RESUMO
Platelet cyclooxygenase appears to be more sensitive to aspirin than the arterial endothelial cell cyclooxygenase. To investigate the dose-related effects of aspirin on platelet-vessel wall interaction in acute vascular injury, male New Zealand White rabbits were treated with either (a) aspirin (150 mg/kg body wt; n = 6), (b) aspirin (30 mg/kg; n = 6), or (c) vehicle (n = 10). After treatment, autologous 111In-platelets were injected and deendothelialization of a 10-cm long segment of abdominal aorta was induced by a balloon catheter. Rabbits were killed 3 h after injury and radioactive counts and percentages of injected radioactivity per gram dry weight of tissue or blood were determined. The 30 mg aspirin group had a significantly lower radioactive count (62.13 +/- SD 6.07 x 10(3) cpm) and percentage of injected radioactivity (0.024 +/- 0.003%) per gram dry weight of damaged aortic tissue than the control (1,167.82 +/- 212.31 x 10(3) cpm/g tissue and 0.435 +/- 0.079%, respectively). By contrast, the 150-mg aspirin group had an elevation of radioactive counts (4,343.12 +/- 556.98 cpm) and percentage (1.632 +/- 0.246%) per gram dry weight of damaged tissue. Infusion of exogenous PGI2 was associated with reduction of lesion radioactivity. These findings were supported by ultrastructural findings. Examined under transmission electron microscopy, the injured aortic wall of 30-mg group was covered throughout the segment by a single layer of platelets without detectable platelet aggregates, while that of the 150-mg group was diffusely packed with multiple layers of platelets. The findings demonstrate that aspirin (30 mg/kg) prevents platelet aggregate formation at the injured arterial wall, whereas 150 mg/kg promotes platelet thrombus formation.
Assuntos
Aspirina/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/enzimologia , Inibidores de Ciclo-Oxigenase , Endotélio/enzimologia , Agregação Plaquetária/efeitos dos fármacos , Animais , Aorta/enzimologia , Aorta/lesões , Relação Dose-Resposta a Droga , Masculino , CoelhosRESUMO
The kinetics of epsilon-aminocaproic acid (EACA) distribution and elimination were studied in six normal subjects after a single 10-gm iv dose. Steady-state distribution volume averaged 30.01 or 0.39 l/kg. Mean elimination t 1/2 was 294 min and the elimination clearance was 0.19 l/min. Renal excretion of unchanged EACA accounted for 68% of its elimination and renal EACA clearance averaged 115% of creatinine clearance. EACA antifibrinolytic effect kinetics were also characterized in five of the subjects by the monitoring of clot lysis times in whole blood and platelet-rich plasma. Peak antifibrinolytic effects were observed 15 to 60 min after peak EACA plasma concentrations were attained. A model of maximal fibrinolysis inhibition (Emax) was used to estimate a half-maximal inhibition (IC50) of 63 +/- 19.7 microgram/ml. This agrees with the value of 0.55 mM or 72 microgram/ml that has been reported for the dissociation constant of the EACA-plasminogen complex and is consistent with the proposed biochemical mechanism of EACA action.
Assuntos
Aminocaproatos/metabolismo , Ácido Aminocaproico/metabolismo , Fibrinólise/efeitos dos fármacos , Adulto , Ácido Aminocaproico/farmacologia , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Infusões Parenterais , Cinética , MasculinoRESUMO
To examine the benefit of determination of the bleeding time as a preoperative screening test, the medical records of all patients who had a prolonged bleeding time during a six-month period were reviewed. At Northwestern Memorial Hospital, where the bleeding time test is part of the presurgical panel, 1,941 bleeding time determinations were performed during six months. Prolonged bleeding times were recorded in 110 preoperative patients, of whom 83 (75 percent) had bleeding risk factors, including drug ingestion, thrombocytopenia, and azotemia. In these patients, the bleeding time ranged unpredictably from 10 to more than 20 minutes. However, of the 27 patients without apparent risk factors, only two had bleeding times of more than 20 minutes. This small number probably does not justify the routine use of the test in all preoperative patients. Rather, the test should be used selectively for those subjects who, on the basis of history or laboratory evidence, are suspected of being at risk of hemorrhage. Moreover, even in these patients, prolongation of the bleeding time may not always be associated with excessive surgical blood loss.
