RESUMEN
Very-low-mass stars (those less than 0.3 solar masses) host orbiting terrestrial planets more frequently than other types of stars. The compositions of those planets are largely unknown but are expected to relate to the protoplanetary disk in which they form. We used James Webb Space Telescope mid-infrared spectroscopy to investigate the chemical composition of the planet-forming disk around ISO-ChaI 147, a 0.11-solar-mass star. The inner disk has a carbon-rich chemistry; we identified emission from 13 carbon-bearing molecules, including ethane and benzene. The high column densities of hydrocarbons indicate that the observations probe deep into the disk. The high carbon-to-oxygen ratio indicates radial transport of material within the disk, which we predict would affect the bulk composition of any planets forming in the disk.
RESUMEN
The role of resident or migratory birds in dispersal of tick species and tick-borne pathogens is still poorly known in Italy. We report here the results of a 3-year project based on sampling ticks from migratory birds, as well as from the vegetation at three stop-over sites for migrants, namely the islands of Ventotene (Latium), Asinara (Sardinia) and Ustica (Sicily). During the spring seasons from 2017-2019, in total 2681 ticks were collected, 2344 of which were sampled from migratory birds and 337 from the vegetation. Ticks were identified by morphology or by molecular tools when necessary. In total, 16 tick species were identified among which the following were exclusively found on birds: Hyalomma rufipes (43.3%), Hy. truncatum (0.1%), Ixodes frontalis (11.8%), Ix. inopinatus (0.2%), Ix. ricinus (3%), Haemaphysalis punctata (0.08%), Hae. erinacei (0.1%), Amblyomma variegatum (0.08%) and Argas vulgaris 0.1%), whereas five species were exclusively collected from the vegetation: Rhipicephalus bursa (10.5%), Rh. turanicus (5.9%), Rh. sanguineus sensu lato (2%), Rh. pusillus (2.4%), Hae. sulcata (0.08%). Hy. marginatum (10.3%) and Ix. ventalloi (9.3%) were found both on birds and on the vegetation on the island Ustica. It is worth noting that the search for ticks on the vegetation did not detect allochthonous tick species. Although we found several interesting local species and allochthonous ticks like Hy. rufipes, Am. variegatum and Ar. vulgaris on birds, further investigations are needed to better define the possible role of migratory birds in the introduction of ticks and tick-borne diseases in Italy, above all after the evidence of imported ticks positive to Crimean Congo hemorrhagic fever (CCHF) virus in several European countries.
Asunto(s)
Virus de la Fiebre Hemorrágica de Crimea-Congo , Fiebre Hemorrágica de Crimea , Infestaciones por Garrapatas , Garrapatas , África/epidemiología , Animales , Aves , Europa (Continente) , Italia/epidemiología , Infestaciones por Garrapatas/epidemiología , Infestaciones por Garrapatas/veterinariaRESUMEN
Cucullanus carettae Baylis, 1923 (Nematoda: Cucullanidae) is found worldwide in loggerhead turtles (Caretta caretta). Regarding the Mediterranean, C. carettae has been identified in the Tyrrhenian and the Ionian Sea and a unique description of a Cucullanus sp. specimen in loggerheads from the Adriatic Sea has been reported in the literature so far. In the framework of a bio-monitoring project of the Abruzzo and Molise coasts, a parasitological survey was performed on stranded and by-caught sea turtles, at the Istituto Zooprofilattico of Abruzzo and Molise "G. Caporale." During necropsy, the gastrointestinal system of 72 stranded loggerhead turtles was analyzed for the presence of endoparasites and fecal samples were collected for coprological examination. Adult C. carettae (n = 123) was found in the upper intestine of one loggerhead turtle, associated with chronic lymphoplasmocytic enteritis. Additionally, five stool samples (6.9%) were positive for Cucullanus sp. eggs. Molecular characterization of adult nematodes was carried out to study phylogenetic relationships among the Cucullanus species. To our knowledge, this is the first morphological and molecular identification of C. carettae in loggerhead turtles from the Adriatic Sea. Additional studies on the distribution of this parasite in the Mediterranean are encouraged.
