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Biomedical subjects

M A Lazzari

Publications and source records attributed to M A Lazzari.

At least 55 records · Page 3Linked to original sources

The influence of sex and different segments of thoracic aorta on bioactive aortic substance (BAS) and prostacyclin (PGI2) synthesis.

BAS is a protein generated by aortic rings isolated from rats. Our previous results clearly established that BAS inhibits platelet aggregation and modifies vascular tone. We have now examined the effect of separated segments of thoracic aorta and the effect of sex on the release of the BAS and PGI2. We evaluated three different segments of thoracic aorta: A = aortic arch, B = the upper segment and C = the lowest segment of the thoracic aorta. We measured the release of BAS and PGI2 from them. The BAS production increased in the first segment (A) when compared with the other two (B and C), whilst PGI2 production was the same along the thoracic aorta. On the other hand female and male thoracic aorta produced the same levels of BAS and 6-keto PGF1 cm.

Animals↗

Effect of acenocoumarine on the breast-fed infant.

Apart from teratogenic phenomena and the potential risk of maternal or neonatal peripartum haemorrhage, the use of oral anticoagulants during pregnancy poses an additional hazard: the risk of transferring some anticoagulant activity to the nursing infant through breast milk. We analysed the coagulation status of seven full term breast-fed neonates whose mothers were under chronic anticoagulant therapy with acenocoumarine as thromboembolic prophylaxis following cardiac valve replacement. Prothrombin Times (PT) observed in neonates were significantly higher than the corresponding maternal values. Data were subsequently compared with those obtained from a control group comprising forty-two full term neonates nursed by non-anticoagulated mothers: coagulation profiles again showed no signs of any noticeable antivitamin K effect. Our results indicate that mothers given acenocoumarine at therapeutic doses may safely breast-feed their infants: anticoagulant activity in breast milk seems to be negligible as assessed by neonates PT.

Acenocoumarol↗

Aspirin effect on the release of plasminogen activator inhibitors by human platelets.

Intrinsic plasminogen activators (PA) were tested in euglobulins (eug) of platelet poor plasma (PPP) with and without washed platelets (WP), treated or not with urokinase (UK), streptokinase (SK), collagen (Col) and aspirin (ASA) using fibrin plates method. A significant decrease of the fibrinolytic activity related to the presence and number of platelets was observed. We confirm the presence of platelet anti-UK and anti-SK activities. The former appears to be higher than the other activity. Low and high concentrations of Col stimulated the release of plasminogen activator-inhibitors (PA-I) from platelets, and ASA could not modify this release. Besides ASA might inhibit some PA release. The high concentration of Col was capable to release anti-UK and anti-SK activities from platelets and perhaps other intrinsic PA-I. The low concentration of Col was only capable to release intrinsic PA-I, suggesting that anti-UK and anti-SK needed a stronger stimuli to be released than intrinsic PA-I. We must consider the possibility that the PA-I and/or activators could be released by different metabolic pathways other than cyclooxygenase pathway.

Aspirin↗

Intraplatelet levels of vWF:Ag and fibrinogen in myeloproliferative disorders.

Several platelet function abnormalities have been described in the myeloproliferative syndromes. We have measured the intraplatelet vWF:Ag and fibrinogen (FI) in the platelet lysates by Laurell technique in 11 patients with polycythemia vera (PV), 10 with essential thrombocythemia (ET), 14 with chronic myelocytic leukaemia (CML) and 3 with myelofibrosis (MF) and these results were correlated with platelet function abnormalities. Decreased intraplatelet levels of vWF:Ag and FI were found in all the patients with ET and MF, in 8 out of 11 PV and 3 out of 14 CML. A statistical significant correlation was observed between the intraplatelet levels of vWF:Ag and FI in the control group and in CML and PV, but no correlation was found in ET and MF. No correlation was observed between the plasmatic and the intraplatelet levels of vWF:Ag and FI in any group. Evidences of platelet activation (spontaneous platelet aggregation or circulating platelet aggregates) were observed in 40% of the cases with ET and PV, and all these cases had low intraplatelet levels of both antigens. None of the cases with MF had evidences of platelet activation and 2 out of 14 patients with CML had platelet activation. The deficiency of the dense bodies was less frequent than the depletion of the alpha granules (5 out of 11 PV, 4 out of 10 ET, 6 out of 14 CML and 2 out of 3 MF). The low intraplatelet contents of vWF: Ag and FI, more frequently observed in ET and PV, may be the result of platelet activation and in vivo release, but megakaryocyte dysfunction is more likely in myelofibrosis.