Assuntos
Tempo de Sangramento , Hemorragia/etiologia , Testes de Função Plaquetária , Procedimentos Cirúrgicos Operatórios , Aspirina/efeitos adversos , Transtornos da Coagulação Sanguínea/induzido quimicamente , Transtornos da Coagulação Sanguínea/complicações , Humanos , Complicações Intraoperatórias , Cuidados Pré-Operatórios , Estudos Retrospectivos , RiscoRESUMO
The present study determined whether inhibitors of angiotensin converting enzyme (ACE) can ameliorate radiation-induced pulmonary endothelial dysfunction and pulmonary fibrosis in rats sacrificed 2 months after a range of single doses of 60Co gamma rays to the right hemithorax. Four indices of pulmonary endothelial function were monitored: right lung ACE and plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Hydroxyproline (HP) content served as an index of pulmonary fibrosis. Rats consumed either control powdered chow or feed containing one of five modifying agents continuously after irradiation. The modifiers included three ACE inhibitors: Captopril, CL242817, and CGS13945, respectively, a thiol, a thioacetate, and a nonthiol compound. All of the ACE inhibitors are analogues of proline. Two additional modifiers were tested: penicillamine, a thiol with no ACE inhibitory activity; and pentoxifylline, a vasodilator that is neither a thiol nor an ACE inhibitor. Radiation produced a dose-dependent decrease in lung ACE and PLA activity, and an increase in PGI2 and TXA2 production and in HP content. All ACE inhibitors attenuated the radiation-induced suppression in lung ACE and PLA activity. All thiol or thioacetate compounds ameliorated the radiation-induced increase in PGI2, TXA2, and HP. The two agents that were both thiols and ACE inhibitors (Captopril and CL242817) spared all of the radiation reactions, while the compound that was neither a thiol nor an ACE inhibitor (pentoxifylline) spared none of the reactions. These data suggest a novel application for ACE inhibitors in general, and for Captopril in particular, as modifiers of radiation pneumotoxicity.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pulmão/efeitos da radiação , Fibrose Pulmonar/tratamento farmacológico , Animais , Captopril/uso terapêutico , Radioisótopos de Cobalto , Indóis/uso terapêutico , Masculino , Prolina/análogos & derivados , Prolina/uso terapêutico , Fibrose Pulmonar/etiologia , Ratos , Ratos Endogâmicos , Relação Estrutura-AtividadeRESUMO
The angiotensin converting enzyme inhibitor captopril ameliorates radiation-induced pulmonary endothelial dysfunction in rats. The present study determined whether captopril also reduces collagen (hydroxyproline) accumulation in the lungs of rats sacrificed 2 months after a range of single doses (0-30 Gy) of 60Co gamma rays to the right hemithorax. Captopril was administered in the feed at a regimen of 0, 25, or 50 mg/kg/day continuously after irradiation. Mast cell counts also were obtained from lungs of all animals exposed to 30 Gy. In rats receiving no captopril, there was a radiation dose-dependent increase in right lung hydroxyproline (HP) content and in HP concentration per g wet weight. Captopril produced a drug dose-dependent suppression in this radiation-induced HP accumulation. At a dose of 50 mg/kg/d, captopril reduced the slope of the radiation dose response curve for lung HP content by a factor of 1.7, and completely prevented the increase in HP concentration. At an isoeffect level of 550 micrograms HP per right superior lobe, this dose of captopril exhibited a DRF of 1.7 +/- 0.2. In rats exposed to 30 Gy, moreover, the number of mast cells per mm2 of alveolar cross-sectional surface area decreased from 105 +/- 8 to 100 +/- 7 and 59 +/- 5 in the groups given 0, 25 or 50 mg/kg/d of captopril, respectively, (vs none in sham-irradiated rats). These data are the first to demonstrate that the ACE inhibitor captopril might provide a novel intervention in the pathogenesis of radiation fibrosis.