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Ascaridoidea/aislamiento & purificación , Intestinos/parasitología , Spirurina/aislamiento & purificación , Tortugas/parasitología , Animales , Ascaridoidea/clasificación , Enteritis/parasitología , Heces/parasitología , Femenino , Masculino , Mar Mediterráneo , Filogenia , Spirurina/clasificaciónRESUMEN
Human granulocytic anaplasmosis (HGA) is an emerging tick-borne zoonosis worldwide. As is the case for many tick-borne diseases, the epidemiological cycle is associated to the environmental conditions, including the presence of wild vertebrate reservoir hosts, vectors, climate and vegetation. In this study a total number of 87 spleen samples of wild ruminants carcasses from Central Italy, and 77 Ixodes ricinus collected from the same dead animals were screened for Anaplasma phagocytophilum by using Real Time PCR. A. phagocytophilum DNA was detected in 75%, 66.7% and 54.2% of the spleen samples from red deer (Cervus elaphus), Apennine chamois (Rupicapra pyrenaica ornata) and roe deer (Capreolus capreolus) respectively, whereas it was detected in the 31.2% of I. ricinus. A total of 27 positive samples were characterized by sequencing a portion of the groEL gene. Two A. phagocytophilum lineages could clearly be delineated from the phylogenetic tree. Four sequences from red deer, 2 from I. ricinus and 1 from Apennine chamois clustered into lineage I together with those previously described as virulent genotypes related to HGA. The presence of A. phagocytophilum DNA in the Apennine chamois represents the first report for this Italian endemic subspecies.
Asunto(s)
Anaplasma phagocytophilum/genética , Anaplasma phagocytophilum/patogenicidad , Anaplasmosis/microbiología , Ciervos/microbiología , Reservorios de Enfermedades , Ehrlichiosis/microbiología , Ixodes/microbiología , Anaplasmosis/epidemiología , Animales , Animales Salvajes/microbiología , Chaperonina 60/genética , Ehrlichiosis/epidemiología , Ehrlichiosis/veterinaria , Genotipo , Humanos , Italia/epidemiología , Filogenia , Rupicapra/microbiología , Bazo/microbiología , ZoonosisRESUMEN
Migratory birds are considered one of the main sources for West Nile virus (WNV) introduction into European countries. Following the WNV epidemic in the late summer of 1998 in a marshy area of Tuscany (Padule of Fucecchio), an extensive ornithological surveillance programme was carried out in the infected areas from 2006 to 2008. Several species of migratory and resident birds were trapped, sampled and serologically tested. The results of this surveillance programme gave a useful indication of potential sources of WNV re-introduction and spread into Italy. The area under study was also investigated and classified into ecological areas through satellite image processing. In August 2008, the WNV infection re-emerged in Italy in the area surrounding the Po river delta, involving three regions: Lombardy, Emilia Romagna and Veneto. Several surveillance activities were immediately put in place, including the extensive monitoring of wild birds found dead or trapped in the framework of other surveillance programmes. These activities were also prolonged in the 2009, when the virus circulation re-occurred at the border of the area already infected in 2008. The possible epidemiological role of the different species of migratory and resident birds is discussed, in relation to the different ecological patterns identified in the area and their potential ability to introduce, spread and support the endemization of WNV infection.
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Enfermedades de las Aves/transmisión , Fiebre del Nilo Occidental/veterinaria , Migración Animal , Animales , Enfermedades de las Aves/epidemiología , Enfermedades de las Aves/virología , Aves , Italia/epidemiología , Vigilancia de la Población , Especificidad de la Especie , Fiebre del Nilo Occidental/epidemiología , Fiebre del Nilo Occidental/transmisiónRESUMEN
The aging heart appears to be more susceptible to ischemia-reperfusion injury than the adult heart. There is no evidence of an age-related difference in the threshold of myocardial ischemia and myocardial stunning. We studied the effects on mechanical, hemodynamic, and metabolic parameters of graded reduction of coronary perfusion pressure from 66 to 29 mmHg in isolated and perfused hearts from adult and senescent rats. Cardiac function was also assessed during recovery following ischemic period. In both adult and senescent hearts developed pressure and +dP/dt linearly decreased and end-diastolic pressure linearly increased with decreasing perfusion pressure. However, all mechanical parameters were more severely impaired in senescent than in adult hearts at 37 mmHg and 29 mmHg perfusion pressure, respectively (p < 0.01 vs. adult). At 29 mmHg, in both adult and senescent hearts lactate production similarly increased whereas creatine kinase leakage did not differ from controls. Developed pressure recovered more slowly in senescent than in adult hearts (p < 0.001) in the absence of cellular damage and in the presence of restoration of coronary flow. Lactate production observed at the same step of coronary perfusion pressure suggests that the ischemic threshold is similar in adult and senescent hearts. The slow recovery of myocardial contractility after the ischemic period observed in senescent hearts suggests an age-related increase in myocardial stunning.
