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Biomedical subjects

M Prosdocimi

Publications and source records attributed to M Prosdocimi.

At least 73 records · Page 4Linked to original sources
PubMed1987

At low extracellular calcium concentration platelet activating factor induces beta-thromboglobulin release from human platelets through thromboxane-endoperoxides formation.

The aim of this study was to investigate the mechanism involved in beta-thromboglobulin (BTG) release induced by platelet activating factor (PAF) in human platelet-rich plasma (PRP) and washed platelets (WP) during aggregation. PAF was used in PRP at increasing concentrations starting at its threshold concentration for irreversible aggregation (TAC: 90-150 nM). In citrated PRP, PAF induced release of BTG (80-95% of total content) and thromboxane B2 (TXB2) formation (30-40 pmol/ml). At low PAF concentrations aggregation and BTG release were blocked by apyrase (a scavenger of ADP), by ASA (an inhibitor of cyclooxygenase) and by BM 13177 (a thromboxane receptor antagonist). Higher concentrations of PAF overcame the effect of apyrase, but only induced reversible aggregation and minor release in the presence of ASA or BM 13177. In heparinized PRP, PAF induced full irreversible aggregation, but only very low BTG release (about 25% of total content) and thromboxane synthesis (2-3 pmol/ml). WP resuspended in the presence of 2 mmol/l Ca2+ seldom responded to PAF alone, as previously shown by others, but full aggregation could be induced by concomitant addition of subthreshold concentrations of PAF (25-50 nM) and epinephrine (1 microM). In these conditions average BTG release from WP was less than 20% of the amount releasable by thrombin. In contrast, when WP were resuspended in the absence of Ca2+, stimulation by PAF + EPI induced sustained BTG release (40-50% of total content) and TXB2 synthesis (15-20 pmol/ml). We conclude that at low Ca2+ concentration PAF induces BTG release mainly through thromboxane-endoperoxides formation. In contrast, when [Ca2+] is normal, PAF does not or weakly induces thromboxane formation and BTG release.

Blood Platelets↗
PubMed1987

Experimental diabetes in the rat: alterations in the vesical function.

Vesical function has been studied in vivo in alloxan-diabetic rats. Rhythmic contractions evoked as a micturition reflex by a controlled distension of the bladder were recorded in urethane-anesthetized animals. These rhythmic contractions are essentially induced by the parasympathetic and inhibited by the sympathetic outflow. The study has been performed on male Sprague-Dawley rats. They were treated at the age of two months with vehicle (control group) or alloxan (100 mg/kg s.c.). Such treatment caused hyperglycemia (greater than 250 mg/dl) and glycosuria in most of the animals. In control animals, analyzed between 5 and 8 months of age, the contractions evoked by vesical distension appeared at a threshold volume between 0.5 and 1 ml, and they had a regular rate. In a first series of experiments, diabetic animals 3 months after treatment showed the evoked response at an average threshold volume of about 1.7 ml. while in animals with 6 months of experimental diabetes the average threshold volume was about 3.2 ml. The rate of contractions in diabetic animals became more and more irregular as the duration of diabetes increased. These marked functional alterations were associated with the evidence of bladder enlargement. In a second series of experiments, bovine brain gangliosides (10 mg/kg i.p./day) or saline were given to diabetic rats between the 30th and the 90th day after alloxan. Ganglioside administration significantly reduced bladder enlargement and the threshold volume for micturition reflex and improved the rate of bladder contractions. It is suggested that alterations of the autonomic nervous system can be expressed as functional vesical dysfunction in experimental diabetes.

Animals↗
PubMed1987

Human platelet factor 4 and protamine sulphate interaction with glycosaminoglycans in the rabbit.

We studied the action of protamine sulphate on human platelet factor 4 (PF4) kinetics in rabbits in the presence of various glycosaminoglycans (CAGs). The animals pretreated with heparin showed high initial PF4 levels with a subsequent slow monoexponential clearance. The PF4 kinetics, in the presence of heparan and dermatan sulphate, reflected the different affinities that PF4 has for these GAGs. Protamine, at dosages that totally neutralized 1000 USP units of heparin pretreatment, caused an immediate disappearance in the circulating PF4. However, a second heparin injection 10 min after protamine, induced a PF4 peak release. It is possible that protamine displaced the PF4 from the binding sites of heparin, releasing it for storage in the body 'pool', from where it can be harvested again. The action of protamine on PF4 kinetics in the rabbits pretreated with 30 mg heparan sulphate was similar to that obtained with heparin pretreatment; however, a higher dose of protamine was required to obtain the optimal effect. After a 20 mg dose of protamine, unexpectedly, a bolus of heparin did not produce any peak release of PF4 in the rabbits pretreated with 30 mg of dermatan sulphate. Although part of the protamine will displace PF4 from the binding sites of the dermatan sulphate molecule, the remaining part of protamine could probably be bound to this GAG without losing its activity so that, upon subsequent heparin injection, it is immediately neutralized, rendering it unavailable for further PF4 harvesting.