Assuntos
Captopril/farmacologia , Colágeno/metabolismo , Pulmão/efeitos da radiação , Mastócitos/efeitos da radiação , Animais , Contagem de Células , Hidroxiprolina/análise , Pulmão/efeitos dos fármacos , Pulmão/ultraestrutura , Masculino , Mastócitos/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/efeitos da radiação , Ratos , Ratos EndogâmicosRESUMO
Platelet aggregation results of 117 patients were analysed. All had documented evidence of stroke, recurrent transient ischemic attacks and other neurologic symptoms, and all were hospitalized in the same Rehabilitation Center. Attention was specifically directed to the 'spontaneous' platelet aggregation (SPA) phenomenon, in terms of its characteristics and relationship to platelet count and aggregation induced by 3 physiologic agents. About 50% of the samples showed SPA but not all of them were hyperaggregable by other aggregating agents. A great deal of variation was found in the aggregation time, slope and extent of SPA. These variations do not always appear to relate to platelet count, or the responsiveness of platelets to other aggregating agents.
Assuntos
Agregação Plaquetária , Adulto , Idoso , Aspirina , Plaquetas , Contagem de Células , Transtornos Cerebrovasculares/sangue , Feminino , Humanos , Ataque Isquêmico Transitório/sangue , Masculino , Pessoa de Meia-Idade , Tromboflebite/sangueRESUMO
We have tested a platelet aggregation inhibitor in the incubation fluid of deendothelialized fragments of the rat aorta and compared it with that of "intact" fragments. Some of the properties of the aortic inhibitor, and its effects on platelet adhesion to collagen fibrils, on platelet factor-3 (PF-3) availability, and on the activated partial thromboplastin time (APTT) and thrombin time (TT) were also evaluated in comparison with similar effects exerted by PGI2. We found that the incubation fluid of deendothelialized aortic samples contained inhibitor activity comparable with that of "intact" samples. The aortic inhibitor had similar properties to PGI2. The aortic inhibitor and PGI2 slightly inhibited light transmission changes of EDTA-PRP following exposure to collagen. However, scanning electron microscopy showed no appreciable difference in platelet adhesion to collagen fibrils. PGI2 and the aortic inhibitor inhibited Kaolin-induced PF-3 availability, but did not prolong the APTT or TT.
Assuntos
Aorta Abdominal/metabolismo , Epoprostenol/biossíntese , Prostaglandinas/biossíntese , Difosfato de Adenosina/farmacologia , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/ultraestrutura , Aspirina/farmacologia , Colágeno/metabolismo , Endotélio/metabolismo , Endotélio/ultraestrutura , Feminino , Humanos , Masculino , Tempo de Tromboplastina Parcial , Adesividade Plaquetária , Agregação Plaquetária , Fator Plaquetário 3/metabolismo , Ratos , Tempo de TrombinaRESUMO
We have reported previously that the antimicrobial nitrofurantoin stimulates superoxide production and methemoglobin formation from HbO2 as an isolated hemeprotein and in hemolysates [M. Dershwitz and R. F. Novak, J. biol. Chem. 257, 75 (1982); M. Dershwitz and R. F. Novak, J. Pharmac. exp. Ther. 222, 430 (1982)]. The production of hydrogen peroxide and methemoglobin by nitrofurantoin has been determined in normal erythrocytes in vitro. Hydrogen peroxide production increased 5-fold during a 20-hr incubation in the presence of 840 microM nitrofurantoin, while methemoglobin content increased to over 20% of the total hemoglobin concentration of the cells. Consequent metabolic and morphologic alterations also occurred. Concomitant with nitrofurantoin-stimulated hydrogen peroxide production were time- and concentration-dependent decreases in cellular levels of GSH and ATP, as well as alterations in red cell morphology. Significant differences in GSH and ATP levels between control and nitrofurantoin-treated erythrocytes occurred after 12 hr and proceeded maximally from 18 to 21 hr. After a 21-hr incubation, 840 microM nitrofurantoin caused the cellular GSH and ATP levels to fall 65 and 75%, respectively, while controls exhibited only 29 and 43% decreases in ATP and GSH levels, respectively. Studies on the concentration dependence of such decreases demonstrated that the EC50 values for depletion of GSH and ATP were similar in blood obtained from an individual donor. The EC50 values varied from approximately 10 microM to 100 microM among the various donors whose blood was studied. Incubation of normal red cells with nitrofurantoin also resulted in an increased conversion of red cells to echinocytes as observed by scanning electron microscopy. These metabolic effects, coupled with increased oxidative stress via hydrogen peroxide generation, lend support to the mechanism for nitrofurantoin-induced hemolysis in erythrocytes compromised by certain enzyme deficiencies which result in low basal levels of GSH or diminished rates of GSH synthesis.