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Envejecimiento , Corazón/fisiopatología , Aturdimiento Miocárdico/fisiopatología , Animales , Creatina Quinasa/metabolismo , Técnicas In Vitro , Ácido Láctico/biosíntesis , Masculino , Ratas , Ratas WistarRESUMEN
BACKGROUND: Tissue factor (TF)-dependent activation of the coagulation is important in the pathophysiology of intravascular thrombus formation. We tested the effects of a monoclonal antibody against TF (AP-1) on lysis time induced by tissue-type plasminogen activator (TPA) and on reocclusion rate in a rabbit model of carotid artery thrombosis. METHODS AND RESULTS: Intravascular thrombosis was obtained by placing an external constrictor around carotid arteries with endothelial injury. Carotid blood flow velocity ws measured continuously with a Doppler flow probe. Thirty minutes after thrombus formation, the rabbits received either AP-1 (0.15 mg/kg IV, n=8) or placebo (n=8). All rabbits also received TPA (80 microg/kg bolus plus 8 microg x kg(-1) x min(-1) infusion for up to 90 minutes or until reperfusion was achieved) and heparin (200 U/kg IV as a bolus). At reperfusion, TPA was discontinued, and the rabbits were followed for an additional 90 minutes. AP-1 shortened lysis time from 44+/-8 minutes (mean+/-SEM) in control rabbits to 26+/-7 minutes in AP-1 rabbits (P<.01). Reocclusion occurred in all control rabbits in 10+/-3 minutes, whereas it occurred in only two of eight AP-1 treated rabbits in 72 and 55 minutes (P<.01). No changes in prothrombin time and ex vivo platelet aggregation in response to various agonists were observed after AP-1 administration, indicating the absence of systemic effects by this antibody. CONCLUSIONS: TF exposure and activation of the extrinsic coagulation pathway play an important role in prolonging lysis time and mediating reocclusion after thrombolysis in this model. AP-1, a monoclonal antibody against TF, might be suitable as adjunctive therapy to TPA.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Trombosis de las Arterias Carótidas/terapia , Activadores Plasminogénicos/uso terapéutico , Tromboplastina/fisiología , Activador de Tejido Plasminógeno/farmacología , Animales , Femenino , Fibrinógeno/análisis , Fibrinopéptido A/análisis , Masculino , Agregación Plaquetaria , ConejosRESUMEN
Some evidence indicate that platelets (PLTs) and leukocytes might contribute to the development of neointimal hyperplasia following arterial injury, via release of several growth factors. To study the relative contribution of these cells and of growth factors released in consequence of activation, smooth muscle cells (SMCs), isolated from the aorta of New Zealand White rabbits, were grown in Dulbecco's medium containing 10% fetal calf serum (FCS). At 70% confluence, SMCs were made quiescent by removing FCS from the medium. Twenty-four hours later, the cells were stimulated with activated platelets, neutrophils, lymphocytes+monocytes, whole leukocytes and platelets + whole leukocytes. Then, 1 microCi of O3H-thymidine were added to SMC cultures to evaluate the degree of proliferation. Relative contribution of different PLT-derived mediators to SMC growth was evaluated by adding either ketanserin, a 5-HT2 receptor antagonist, ridogrel, a thromboxane A2 (TxA2) receptor antagonist, BN52021, a platelet activating factor (PAF) receptor antagonist, and trapidil, a platelet-derived growth factor (PDGF) receptor antagonist, or all antagonists together. SMC proliferation was significantly increased by platelet activation. This effect was reduced by adding either ketanserin, ridogrel, BN 52021 or trapidil. Neutrophils, lymphocytes + monocytes and whole leukocytes also increased SMC proliferation. Simultaneous stimulation of SMCs by platelets and whole leukocytes was associated with a significant increase in SMC proliferation as compared to platelets or leukocytes alone. Thus, TxA2, 5-HT, PAF, and PDGF all contribute to SMC proliferation in vitro. Adding all antagonist together resulted in an additive antiproliferative effect. Leukocytes are also important in SMC proliferation. Interaction between platelets and leukocytes may play a pivotal role in the modulation of this phenomenon.
