endothelium-dependent relaxation, decreasing down the thoracic aorta of hypercholesterolemic rabbits, and correlated with cholesterol content in the aortic wall, may be considered as an index of a very early atherogenic damage, prior to variation in the parameters of energy metabolism and purine turnover.

Acetylcholine↗
PubMed1988

Resveratrol activity on guinea pig isolated trachea from normal and albumin-sensitized animals.

The relaxant effect of resveratrol on guinea pig isolated trachea (EC50 = 100 microM) was not due to interactions with histaminergic or cholinergic systems, but appeared to be influenced by beta-blockers, indomethacin and mepacrine. Antigen-induced contraction on sensitized trachea was partially antagonized by resveratrol. Resveratrol action may be partially related to arachidonic acid metabolism.

Adrenergic beta-Antagonists↗
PubMed1988

Anti-inflammatory and peripheral analgesic activity of esculetin in vivo.

Esculetin determined a reduction in oedema and granulocyte infiltration in the Croton oil ear test in vivo. The drug was able to inhibit Acethylcholine-writhing test and showed a LD50 of 1450 mg/kg i.p. and greater than 2000 mg/kg by mouth. In our experimental conditions, esculetin has an anti-inflammatory and analgesic effect.

Acetylcholine↗
PubMed1988

Anti-inflammatory activity of benzopyrones that are inhibitors of cyclo- and lipo-oxygenase.

The anti-inflammatory activity of three benzo-pyrones with prevalent lipooxigenase-inhibitory activity was studied using the Croton oil ear test in mice, in comparison with nordihydroguaieretic acid (NDGA) and indomethacin. Kaempferol, quercetin and NDGA possess a strong and prolonged anti-inflammatory effect, whereas the action of indomethacin appears relevant, but not long-lasting. In contrast the anti-inflammatory activity of esculetin is rather weak, but persistent.

Animals↗
PubMed1987

Depression and excitation induced in mice by two geometric isomers of (+)13,14-didehydro-20-methyl-carboprostacyclin, FCE 22177 and FCE 22176. Comparison with effects on blood pressure and platelet aggregation.

Two geometric isomers of a stable derivative of PGI2 (13,14-didehydro-20-methyl-carbo PGI2), FCE 22177 (5E) and FCE 22176 (5Z), have been injected i.v. in mice (5-400 mcg/Kg) to investigate the effects at CNS level (Irwin's test). The synthetic mixture of the two isomers (5E:5Z = 7:3) was also tested. Isomers 5E and 5Z induced opposite effects: 5E (similar to PGI2) was depressive, 5Z induced stimulation. The mixture showed a strong depressive symptomatology. The two isomers and their mixture induced motor incoordination and impaired the performance of mice in the rotarod test (200 mcg/Kg i.v.). Mice were depressed after 5E and mixture; whilst 5Z induced excitation, in accordance with Irwin's test. 5E and 5Z showed analogous effects on mean blood pressure (hypotension) and heart rate (increase) in normotensive rats, but 5E was 7 times more active than 5Z. The two isomers showed analogous inhibitory effect on guinea-pig platelet aggregation in vitro, but 5E was 30 times more active than 5Z. In conclusion, the two geometric isomers have similar effects on blood pressure, heart rate and platelet aggregation, even if differing quantitatively. In contrast, 5E and 5Z have opposite effects at CNS level on motor function and behaviour. The data suggest the presence of two different sites of action for PGI2 in CNS (Ca2+- and adenylate cyclase-linked?). The two geometric isomers, 5E and 5Z, may be useful to study the PGI2 receptor sites in different tissues.

Animals↗
PubMed1985

Effects of pirenzepine on plasma insulin, glucagon and pancreatic polypeptide levels in normal man.

The secretion of various pancreatic hormones (insulin, glucagon and pancreatic polypeptide) is affected to a different extent by the cholinergic system. In 7 healthy subjects the effects of treatment for 1 week with pirenzepine, an anticholinergic drug selective for muscarinic receptors, on basal secretion of these hormones and on that induced by i.v. glucose (IVGTT) and arginine were evaluated. The drug did not reduce basal levels of insulin and glucagon whereas it caused an appreciable reduction in basal pancreatic polypeptide (PP). The responses of insulin and blood glucose to IVGTT and to arginine were not changed by treatment, nor was that of plasma glucagon to arginine. The infusion of arginine did induce an increase in PP level, which reached a statistically significant maximum at 90 min. This response was not particularly different after administration of pirenzepine. Thus, the results confirm the finding that arginine stimulates PP secretion in vivo and that pirenzepine reduces the basal level of the hormone, whereas it did not appear to affect the response to arginine. The findings exclude any direct action of the drug on insulin or glucagon secretion or on glucose metabolism in general.

Adult↗