Assuntos
Eritrócitos/efeitos dos fármacos , Nitrofurantoína/farmacologia , Trifosfato de Adenosina/sangue , Relação Dose-Resposta a Droga , Eritrócitos/análise , Eritrócitos/ultraestrutura , Glutationa/sangue , Humanos , Peróxido de Hidrogênio/sangue , Técnicas In Vitro , Metemoglobina/análise , Microscopia Eletrônica de VarreduraRESUMO
Rats were killed after 6 weeks of continuous ingestion of the pneumotoxic alkaloid monocrotaline (2.2 mg/kg/day), the neutrophil elastase inhibitor SC39026 (60 mg/kg/day), or both. Pulmonary reactions were evaluated by light and electron microscopy. Lung endothelial function was monitored by angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Lung hydroxyproline content was measured as an index of interstitial fibrosis. Cardiac right ventricular hypertrophy was determined by the right ventricle to the left ventricle plus septum weight ratio (RV/LV + S). Rats receiving SC39026 alone did not differ significantly from untreated control animals with respect to any of the quantitative endpoints, although rarefaction of Type I pneumocytes was observed in the electron micrographs of these animals. Monocrotaline-treated rats, in contrast, developed a significant increase in RV/LV + S, and exhibited pulmonary edema, inflammation, fibrosis, and muscularization and occlusive mural thickening of the pulmonary small arteries and arterioles. These monocrotaline-induced structural changes were accompanied by decreased lung ACE and PLA activities, and increased PGI2 and TXA2 production, and by an increase in lung hydroxyproline content. Cotreatment with SC39026 ameliorated the monocrotaline-induced pulmonary vascular wall thickening and the cardiac right ventricular hypertrophy. These data suggest that inappropriate neutrophil elastase activity contributes to monocrotaline pulmonary vasculopathy and hypertension. On the other hand, cotreatment with SC39026 had no significant effect on the severity of the monocrotaline-induced lung inflammatory reaction, the pulmonary endothelial dysfunction, or the increase in lung hydroxyproline content.