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Plaquetas/efectos de los fármacos , Leucocitos/efectos de los fármacos , Músculo Liso/citología , Factor de Crecimiento Derivado de Plaquetas/farmacología , Receptores del Factor de Crecimiento Derivado de Plaquetas/efectos de los fármacos , Animales , Aorta/citología , Bovinos , Técnicas In Vitro , Monocitos/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/farmacología , ConejosRESUMEN
The extrinsic coagulation pathway is activated when tissue factor (TF) is exposed as a consequence of arterial damage. TF binds to factor VII (FVII) or activated FVII (FVIIa), generating a complex that activates both FX and FIX, ultimately leading to thrombin formation. To determine whether inhibition of FVII binding to TF would result in antithrombotic effects, active site-blocked FVIIa (FVIIai) was used in a rabbit model of intravascular thrombus formation. In addition, to study the interaction between extrinsic coagulation pathway activation and platelet aggregation, in the same model of intravascular thrombus formation, recombinant human FVIIa was administered in antiplatelet-treated rabbits. Cyclic flow variations (CFVs), due to recurrent thrombus formation, were initiated by placing an external constrictor around the endothelially-injured rabbit carotid arteries (Folt's model). Carotid blood flow was measured continuously by a Doppler flow probe placed proximally to the constrictor. CFVs were induced in 29 New Zealand White rabbits. After CFVs were observed for 30 min, the animals were randomly divided in four groups: 5 animals received via a small catheter (26G) placed proximally to the stenosis, an intra-arterial infusion of human recombinant FVIIai (0.1 mg/kg/min for 10 min); 9 animals received AP-1, a monoclonal antibody against rabbit TF (0.1 mg/kg i.v. bolus); 7 animals received ridogrel, a dual thromboxane A2 synthetase inhibitor and thromboxane A2 receptor antagonist (10 mg/kg i.v. bolus); finally, 8 rabbits received aurintrycarboxilic acid (ATA), an inhibitor of platelet glycoprotein Ib/von Willebrand factor interaction (10 mg/kg i.v. bolus). FVIIai abolished CFVs in 5 of 5 animals (CFV frequency minutes 0 cycles/hour; p < 0.05; carotid blood flow velocity minutes 106 +/- 9% of the baseline values; NS vs baseline). AP-1 abolished CFVs in 7 of 9 animals (CFV frequency minutes 0 cycles/hour; p < 0.05; carotid blood flow velocity minutes 58 +/- 35% of the baseline values; NS vs baseline). Finally, in all the animals receiving ridogrel or ATA CFVs were abolished (CFV frequency 0 cycles/hour; p < 0.05 in both groups; carotid blood flow velocity, respectively 62 +/- 32 and 66 +/- 40% of the baseline values; NS vs baseline in both groups). Thirty minutes following inhibition of CFVs, in the FVIIai treated rabbits, human recombinant FVIIa was infused, via the small catheter placed proximally to the stenosis, at the dose of 0.1 mg/kg/min for 10 min. In the other three groups, FVIIa, at the same dose, was infused i.v. Infusion of FVIIa restored CFVs in all FVIIai treated animals and in 6 of 7 AP-1 treated animals, thus indicating that AP-1 and FVIIai bindings to TF was competitive and was replaced by FVIIa. Infusion of FVIIa failed to restore CFVs in ridogrel e ATA treated rabbits (1 of 7 and 0 of 8 rabbits, respectively), showing that activation of extrinsic coagulation by FVIIa was overcome by inhibition of platelet function. Activated partial thromboplastin time, and ex vivo platelet aggregation in response to ADP and thrombin, were not different after FVIIai infusion, while prothrombin time was slightly but significantly prolonged as compared to baseline values. Thus, FVII-VIIa plays an important role in initiating thrombus formation in vivo. Administration of FVIIai exerts a potent antithrombotic effects in this model without affecting systemic coagulation. In addition, in this model platelets exert an important role in arterial thrombosis, since in the presence of inhibition of platelet function, activation of the extrinsic coagulation pathway failed to restore thrombus formation.
Asunto(s)
Trombosis de las Arterias Carótidas/tratamiento farmacológico , Modelos Animales de Enfermedad , Factor VII/antagonistas & inhibidores , Factor VIIa/uso terapéutico , Fibrinolíticos/uso terapéutico , Enfermedad Aguda , Animales , Coagulación Sanguínea/efectos de los fármacos , Trombosis de las Arterias Carótidas/sangre , Arteria Carótida Común , Evaluación Preclínica de Medicamentos , Factor VIIa/antagonistas & inhibidores , Femenino , Humanos , Masculino , Conejos , Distribución Aleatoria , Proteínas Recombinantes/uso terapéutico , RecurrenciaRESUMEN
In the present study we tested the effects of different antithrombotic interventions on platelet deposition in experimentally-stenotic rabbit carotid arteries with endothelial injury. Platelet deposition, quantitated by labeling autologous platelets with 111In-oxine, was significantly reduced compared to control animals by all interventions tested, i.e., R 68070, a drug with thromboxane A2 synthase and receptor blocking properties, BN 52021, a PAF receptor antagonist, aurintricarboxylic acid (ATA), an inhibitor of platelet glycoprotein (Gp) Ib/von Willebrand factor (vWf) interaction, AZ-1, a monoclonal antibody against rabbit GP IIb/IIIa, the platelet receptor for fibrinogen, and AP-1, a monoclonal antibody against rabbit tissue factor. ATA was significantly more effective than all the other interventions in reducing platelet deposition in the stenotic vessels. We conclude that inhibition of Gp Ib/vWf interaction may be a more suitable target for antithrombotic therapy under conditions of high shear stress, like those produced in this model.