Animals↗
PubMed1986

The effect of AD6 (8-monochloro-3-beta-diethylamino-ethyl-4-methyl-7-ethoxy- carbonylmethoxycoumarin) on washed human platelet aggregation induced by platelet activating factor (PAF) and epinephrine.

The effect of AD6 (8-monochloro-3-beta-diethylamino-ethyl-4-methyl-7- ethoxycarbonylmethoxycoumarin) was studied in vitro on washed human platelet aggregation and beta-thromboglobulin (beta TG) release induced by PAF alone or in combination with epinephrine. AD6 caused concentration-dependent inhibition of aggregation and beta TG release. Acetylsalicylic acid and the ADP scavenger apyrase were ineffective on the same parameters, while the specific PAF antagonist CV 3988, the Ca2+ antagonist diltiazem and the cyclo-oxygenase-lipoxygenase inhibitors nordihydroguaiaretic acid and BW 755C inhibited aggregation. The results indicate that AD6 is an inhibitor of platelet aggregation in vitro with a mode of action different from cyclo-oxygenase blockade.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1986

Regulation of prostacyclin production by vascular cells in in vitro and in vivo experimentals systems.

Prostacyclin (PGI2) is the major product of arachidonic acid (AA) metabolism in vascular cells. Its physiological role is linked to the cells' ability to produce PGI2 continuously in response to a variety of stimuli. Human endothelial cells or bovine smooth muscle cells in culture responded only once with PGI2 production to stimulation with AA, thrombin or ionophore A23187. Their refractoriness lasted about 6 hours. The same time was required by the cells to recover completely after inhibition of cyclooxygenase activity by aspirin. When the cells were repeatedly stimulated with AA in the presence of plasma no refractoriness was apparent. These results suggest that vascular cyclooxygenase is irreversibly self-inactivated during oxygenation with AA. As shown in other experimental systems, deactivation could be attributed to the attack on the enzyme by oxidizing species formed during AA conversion and the plasmatic free radical-scavenger systems could protect the cells from inactivation. Thus, vascular cells in an artificial medium cannot be stimulated continuously to produce PGI2, but this process is regulated by negative feed-backmechanisms. When the cells are stimulated in the presence of plasma i.e. in more physiological conditions, they are much less sensitive to inactivation.

Animals↗
PubMed1986

Action of AD6 (8-monochloro-3-beta-diethylaminoethyl-4-methyl-7-ethoxycarbonylmet hox y coumarin) on human platelets in vitro.

The action of AD6 was tested in vitro on human platelets by measuring beta-thromboglobulin (BTG), platelet factor 4 (PF4) and thromboxane B2 (TXB2) release as well as aggregation. BTG and PF4 release from blood anticoagulated with sodium citrate was inhibited by AD6 during a 3 h incubation. Platelet rich plasma (PRP) was stimulated with ADP, collagen, sodium arachidonate, PAF, A23187 and epinephrine, while resuspended washed platelets (WP) were stimulated by thrombin. AD6 (5-100 microM) inhibited dose dependently aggregation, BTG, PF4 and TXB2 release induced by threshold concentration of all the tested aggregating agents; however AD6 action could be overcome by increasing the concentration of the stimulating agents. After cyclo-oxygenase blockade by acetylsalicylic acid (ASA), PRP was stimulated by a supramaximal concentration of PAF. Under these circumstances we could observe a reversible aggregation and a partial release of BTG and PF4, AD6 was able to further reduce aggregation and release. Cyclic AMP accumulation induced in WP by prostacyclin was not modified by AD6 (100 microM), while theophylline greatly potentiated prostacyclin action. We conclude that AD6 is an inhibitor of platelet activation in vitro. Its mode of action is different from cyclo-oxygenase blockade and provides inhibition of platelet activation by a number of different stimuli.

Anticoagulants↗
PubMed1986

Enkephalin modulation of neural transmission in the cat stellate ganglion: pharmacological actions of exogenous opiates.