Antigens↗

Aspirin effect on platelet antiplasmins release.

Euglobulins of platelet poor plasma containing resuspended washed platelets produced a significant decrease of the lysis areas with regard to euglobulins of platelet poor plasma alone; this decrease correlated with the number of platelets. Euglobulins of platelet poor plasma containing washed platelets activated with collagen (2 and 20 micrograms/ml) showed lower lysis areas on fibrin plates compared with euglobulins containing non-activated platelets (p 0.001). The higher number of platelets, the lower the lysis area. Aspirin had no effect upon antiplasmin activity either in non-activated or in activated platelets. We must consider the possibility that platelet antiplasmins could be released by different metabolic pathways than via the cyclooxygenase pathway or that they are not stored in -granules.

Adenosine Diphosphate↗

Antithrombotic therapy in children and adolescents.

This report documents our experience with long term antithrombotic therapy (acenocoumarol plus aspirin) in 31 children and adolescents, from 5 months to 16 years of age. The valves replaced were mitral in 20 patients, aortic in 4, mitral-aortic in 4 and tricuspid in 3; the overall follow-up time was of 1336 months. Anticoagulant requirement in each children was not in correlation with age, but a significant increase (p less than 0.01) was found in association with sexual development. Our total incidence of embolic episodes was 1.49/1000 patient-months. The embolic incidence on adequate anticoagulated patients was 0.74/1000 patient-months and 93.7% of all patients were free of thrombo-embolic accidents up to 96 months of follow-up. Minor haemorrhage in relation to an excess of anticoagulant was 1.49/1000 patient-months. There has been only one major bleeding episode associated with severe sepsis, with an incidence of 0.74/1000 patient-months. No major difficulties were found in the management of anticoagulant treatment and its association with antiplatelet drugs in children.

Acenocoumarol↗

Biological profile of a bioactive aortic substance (BAS), released by vessel rings from indomethacin-treated rats.

The biological activity of a stable unknown material(s), generated by aortic rings (bioactive aortic substance = BAS) isolated from rats injected with a high dose of indomethacin, was explored on contractions of several smooth muscle preparations from normal rats and its effects compared with those elicited by prostacyclin (PGI2) or by 6-keto-prostaglandin F1 alpha (6-k-PGF1 alpha). The BAS evoked, as did PGI2 or 6-k-PGF1 alpha, positive inotropism in strips from rat stomach, ileum and urinary bladder, but failed to influence uterine contractions as did prostacyclin or its non-enzymatic metabolite. When tested in rat aortic strips both, PGI2 and the BAS produced relaxation, whereas 6-k-PGF1 alpha was not active. Moreover, lipid substances present in the incubates of aortic rings, were extracted and explored for effects on contractions of rat aortic strips and on arachidonate-evoked human platelet aggregation. These extracts were devoid of influence on both parameters. On the contrary, dried aqueous residues, after the lipid extraction of the supernatants of aortic ring incubates, exhibited human platelet antiaggregatory capacity as well as the ability to evoke positive and negative inotropism similar to those triggered by the BAS in different smooth muscle preparations. Experiments with BAS were also performed employing smooth muscle strips exposed to indomethacin, atropine, propranolol, phentolamine and cyproheptadine. The presence of these antagonists of several neuromodulators and of indomethacin failed to alter de BAS-induced inotropic capacity observed in controls. The findings suggest that the effects attributable to the BAS are not subserved by prostacyclin or other prostanoids, nor by acetylcholine, norepinephrine, histamine or 6-OH-tryptamine.

6-Ketoprostaglandin F1 alpha↗

Platelet aggregating substance from mononuclear leukocytes.

Human peripheral blood mononuclear leukocytes (ML) in suspension stimulated with arachidonic acid (AA) were able to induce platelet aggregation. Shape change followed by first and second wave aggregation was the pattern of the platelet response. ML not treated with AA did not induce platelet aggregation nor did AA done at the concentration employed. The aggregating activity was not due to the ML presence, since cell-free supernatants of ML stimulated with AA induced similar platelet aggregation as the whole suspension. Aspirin incubated with ML-AA produced 65% reduction of the above aggregatory activity described while 38% and 45% reduction was obtained when ML-AA was incubated with 5, 8, 11, 14 eicosatetraynoic acid (ETYA) and nordihydroguaiaretic acid (NDGA). Complete platelet cyclooxygenase integrity was necessary to obtain the second wave of aggregation induced by ML-AA, while this was not required for the first wave response. We propose that ML-AA are able to produce a platelet activating substance(s) derived from AA metabolism involving cyclo and lipoxygenase actions. It is unlikely that this substance(s) is a hydroperoxyfatty acid or thromboxane A2 (TXA2) since it is active for at least two hours once generated.