Asunto(s)
Ácido Aurintricarboxílico/farmacología , Estenosis Carotídea/tratamiento farmacológico , Endotelio Vascular/efectos de los fármacos , Radioisótopos de Indio , Inhibidores de Agregación Plaquetaria/farmacología , Análisis de Varianza , Animales , Anticuerpos Monoclonales/uso terapéutico , Velocidad del Flujo Sanguíneo , Estenosis Carotídea/sangre , Modelos Animales de Enfermedad , Endotelio Vascular/lesiones , Inhibidores Enzimáticos/farmacología , Femenino , Masculino , Complejo GPIb-IX de Glicoproteína Plaquetaria/antagonistas & inhibidores , Conejos , Tromboxano-A Sintasa/antagonistas & inhibidores , Resultado del Tratamiento , Factor de von Willebrand/antagonistas & inhibidoresRESUMEN
Reactive oxygen metabolites have been reported to affect platelet aggregation. However, this phenomenon is still poorly understood. In the present study we investigated the effects of superoxide radical and hydrogen peroxide (H2O2) on platelet function in vitro and correlated those effects to possible changes of platelet concentrations of cyclic nucleotides and thromboxane, since these systems play a key role in the response of platelets to activating stimuli. Human platelets were exposed to xanthine-xanthine oxidase (X-XO), a system that generates both superoxide radicals and H2O2. Sixty seconds of incubation with X-XO impaired aggregation in response to ADP (by 48%), collagen (by 71%), or the thromboxane mimetic U-46619 (by 50%). This effect was reversible and occurred in the absence of cell damage. Impairment of aggregation in platelets exposed to X-XO was due to H2O2 formation, since it was prevented by catalase but not by superoxide dismutase. Similarly, incubation with the pure H2O2 generator glucose-glucose oxidase also markedly inhibited ADP-induced platelet aggregation in a dose-dependent fashion. Impaired aggregation by H2O2 was accompanied by a > 10-fold increase in platelet concentrations of guanosine 3',5'-cyclic monophosphate (cGMP), whereas adenosine 3',5'-cyclic monophosphate levels remained unchanged. The inhibitory role of increased cGMP formation was confirmed by the finding that H2O2-induced impairment of platelet aggregation was largely abolished when guanylate cyclase activation was prevented by incubating platelets with the guanylate cyclase inhibitor, LY-83583. Different effects were observed when arachidonic acid was used to stimulate platelets. Exposure to a source of H2O2 did not affect aggregation to arachidonate. Furthermore, in the absence of exogenous H2O2, incubation with catalase, which had no effects on platelet response to ADP, collagen, or U-46619, virtually abolished platelet aggregation and markedly reduced thromboxane B2 production (to 44% of control) when arachidonic acid was used as a stimulus. In conclusion, our data demonstrate that H2O2 may exert complex effects on platelet function in vitro. Low levels of endogenous H2O2 seem to be required to promote thromboxane synthesis and aggregation in response to arachidonic acid. In contrast, exposure to larger (but not toxic) concentrations of exogenous H2O2 may inhibit aggregation to several agonists via stimulation of guanylate cyclase and increased cGMP formation.
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Plaquetas/efectos de los fármacos , Especies Reactivas de Oxígeno/farmacología , Nucleótidos de Adenina/metabolismo , Plaquetas/metabolismo , Plaquetas/fisiología , Catalasa/farmacología , Humanos , Peróxido de Hidrógeno/farmacología , Nucleótidos Cíclicos/metabolismo , Agregación Plaquetaria/efectos de los fármacos , Superóxido Dismutasa/farmacología , Superóxidos/farmacología , Tromboxanos/biosíntesisRESUMEN
Tissue factor (TF) is a transmembrane protein that binds factor VII/VIIa, thus activating the extrinsic blood coagulation pathway. Since this pathway appears to be involved in the formation of intravascular thrombi, the anti-rabbit TF monoclonal antibody, AP-1, was produced and tested as an antithrombotic agent in a rabbit model of recurrent intravascular thrombosis. In this model, a plastic constrictor is positioned around the injured rabbit carotid arteries, and flow is monitored with a Doppler flow probe. This produces cyclic flow variation (CFV) in the carotid artery, which is caused by recurrent formation and dislodgment of thrombi at the site of the stenosis. After monitoring CFV pattern for 30 minutes, AP-1 was infused intravenously into nine rabbits at doses of 0.05 to 1.5 mg/kg body weight, and a control monoclonal antibody that does not react with rabbit TF was infused into four additional rabbits. In all rabbits receiving AP-1, CFV was abolished, and a steady normal blood flow was restored, indicating that thrombus formation had been blocked by AP-1. By contrast, in all rabbits that received the control monoclonal antibody, CFV continued unaltered. There was no change in the partial thromboplastin time and ex vivo platelet aggregation to several different agonists after infusion of AP-1, indicating an absence of systemic effects on the coagulation process. We conclude that activation of the extrinsic coagulation pathway has a key role in triggering intravascular thrombosis and that an anti-TF monoclonal antibody is an effective antithrombotic agent that could have therapeutic potential for humans.