Assuntos
Cardiomegalia/tratamento farmacológico , Clorobenzoatos/farmacologia , Pneumopatias/tratamento farmacológico , Elastase Pancreática/antagonistas & inibidores , Alcaloides de Pirrolizidina/antagonistas & inibidores , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/patologia , Epoprostenol/biossíntese , Hidroxiprolina/metabolismo , Pneumopatias/induzido quimicamente , Pneumopatias/patologia , Masculino , Monocrotalina , Tamanho do Órgão/efeitos dos fármacos , Peptidil Dipeptidase A/metabolismo , Alcaloides de Pirrolizidina/toxicidade , Ratos , Ratos Endogâmicos , Tromboxano A2/biossíntese , Ativador de Plasminogênio Tecidual/metabolismoRESUMO
We conducted studies to determine at what time point an add-on prothrombin time (PT) or activated partial thromboplastin time (APTT) test can be honored on specimens that have been received in the laboratory hours earlier without yielding results with clinically significant differences from those if the test had been performed on the original unstored plasma. PT and APTT tests were performed on blood samples from 20 healthy subjects, 30 patients receiving warfarin, and 30 patients receiving heparin anticoagulation therapy. The tests were performed on plasma prepared initially after the samples were obtained. The same tests were assayed on plasma that had been left on spun-down blood cells at room temperature for 2, 4, and 8 hours. We found that the PT of the majority of plasma samples from healthy subjects and from patients receiving oral anticoagulant therapy tended to become shorter on storage. However, the difference in PT values was small and had no clinical significance. In most cases, the APTT values for the stored plasma from healthy subjects tended to increase with time. Except in one specimen in which the 8-hour add-on APTT was 1.2 seconds longer than the APTT result for the original sample, all others had APTT results less than 1.2 seconds longer than the original values. In patients receiving heparin, the differences in APTT values between the initial and add-on tests were larger than those observed for healthy subjects. However, those differences are not beyond what we would accept for duplicate checks for heparinized samples with high APTT values. Unlike samples from healthy subjects, there was no obvious trend of time-related prolongation of the APTT in heparinized plasma. These results led us to believe that within an 8-hour period and with plasma on spun-down cells at room temperature, add-on tests for PT and APTT could be performed with results similar to what would be obtained from testing unstored samples.
Assuntos
Tempo de Tromboplastina Parcial , Plasma , Tempo de Protrombina , Anticoagulantes/uso terapêutico , Citratos , Estabilidade de Medicamentos , Heparina/uso terapêutico , Humanos , Valores de Referência , Citrato de Sódio , Fatores de Tempo , Varfarina/uso terapêuticoRESUMO
The effects of citrate concentration on adenosinediphosphate-, epinephrine-, collagen-, and ristocetin-induced human platelet aggregation were investigated. Relatively small increments in citrate concentration markedly inhibited platelet aggregation by all three physiologic agents. The inhibitory effect was greatest on epinephrine-induced aggregation, and least on collagen-induced aggregation. Ristocetin-induced aggregation was not affected by excess citrate anticoagulation. These findings indicate the importance of controlling the citrate:blood ratio in clinical platelet aggregation studies and in the assessment of antiplatelet drugs.
Assuntos
Citratos/sangue , Agregação Plaquetária , Difosfato de Adenosina/farmacologia , Colágeno/farmacologia , Epinefrina/farmacologia , Humanos , Agregação Plaquetária/efeitos dos fármacos , Ristocetina/farmacologia , Fatores de TempoRESUMO
Thromboelastography (TEG) has been used increasingly as an intraoperative hemostasis monitoring device. Low-molecular-weight heparins are given increasingly to reduce the development of antibodies against the heparin-platelet factor 4 complex, and heparinoids are given to patients who have developed the antibody. We studied the effect of unfractionated heparin, a low-molecular-weight heparin (enoxaparin sodium [Lovenox]), and a heparinoid (danaparoid sodium [Orgaran]) on blood clotting assayed with TEG (TEG clotting) in vitro and the efficacy of protamine sulfate and heparinase for reversing the effect. Heparin, enoxaparin, and danaparoid all caused a dose-dependent inhibition of TEG clotting of normal blood. Concentrations of enoxaparin and danaparoid that totally inhibited TEG clotting only minimally prolonged the activated partial thromboplastin time. While inhibition of TEG clotting by heparin and enoxaparin was reversed by protamine sulfate and heparinase, inhibition by danaparoid was reversed only by heparinase. Abnormal TEG clotting was observed in patients receiving enoxaparin whose plasma level of the drug was more than 0.1 antiXa U/mL. However, the degree of TEG abnormality did not always coincide with plasma levels of the drug.
Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Enoxaparina/farmacologia , Heparina/farmacologia , Heparinoides/farmacologia , Tromboelastografia , Anticorpos/sangue , Autoanticorpos/sangue , Sulfatos de Condroitina/farmacologia , Dermatan Sulfato/farmacologia , Combinação de Medicamentos , Heparina/imunologia , Heparina Liase/farmacologia , Heparitina Sulfato/farmacologia , Humanos , Tempo de Tromboplastina Parcial , Fator Plaquetário 4/imunologia , Protaminas/farmacologia , Tempo de ProtrombinaRESUMO
The effect of storage on the aggregability of platelets in plasma and in whole blood was studied with blood samples obtained from 11 normal subjects. Compared to aggregation of platelets in fresh samples, those stored in plasma showed an increase in aggregation, and in whole blood a decrease in aggregation. The decreased aggregation in the latter samples was prevented by including exogenous glucose in stored blood samples. Similar studies were performed on 25 patient platelet samples that had been judged as hyperaggregable by standard procedure, including the presence of "spontaneous" aggretation in 13 specimens. Only seven samples prepared from stored blood still showed hyperaggregability; spontaneous aggregation remained in only five samples.
Assuntos
Preservação de Sangue , Sangue , Plasma , Agregação Plaquetária/efeitos dos fármacos , Plaquetas , Glucose/farmacologia , Humanos , Potássio/farmacologia , Manejo de EspécimesRESUMO
The effects of the source and concentration of thrombin, and those of divalent cations, on the thrombin time (TT) of heparinized plasma were investigated. A correlation between TT and the heparin concentration was obtained only when the thrombin was of human origin and when it was reconstituted in divalent cation solutions. Relatively small variations in thrombin concentration resulted in marked differences in TT of heparinized plasma. Bovine thrombin gave a very prolonged TT of heparinized plasma compared with human thrombin, though the two thrombins gave identical TT's for non-heparinized control plasma. Divalent cation solution, in which thrombin was reconstituted, had a profound influence on TT of heparin plasma. When thrombin was reconstituted in 0.1 M MnCl2 solution, the TT of a plasma containing 0.5 unit heparin per ml. was the same as that of a plasma containing no heparin. The reliability of the thrombin time test as a means of monitoring heparin anticoagulation must be established by individual laboratories via extensive testing of clinical samples.
Assuntos
Testes de Coagulação Sanguínea , Heparina , Trombina , Animais , Coagulação Sanguínea/efeitos dos fármacos , Cloreto de Cálcio , Cátions Bivalentes , Bovinos , Humanos , Plasma , Tromboplastina , Fatores de TempoRESUMO
The authors performed whole-blood clotting time (WBCT), activated partial thromboplastin time (APTT), and whole-blood recalcification time (WBRCT) tests on normal blood or citrated plasma, each milliliter containing 0-0.5 unit heparin, and on samples from patients, of whom many were receiving heparin anticoagulation therapy. Six partial thromboplastin reagents were used. Linearity between clotting time and heparin concentration was observed with WBCT and APTT, determined with Hyland partial thromboplastin (kaolin-activated) and Dade ("Improved" Activated Cephaloplastin and Actin) reagents. With a General Diagnostics preparation (Platelin -plus, celite as the activator) and another Hyland partial thromboplastin reagent (silica-activated), the sensitivity to heparin decreased to beyond 0.3 unit/ml plasma. No correlation was observed with the old Dade Activated Cephaloplastin reagent, WBRCT was completely insensitive to heparin in concentrations as high as 0.24 unit/ml blood. With patient samples, correlations were observed between WBCT and Hyland (kaolin) APTT, and between Hyland and Dade Actin APTT. However, WBCT and WBRCT, and APTT and WBRCT, correlated poorly.