Neural ganglionic transmission was studied in vivo in the cat, using closed chest anesthetized preparations. The right stellate ganglion and its branches were exposed retropleurally and prepared for electrical stimulation of pre- and postganglionic nerve fibers. The axillary artery was cannulated allowing direct administration of drugs in the arterial blood supplying the ganglion. Stimulation of postjunctional receptors could thus be obtained by local administration of selective agents. Local administration of nicotinic, muscarinic or histaminergic agents increased heart rate and blood pressure. Opiates were given either i.v. or locally through the axillary artery: we tested the effects of morphine, Leu-enkephalin (Leu-enk), Met-enkephalin (Met-enk), [D-ala2]-Met-enkephalinamide (DAME) and etorphine. When given locally, Leu-enk (from 10 micrograms), Met-enk (from 20 micrograms), DAME (from 5 micrograms) and etorphine (from 0.2 micrograms) inhibited tachycardia induced by preganglionic stimulation and reduced the amplitude of the compound action potential recorded from the postganglionic nerve. Morphine (10-200 micrograms) had no effect. On the other hand, tachycardia induced by postganglionic nerve stimulation was unaffected by opiates in the same experimental conditions. Intravenous administration of similar doses of opiates had no effect on ganglionic transmission. When tachycardia was induced by chemical stimulation of nicotinic (DMPP), muscarinic (McN-A-343-11) or histamine receptors in the stellate ganglia, opiates were still active in reducing the effect of these chemicals. These data provide evidence that exogenous opiates exert a depressing action on postsynaptic responses of sympathetic ganglia tested in vivo, although an additional action on presynaptic terminals is not excluded. As endogenous opiates are normally present in various sympathetic ganglia, including the stellate ganglion of the cat, it is possible that they play some modulatory role on ganglionic transmission in physiological conditions.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1986

The action of AD6 on experimental arrhythmias and on action potentials of cardiac fibers.

AD6 is a coumarinic derivative which increases both coronary blood flow and prostacyclin production, while it decreases platelet responsiveness. We tested its action on experimental cardiac arrhythmias. AD6 (2.5-10 mg/kg) was able to antagonize the arrhythmogenic action of aconitine in rats and of adrenaline in cats. AD6 action was also tested in vitro. The drug (20-50 microM) prolonged the functional refractory period of guinea-pig atrial and ventricular muscle and lengthened the refractory period shortened by hypoxia. Intracellular electrophysiological experiments showed that AD6 prolongs action potential duration (APD) of guinea-pig atrial myocardium, sino-atrial node and cat Purkinje fibers. The results obtained in vitro may explain the effect on experimental arrhythmias, therefore suggesting a protective action on cardiac rhythm disturbances.

Aconitine↗
PubMed1985

Disappearance of human platelet factor 4 (PF4) in rabbits: does an immediate component exist?

Twelve male New Zealand rabbits were injected with 21 micrograms/kg of human platelet factor 4 antigen (PF4). The decay of the protein followed a monoexponential curve for the first 5 mins, with a half-life (t 1/2) of 1.94 mins and a calculated concentration at 0 time (CO) of 79.4 ng/ml. Five rabbits were pre-treated with heparin (2.500 I.U. i.v.) and 3 mins later were injected with the same amount of PF4. PF4 decay followed a monoexponential curve with a t 1/2 of 25.3 mins, and with CO of 380.8 ng/ml. This value is not greatly different from the one calculated assuming an immediate and uniform distribution in plasma (482.7 ng/ml for a plasma volume of 43.5 ml/kg). The 12 rabbits injected with PF4 were divided in 3 groups, in which heparin was given at 10', 30' or 60' after PF4, respectively. After heparin the peak levels of PF4 were 139.9 ng/ml, 65.3 ng/ml and 52.7 ng/ml, respectively. The following monoexponential PF4 decay had t 1/2 of 20.7, 25.6 and 26.0 mins, respectively. In a separate group of 4 animals, we studied heparin decay after an intravenous bolus of 2.500 I.U. Heparin decay could not be described by a monoexponential equation and was different from the decay of PF4 injected after heparin. On the basis of the present data we suggest the presence of an immediate component of PF4 decay, most likely due to uptake by the tissues. Heparin pretreatment may avoid this uptake process.

Animals↗
PubMed1985

Inhibition by AD6 (8-monochloro-3-beta-diethylaminoethyl-4-methyl-7-ethoxycarbonyl methoxy coumarin) of platelet aggregation in dog stenosed coronary artery.