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Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Estenosis Carotídea/complicaciones , Estenosis Carotídea/terapia , Tromboplastina/inmunología , Trombosis/prevención & control , Animales , Arterias Carótidas/metabolismo , Femenino , Inmunohistoquímica , Masculino , Conejos , Tromboplastina/metabolismo , Trombosis/etiología , Distribución TisularRESUMEN
BACKGROUND: Platelet activating factor (PAF) is a phospholipid released upon stimulation by a variety of cells and has been implicated in several pathophysiological events such as asthma and inflammatory diseases. However, although the ability to aggregate platelets in vitro was the first biological activity ascribed to PAF, its role in contributing to the in vivo formation of arterial thrombi has not been thoroughly clarified. METHODS AND RESULTS: Intravascular platelet aggregation was initiated in two different animal models of arterial stenosis and endothelial injury. An external constrictor was positioned around rabbit carotid arteries and canine coronary arteries. After placement of the constrictor, a typical pattern of flow developed in the stenotic vessels. This pattern of flow, characterized by progressive reductions of carotid or coronary blood flow followed by spontaneous or induced restorations of flow (cyclic flow variations, CFVs), is related to recurrent platelet aggregation at the site of the stenosis followed by dislodgment of the thrombus. After observing CFVs for 30 minutes, BN52021 (up to 1.2 mg/kg), a potent and selective PAF antagonist, was given intravenously to rabbits (n = 12) and dogs (n = 10). BN52021 completely inhibited CFVs in 10 of 12 rabbits, whereas it was relatively ineffective in abolishing CFVs in dogs (only 2 of 10 animals inhibited). This different effect of BN52021 was not explained by too small a dose of the drug to achieve a complete blockade of PAF receptors in dogs, since ex vivo platelet aggregation was completely inhibited in both rabbits and dogs in response to exogenous PAF at concentrations up to 10(-5) mol/L. In a second group of 10 dogs, the hypothesis that PAF may become an important mediator of CFVs in dogs only several hours after endothelial injury was tested. After 30 minutes of baseline CFVs, these animals received a bolus of BN52021 up to 1.2 mg/kg. After this treatment, CFVs were completely abolished in 2 of 10 animals. The remaining 8 dogs were followed for an additional 8-hour period, at the end of which a second bolus of BN52021 was given. At this time, BN52021 was effective, as CFVs were abolished in 6 of 8 animals. These effects of BN52021 at 8 hours were not the consequence of a cumulative dose of the compound, since ex vivo platelet aggregation in response to PAF returned to baseline values immediately before administering the second dose. To identify possible sources of PAF other than aggregating platelets at the site of arterial stenosis, dogs in a third group were killed after 30 minutes (n = 7) and after 8 hours (n = 8) of CFVs. Histological sections of the stenotic coronary artery showed a marked leukocyte infiltration in these arterial segments after 8 hours of CFVs, whereas sections from dogs killed after 30 minutes showed only moderate or no infiltration. CONCLUSIONS: These data demonstrate that PAF plays an important role as a mediator of platelet aggregation in vivo in rabbits and dogs. In the canine model, PAF appears to become more important after leukocyte infiltration of the arterial wall, as it may contribute to initiating enough platelet activation to lead to cyclic flow variations at sites of arterial stenosis and endothelial injury. Data from the present study suggest that PAF antagonists may be used as antiplatelet agents.