Assuntos
Heparina/uso terapêutico , Tromboplastina , Testes de Coagulação Sanguínea , Estudos de Avaliação como Assunto , Humanos , Monitorização Fisiológica , Estatística como AssuntoRESUMO
The purpose of this study was to evaluate the angiotensin converting enzyme (ACE) inhibitor CL242817 as a modifier of radiation-induced pulmonary endothelial dysfunction and pulmonary fibrosis in rats sacrificed 2 months after a single dose of 60Co gamma rays (0-30 Gy) to the right hemithorax. CL242817 was administered in the feed continuously after irradiation at a regimen of 60 mg/kg/day. Pulmonary endothelial function was monitored by lung ACE activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Pulmonary fibrosis was evaluated by lung hydroxyproline (HP) content. Lung ACE and PLA activities decreased with increasing radiation dose, and cotreatment with CL242817 significantly ameliorated both responses. CL242817 dose-reduction factors (DRF) were 1.3-1.5 for ACE and PLA activity. Lung PGI2 and TXA2 production increased with increasing radiation dose, and CL242817 almost completely prevented both radiation responses. The slope of the radiation dose-response curves in the CL242817-treated rats was essentially zero, precluding calculation of DRF values for PGI2 and TXA2 production. Lung HP content also increased with increasing radiation dose, and CL242817 significantly attenuated this response (DRF = 1.5). These data suggest that the ability of ACE inhibitors to ameliorate radiation-induced pulmonary endothelial dysfunction is not unique to captopril [Ward et al., Int. J. Radiat. Oncol. Biol. Phys. 15, 135-140 (1988)], rather it is a therapeutic action shared by other members of this class of compounds. These data also provide the first evidence that ACE inhibitors exhibit antifibrotic activity in irradiated rat lung.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pulmão/efeitos da radiação , Prolina/análogos & derivados , Fibrose Pulmonar/etiologia , Lesões Experimentais por Radiação/prevenção & controle , Animais , Radioisótopos de Cobalto , Endotélio/efeitos dos fármacos , Endotélio/efeitos da radiação , Raios gama , Pulmão/efeitos dos fármacos , Masculino , Prolina/uso terapêutico , Fibrose Pulmonar/prevenção & controle , Ratos , Ratos EndogâmicosRESUMO
The mechanism of reduced fibrinolysis in lungs of rats whose right hemithorax had been exposed to a single dose of 25 Gy of 60Co gamma rays was determined, and fibrinolytic changes were correlated with perfusion and morphologic alterations. Reduced fibrinolytic activity in the irradiated lung was evident after 1 month, and decreased further at 2 months. From 2 to 6 months postirradiation, right lung fibrinolytic activity reached a plateau at about half of the activity in the shielded left lung or in sham-irradiated control lungs. The reduced fibrinolytic activity was largely due to decreased plasminogen activator activity, rather than to increased inhibitor activity. Changes in fibrinolytic activity of the irradiated lung closely paralleled changes in arterial perfusion. Mild ultrastructural changes in the irradiated lung (endothelial blebbing and interstitial edema) preceded fibrinolytic and perfusion defects. In contrast, marked changes such as fibrin deposition in the alveolar space and interstitial hypercellularity and fibrosis occurred after pulmonary fibrinolytic activity and perfusion were reduced.