5,8,11,14-Eicosatetraynoic Acid↗

Rat's vessel wall generates an antiaggregatory substance independent of prostacyclin production.

We have investigated whether the vessel wall may release or synthetize some substance able to modify the platelet function independent of prostacyclin (PGI2) production. Twenty female rats were injected with indomethacin. 18 hours after the injection animals were sacrificed and rings cut from thoracic and abdominal aorta were obtained. They were incubated in Krebs solution for different periods of time after which an aliquot from the indomethacin treated rat's aortic ring (ITRAR) was assayed on platelet aggregation induced by several agonists. The supernatant from the 40 min. incubation mixture of ITRAR released a substance which completely inhibits platelet aggregation induced by arachidonic acid (AA), ADP, epinephrine, collagen, ristocetin and thrombin. The time of appearance of the substance varied with a mean of 17 min.. It is released with and without AA stimulation. Once generated it is active for at least three hours; its antiaggregating activity remains even if it is boiled for 15 sec, incubated at 37 degrees C, or if the vessel is treated with tranylcypromine. Platelet aggregation inhibition is still evident if the supernatant from ITRAR is transferred to a platelet rich plasma (PRP) from a normal donor who had taken an aspirin 24 hours before sampling. All these results indicate that this substance released from ITRAR is not prostacyclin. Nordihydroguaiaretic or eicosatetraynoic acid which are lipoxygenase inhibitors could not modify the ITRAR's release; nor did mepacrine which is a phospholipase inhibitor. Since mepacrine does not completely inhibit phospholipase activities we cannot exclude the possibility that the substance is derived from AA. More studies are in progress to elucidate the biochemical properties of this substance.

5,8,11,14-Eicosatetraynoic Acid↗

Human lymphocyte aggregation?

The purpose of the present study was to assess lymphocyte (L) aggregation. Mononuclear cells were obtained according to Boÿum. Blood was defibrinated with glass beads and laid on Ficoll-Hypaque gradients. Monocyte depletion was achieved by adherence to plastic for 18 hs. L aggregation was assayed using the turbidimetric method. When L were challenged with collagen (1-8 micrograms/ml), ADP (2.5 microM), epinephrine (1 X 10(-4) M), ristocetin (1.5 mg/ml) and bovine F VIII no aggregation could be observed. When L were stimulated by arachidonic acid (AA) (160 microM) a complete and irreversible aggregation was obtained. This effect was markedly inhibited when L were previously incubated with aspirin (40 micrograms/ml). On the other hand 5, 8, 11, 14 eicosatetraynoic acid (ETYA), a lypoxygenase inhibitor, was not able to reverse L aggregation induced by AA. Leukotriene B4, C4 and D4 were not able to induce L aggregation. When TXA2 like material from platelets and L was transferred to L preincubated with aspirin a normal aggregation response was obtained. All these results lead to the concept that the main pathway involved in L AA metabolism is probably cyclo-oxygenase. Ionophore A 23187 was not able to induce L aggregation at any concentration employed (0.1 - 100 microM) and 6 keto PGE1 could not inhibit AA induced lymphocyte aggregation.

5,8,11,14-Eicosatetraynoic Acid↗

Lipoxygenase inhibitors alter aggregation and adhesiveness of human blood platelets from aspirin-treated patients.

The influences of arachidonic acid (AA) and of inhibitors of lipoxygenases (eicosatetraynoic acid-ETYA- and nordihydroguaiaretic acid -NDGA-) on platelet aggregation evoked by collagen or adenosinediphosphate (ADP) as well as platelet adhesiveness to collagen of platelet-rich-plasma (PRP) from aspirin-treated patients were explored. ETYA or NDGA (10(-8) and 10(-7) M) clearly diminished the per cent aggregation evoked by collagen or ADP and delayed its onset. On the other hand AA (0.2 mM) enhanced the aggregation and shortened the lag phase evoked by collagen at 1.2 and 2.6 micrograms/ml, but not at 5.2 micrograms/ml. Platelet-collagen adhesion of PRP was significantly reduced by ETYA or NDGA (10(-7) M) and augmented by AA (2 mM). The results strongly suggest that lipoxygenase products of arachidonate metabolism play an important role in promoting the mechanism(s) underlying human platelet aggregation and adhesiveness.

5,8,11,14-Eicosatetraynoic Acid↗