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Diterpenos , Factor de Activación Plaquetaria/fisiología , Agregación Plaquetaria/fisiología , Animales , Velocidad del Flujo Sanguíneo/fisiología , Trombosis de las Arterias Carótidas/sangre , Trombosis de las Arterias Carótidas/fisiopatología , Trombosis Coronaria/sangre , Trombosis Coronaria/fisiopatología , Perros , Femenino , Ginkgólidos , Lactonas/farmacología , Leucocitos/metabolismo , Masculino , Extractos Vegetales/farmacología , Factor de Activación Plaquetaria/antagonistas & inhibidores , Conejos , Flujo Sanguíneo Regional/fisiología , Factores de TiempoRESUMEN
The aim of the present study was twofold: 1) to assess whether inhibition of thromboxane A2 (TxA2) synthase exerts more potent antiplatelet effects when applied concomitantly with TxA2 and prostaglandin (PG)H2 receptor blockade and 2) whether these effects are mediated through redirection of PG endoperoxides toward the synthesis of antiplatelet PGs, such as PGI2 and PGE2. Thus, cyclic flow variations (CFVs), due to recurrent platelet aggregation, were initiated in the stenotic, endothelially injured carotid arteries of 39 rabbits. After 30 min of CFVs, the animals received: 1) SQ29548 (up to 0.6 mg/kg bolus + 0.2 mg kg-1 hr-1, n = 13), a TxA2/PGH2 receptor antagonist; 2) dazoxiben (up to 15 mg/kg bolus + 5 mg kg-1 hr-1, n = 13), a TxA2 synthase inhibitor and 3) picotamide (up to 20 mg/kg bolus + 20 mg kg-1 hr-1, n = 13), a drug with simultaneous TxA2 synthase and receptor blocking properties. CFVs were abolished in 6, 7, and 12 animals treated with SQ29548, dazoxiben, and picotamide, respectively (P < .01 for picotamide versus SQ29548 and dazoxiben). The animals in which CFVs were not abolished by SQ29548 or dazoxiben received the other drug at the same dose. CFVs were abolished by dazoxiben in five of seven rabbits that initially did not respond to SQ29548 and by SQ29548 in five of six animals that did not respond to dazoxiben. All animals that responded to the combination of SQ29548 and dazoxiben, as well as those that responded to picotamide, received increasing intravenous infusions of epinephrine to restore CFVs.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Inhibidores de Agregación Plaquetaria/farmacología , Receptores de Prostaglandina/antagonistas & inhibidores , Receptores de Tromboxanos/antagonistas & inhibidores , Tromboxano-A Sintasa/antagonistas & inhibidores , Animales , Aspirina/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes , Sinergismo Farmacológico , Epinefrina/farmacología , Ácidos Grasos Insaturados , Femenino , Hidrazinas/farmacología , Imidazoles/farmacología , Masculino , Ácidos Ftálicos/farmacología , Agregación Plaquetaria/efectos de los fármacos , Prostaglandinas/sangre , Conejos , Receptores de Tromboxano A2 y Prostaglandina H2RESUMEN
Previous studies have shown that experimental canine coronary artery stenosis associated with endothelial injury results in a typical pattern of coronary flow characterized by gradual decreases in coronary flow to almost zero values followed by restorations of flow to normal values. This pattern of flow, called cyclic flow reductions (CFRs), is the consequence of recurrent platelet aggregation at the site of the stenosis and endothelial injury and subsequent dislodgement of the thrombus. In the present study, platelet activation and aggregation in vivo was induced by placing an external constrictor around carotid arteries with endothelial injury in anesthetized rabbits. Carotid blood flow velocity was measured continuously with a Doppler flow probe positioned proximally to the constrictor. After placement of the constrictor, CFRs developed in 14 of 14 rabbits with a mean frequency of 16.5 +/- 2.3 cycles/h. CFRs were observed for 30 min, and the animals were treated with either an i.v. bolus of aspirin (10 mg/kg) or R 68070 (20 mg/kg), a drug with simultaneous TxA2 synthase and TxA2/PGH2 receptor blocking properties. Aspirin completely inhibited CFRs in 4 of 7 rabbits, whereas R 68070 eliminated CFRs in 7 of 7 animals. In the 3 animals that did not respond to aspirin, administration of ketanserin (0.25 mg/kg i.v.), a selective serotonin S2 receptor antagonist, completely abolished CFRs. Both aspirin and R 68070 resulted in a marked reduction in serum TxB2 formation and in a complete inhibition of ex vivo platelet aggregation in response to arachidonic acid, whereas aggregation in response to U46619, a TxA2 mimetic, was inhibited only in R 68070-treated rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)
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Estenosis Carotídea/sangre , Endotelio Vascular/lesiones , Agregación Plaquetaria/fisiología , Animales , Ácido Araquidónico/farmacología , Aspirina/farmacología , Modelos Animales de Enfermedad , Femenino , Masculino , Ácidos Pentanoicos/farmacología , Endoperóxidos de Prostaglandinas Sintéticos/farmacología , Piridinas/farmacología , Conejos , Tromboxano-A Sintasa/antagonistas & inhibidoresRESUMEN
The influence of theophylline ethylenediamine (100 mg/kg i.p.) on gluconeogenesis was studied in normal and in adrenodemedullated and reserpinized rats after overnight fasting by measuring the time-course of Alanine-14C incorporation into Glucose-14C. In the normal rat, theophylline produced a moderate hyperglycemia associated with an increased conversion of alanine to glucose at all time intervals. In addition, a marked rise of plasma levels of insulin and glucagon was observed. In sympathetctomized rats, plasma glucose and gluconeogenesis were again enhanced by theophylline, but the pattern of these modifications differed from that of normal rats since the peak values occurred earlier. Subsequently, both parameters rapidly declined reaching values lower than controls at the end of the experiment. Insulin response to theophylline was higher in sympathectomized animals in comparison to normal rats, while glucagon response was approximately of the same magnitude in the two groups. From these findings it was concluded that theophylline is able to stimulate gluconeogenesis from alanine both in the normal and sympathectomized rat. The different pattern of alanine conversion to glucose seems to depend on the different participation of insulin and catecholamines in the two groups.