The action of AD6 as an anti-thrombotic agent was studied in a model of coronary artery thrombosis and on platelet aggregation in the dog. AD6 (10-100 microM) in vitro inhibited aggregation induced by ADP, epinephrine, collagen and PAF (platelet aggregating factor) used at their threshold concentration for maximal aggregation. Arterial thrombosis was induced in a coronary vessel by critically reducing (about 70%) the vessel lumen. Thrombus formation was estimated by measuring coronary flow in the stenosed vessel. Using this procedure on the left descending coronary artery (LAD), we obtained reproducible blood flow changes in 18 dogs. AD6 was given i.v. at three different doses. At 0.25 mg/kg two out of four dogs showed decreased thrombus formation at the stenosis site. Seven out of eleven dogs treated with 0.5 mg/kg and two out of three treated with 1.5 mg/kg showed decreased thrombus formation. Major decreases in coronary resistance, evaluated by measuring blood flow in the unstenosed left circumflex artery (LCX), were evident only after the highest dose. We conclude that AD6 has an inhibitory action on dog platelet aggregation and reduces thrombus formation in a stenosed coronary vessel.

6-Ketoprostaglandin F1 alpha↗
PubMed1985

Coronary and systemic 6-ketoprostaglandin F1 alpha and thromboxane B2 during myocardial ischemia in dog.

The left anterior descending coronary artery (LAD) of five dogs was ligated, and blood was withdrawn from the great cardiac vein, left marginal cardiac vein, femoral vein, and aorta. After ligation, immunoreactive 6-ketoprostaglandin (PG) F1 alpha rose from less than 0.1 to a mean value of 1.2 pmol/ml plasma in the great cardiac vein (GCV) and 0.88 pmol/ml in the left marginal vein, with no change in peripheral circulation. Immunoreactive thromboxane (TX) B2 remained below 0.075 pmol/ml throughout the experiments. LAD of 11 dogs was stenosed 60-80% with consequent cyclical reductions in blood flow. 6-Keto-PGF1 alpha in GCV rose in seven dogs (range 0.5-2.2 pmol/ml) and remained unchanged in four. No change was observed in peripheral plasma levels of 6-keto-PGF1 alpha. In these experimental conditions TXB2 remained below 0.075 pmol/ml. Lactate concentrations rose in both experimental conditions in GCV but not in peripheral circulation or in the left marginal vein. This study confirms a link between cardiac ischemia and increased coronary prostacyclin release, but we were unable to detect a similar correlation with TXB2 in plasma.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Clearance and in vivo release by heparin of human platelet factor 4 (PF4) in the rabbit.

13 male New Zealand rabbits were injected with two different doses (25 micrograms/Kg and 100 micrograms/Kg) of human platelet factor 4 antigen (PF4). The disappearance of the protein was extremely fast with an half-life for the fast component of 1.07 +/- 0.16 and 1.76 +/- 0.11 min respectively. The half-life for the slow component, detectable only with the highest dosage, was 18.8 min. The administration of 2500 I.U. of heparin 30 min after PF4 administration induced a partial release of the injected protein and its clearance from plasma was slow, with half-life of 23.3 +/- 5.9 min and 30.9 +/- 2.19 min respectively.

Animals↗
PubMed1983

Effect of diamide on isolated guinea pig atria.

Diamide [(diazinedicarboxylic acid-bis (dimethylamide)] 50 micrograms/ml induced a positive inotropic and chronotropic effect on spontaneously beating atria from normal and reserpine pretreated guinea pigs and a positive inotropic action on electrically driven left atria. Cumulative addition of diamide 600 micrograms/ml caused a systolic standstill of atria. D(-) INPEA 2 micrograms/ml, a beta-adrenergic blocking agent, antagonized the positive chronotropic action of diamide 50 micrograms/ml while it did not affect the positive inotropic action caused by diamide. In isolated atria perfused with Ca2+ free medium and recovered by stepwise addition of calcium chloride, the calcium level required to restore normal activity was 1.04 mmol/1 while it was 0.52 mmol/l in the presence of diamide. Ruthenium red 10 micrograms/ml, a specific inhibitor of calcium transport in mitochondria, antagonized diamide-induced recovery of the cardiac activity in calcium poor medium. Two different mechanisms, that involve calcium movements and beta-receptor, have been proposed for diamide action on heart muscle.

Animals↗
PubMed1981

Effect of adenosine on oxygen uptake and electrolyte content of frog sartorius muscle.

Adenosine and ATP depressed resting O2 uptake in frog sartorius. This action was blocked by low levels of caffeine and by 8-phenyltheophylline. It was mimicked by a polymer of adenosine. Adenosine also decreased radioactive calcium uptake in muscles. Potassium and magnesium content were increased while sodium and calcium content were decreased by adenosine. Adenosine did not decrease oxygen uptake in muscles from frogs sacrificed in winter months. However, adenosine deaminase, which inactivates adenosine by removing the amino group, increased oxygen uptake, calcium content and lactate release of these muscles. Our results suggest that adenosine reduces resting metabolism, possibly through reducing passive leaks of electrolytes.

Adenosine↗