Assuntos
Antifibrinolíticos/efeitos da radiação , Pulmão/efeitos da radiação , Ativadores de Plasminogênio/efeitos da radiação , Lesões Experimentais por Radiação/fisiopatologia , Animais , Fibrinólise/efeitos da radiação , Raios gama , Pulmão/fisiopatologia , Pulmão/ultraestrutura , Masculino , Artéria Pulmonar/efeitos da radiação , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
Pulmonary prostacyclin (PGI2) production, arterial perfusion, and ultrastructure were correlated in rats sacrificed from 1 day to 6 months after a single exposure of 25 Gy of gamma rays to the right hemithorax. PGI2 production by the irradiated lung decreased to approximately half the normal value 1 day after irradiation (P less than 0.05), then increased steadily throughout the study. By 6 months postirradiation, the right lung produced two to three times as much PGI2 as did either shielded left lung or sham-irradiated lungs (P less than 0.05). Perfusion scans revealed hyperemia of the right lung from 1 to 14 days after irradiation. From its peak at 14 days postirradiation, however, perfusion of the irradiated lung decreased steadily, then reached a plateau from 3 to 6 months at less than half that in the shielded left lung. Electron micrographs of the right lung revealed perivascular edema from 1 to 30 days after irradiation. The right lung then exhibited changes typical of radiation pneumonitis followed by progressive interstitial fibrosis. Platelet aggregates were not observed at any time. Thus, decreased PGI2 production is an immediate but transient response of the lung to radiation injury. Then from 2 to 6 months after irradiation, the fibrotic, hypoperfused lung produces increasing amounts of the potent vasodilator and antithrombotic agent, PGI2. Pulmonary PGI2 production and arterial perfusion are inversely correlated for at least 6 months after hemithoracic irradiation.
Assuntos
Epoprostenol/efeitos da radiação , Pulmão/efeitos da radiação , Artéria Pulmonar/efeitos da radiação , Lesões Experimentais por Radiação/metabolismo , Animais , Epoprostenol/biossíntese , Raios gama , Pulmão/metabolismo , Pulmão/ultraestrutura , Masculino , Microscopia Eletrônica , Lesões Experimentais por Radiação/patologia , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
The purpose of this study was to determine whether radiation-induced pulmonary endothelial dysfunction exhibits split-dose sparing. Rats were sacrificed 2 months after a range of 60Co gamma-ray doses (0-40 Gy) delivered to the right hemithorax in either a single fraction or in two equal fractions separated by 24 h. Pulmonary angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production served as indices of lung endothelial function. There were dose-dependent decreases in ACE and PLA activity and increases in PGI2 and TXA2 production after both single and split-dose exposures. The D2-D1 values determined from the two-fraction minus single-fraction isoeffective doses were 3.9 Gy for ACE activity, 7.2 Gy for PLA activity, 4.8 Gy for PGI2 production, and 4.7 Gy for TXA2 production. Thus these data demonstrate that over the present range of radiation doses approximately 4-7 Gy is repairable as subeffective endothelial damage during the 24-h interval between fractions. These values agree with previously published estimates of split-dose sparing in mouse lung based on lethality and breathing rate assays.
Assuntos
Pulmão/efeitos da radiação , Animais , Radioisótopos de Cobalto , Endotélio/enzimologia , Endotélio/metabolismo , Endotélio/efeitos da radiação , Epoprostenol/metabolismo , Raios gama , Pulmão/enzimologia , Pulmão/metabolismo , Masculino , Peptidil Dipeptidase A/metabolismo , Ativadores de Plasminogênio/metabolismo , Doses de Radiação , Ratos , Ratos Endogâmicos , Tromboxano A2/metabolismoRESUMO
Rats were sacrificed 2 months after a single dose of 10-30 Gy of 60Co gamma rays delivered to either a right unilateral or a bilateral thoracic port. Four indices of lung endothelial function were measured: the activities of angiotensin-converting enzyme (ACE) and plasminogen activator (PLA) and the production of prostacyclin (PGI2) and thromboxane (TXA2). The number of macrophages recovered by bronchoalveolar lavage (BAL) and the degree of right ventricular hypertrophy (an index of pulmonary hypertension) also were determined. Right lung ACE and PLA activity decreased linearly, and PGI2 and TXA2 production increased linearly with increasing radiation dose. The response curves for right unilateral and bilateral thoracic irradiation were not significantly different. In contrast, bilateral irradiation was more toxic than unilateral, since rats exposed to the former exhibited decreased body weight, an increased incidence of pleural effusions, an increase in the number of macrophages recovered by BAL, and right ventricular hypertrophy. These data demonstrate that pulmonary endothelial dysfunction induced by hemithorax irradiation represents a direct response of the endothelium to radiation injury and is not secondary to other phenomena such as shunting of function to the shielded lung.