Asunto(s)
Alanina/metabolismo , Gluconeogénesis/efectos de los fármacos , Simpatectomía , Teofilina/farmacología , Animales , Glucemia/metabolismo , Glucagón/sangre , Insulina/sangre , Masculino , RatasRESUMEN
The intravenous infusion of prostaglandin (PG) E1, E2, and A1 into normal rats at a dose of 2 mug/min significantly lowered plasma insulin levels with a tendency to recovery in the post infusion period. Whereas PGA1 infusion resulted in a moderate but significant hypoglycaemia, the administration of E-series PGs always produced a hyperglycaemic effect. The interference of PGE1 on insulin response to classical insulinogogues (glucagon, aminophylline, and tolbutamide) was also investigated. The results of these experiments demonstrate that PGE1 exerts an inhibitory action on insulin response to all insulin releasing agents investigated. As regards the haemodynamic effects of PGs, PGE1 and PGE2 lowered the arterial blood pressure by about 20 percent, while PGA1 was almost completely ineffective. On the other hand, the lowering effect of PGE1 on circulating insulin levels remained unchanged in rats treated with reserpine. These findings thus rule out a sympathetic over-activity secondary to the lowered arterial blood pressure as the mechanism of action of PGE1. A possible direct interference with the adrenergic receptor system of the pancreatic islets was also ruled out since the inhibitory effect of PGE1 was not overcome by phentolamine pre-treatment.
Asunto(s)
Insulina/sangre , Prostaglandinas A/farmacología , Prostaglandinas E/farmacología , Aminofilina/farmacología , Animales , Glucemia/metabolismo , Presión Sanguínea/efectos de los fármacos , Depresión Química , Glucagón/farmacología , Masculino , Fentolamina/farmacología , Ratas , Reserpina/farmacología , Estimulación Química , Tolbutamida/farmacologíaRESUMEN
The influence of intraperitoneal administration of aminophylline on the rate of hepatic glucose production and peripheral uptake (Ra and Rd) was studied in normal and in adrenodemedullated and reserpinized rats by using the primed constant infusion of Glucose-2-3H. In normal rats, the dose of 100 mg. per kilogram of aminophylline produced a marked increase of Ra and Rd. Since Ra rose more rapidly than Rd did initially, hyperglycemia developed. Thereafter, glucose production and uptake increased to nearly the same extent, and a new steady state was reached at plasma glucose levels almost twice those of the baseline. Smaller and transient modifications were observed after the administration of 20 mg. per kilogram of aminophylline. With the higher dose, insulin levels markedly rose (reaching a tenfold peak above the basal value) while minor increments were observed with the lower dose. In a group of normal rats which were given glucose (10 mg. per kilogram per minute) in order to achieve a degree of hyperglycemia comparable to that brought about by the higher dose of aminophylline, an almost identical enhancement of glucose uptake was recorded. However, insulin levels were much higher in aminophylline-treated rats as compared to normal rats. From these finding it was concluded that aminophylline induces resistance to insulin effect. When aminophylline was injected into demedullated rats pretreated with reserpine, at the dose of 100 mg. per kilogram, a marked enhancement of Ra, and consequently of glycemia, was recorded initially; later, severe hypoglycemia developed depending on both a progressive exhaustion of hepatic glucose production and a marked increase of glucose utilization. Insulin levels dramatically increased in these experiments. These results suggest that aminophylline directly increases glucose production by the liver and insulin secretion. The simultaneous activation of the sympathetic system blunts the insulin response and counteracts the restraining effect of insulin on the liver and the stimulatory effect of insulin on overall glucose uptake as well.