RESUMEN
Bisphosphonates are antiatherosclerotic, suppress monocyte-macrophages, and modulate proinflammatory mediators. Prostaglandin (PG) E(2), thromboxane (TX) A(2), and cyclooxygenase-2 (COX-2) enzyme are involved in inflammation and atherosclerosis. We studied the effects of four bisphosphonates (etidronate, clodronate, tiludronate, and alendronate) on PGE(2) and TXB(2) production in human whole blood and monocytes. PGE(2) and TXB(2) were determined by direct radioimmunoassay and COX-2 expression by Western blot. In whole blood, the bisphosphonates did not modulate the increase in PGE(2) and TXB(2) concentrations induced by calcium ionophore A23187 or lipopolysaccharide (LPS). None of the bisphosphonates did change PGE(2) and TXB(2) concentration after spontaneous clotting. A23187- and spontaneous clotting-induced PGE(2) and TXB(2) productions were inhibited over 90% by acetylsalicylic acid (ASA), and LPS-induced PGE(2) and TXB(2) formations were inhibited over 90% by nimesulide. None of the bisphosphonates altered these inhibitions. In monocytes, etidronate and clodronate augmented A23187-stimulated PGE(2) production 2.5- to 3.2-fold (p < 0.05). LPS- or A2318-induced elevations in TXB(2) were not influenced by the bisphosphonates. The tested bisphosphonates neither induced COX-2 expression nor modulated LPS-induced COX-2 expression in monocytes. The results suggest that the antiatherosclerotic effects of bisphosphonates are not mediated via PGE(2), TXA(2), or COX-2, and the bisphosphonates do not interfere with the suppression of platelet COX-1 activity by ASA and COX-2 activity by nimesulide.
Asunto(s)
Conservadores de la Densidad Ósea/farmacología , Calcimicina/farmacología , Dinoprostona/biosíntesis , Difosfonatos/farmacología , Lipopolisacáridos/farmacología , Monocitos/metabolismo , Tromboxano B2/biosíntesis , Aspirina/farmacología , Western Blotting , Ácido Clodrónico/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Dinoprostona/sangre , Ácido Etidrónico/farmacología , Femenino , Humanos , Técnicas In Vitro , Lipoproteínas LDL/metabolismo , Masculino , Monocitos/efectos de los fármacos , Radioinmunoensayo , Sulfonamidas/farmacología , Tromboxano B2/sangreRESUMEN
8-Isoprostaglandin F2alpha is one of a series of isoprostanes formed by free radical catalysed peroxidation of arachidonic acid. Urinary 8-isoprostaglandin F2alpha is a new marker which reflects oxidative stress in vivo and can be utilized as a diagnostic tool to assess the extent of oxidative stress in various disease states associated with lipid peroxidation. Increased levels of 8-isoprostaglandin F2alpha in cardiac ischemia/reperfusion provide evidence for oxidative stress during coronary perfusion. In animal studies, the restoration of blood flow after lower limb ischemia is followed by reperfusion syndrome. In this study we investigated whether lower limb ischemia/reperfusion is associated with oxidative stress, as reflected by urinary levels of 8-isoprostaglandin F2alpha. Ten patients (mean age 72 years, range 61-82 years) suffering from chronic lower limb ischemia and 10 healthy volunteers (mean age 69 years, range 60-79 years) participated in the study. In all patients, diagnostic angiography had revealed stenosis or occlusion either in the aortoiliac or femoropopliteal region. Surgical revascularization consisted of femoropopliteal reconstruction, femorofemoral reconstruction, aortobifemorial reconstruction, or femoral endartectomy. Urine samples from patients were collected a day before surgery and in the second postoperative day. Urinary 8-isoprostaglandin F2alpha was extracted on a C2 silica cartridge and determinated by radioimmunoassay. After revascularization, 8-isoprostaglandin F2alpha excretion (pg/micromol creatinine, mean +/- SD) was decreased by 2.5-fold (preoperative 48.9 +/- 8.9, postoperative 19.1 +/- 9.5, P < 0.001). The postoperative values were similar to the concentrations measured in healthy volunteers (18.0 +/- 11.0). All revascularizations were successful, and the increase in ankle-brachial index (preoperative 0-0.6, postoperative 0.4-0.8) revealed improved blood flow in the ischemic lower limb. We suggest that, as assessed by the quantitation of urinary 8-isoprostaglandin F2alpha, chronic lower limb ischemia is associated with increased oxidative stress, which is decreased by revascularization.
Asunto(s)
Dinoprost/análogos & derivados , Dinoprost/metabolismo , Dinoprost/orina , Isquemia/fisiopatología , Extremidad Inferior/irrigación sanguínea , Revascularización Miocárdica/efectos adversos , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Femenino , Depuradores de Radicales Libres/análisis , Humanos , Isquemia/cirugía , Extremidad Inferior/cirugía , Masculino , Persona de Mediana Edad , Estrés Oxidativo/fisiología , Radioinmunoensayo/métodosRESUMEN
This study investigated the effects of smoking cessation with and without nicotine substitution on the excretion of major urinary metabolites of thromboxane A2 and prostacyclin, 11-dehydrothromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1alpha, respectively, as well as on the excretion of leukotriene E4 in man. Urine samples were obtained from 20 healthy non-smoking controls and from 60 healthy smoking volunteers before, and 3, 7 and 14 days after smoking cessation. Fifteen smokers quit smoking without nicotine substitution, 15 used nicotine chewing gum and 30 used nicotine patches as a substitution therapy. Urinary thiocyanate as well as cotinine and trans-3'-hydroxycotinine excretions were used as compliance and nicotine substitution indicators. 11-Dehydrothromboxane B2, 2,3-dinor-6-ketoprostaglandin F1alpha and leukotriene E4 excretion was about two, three and five times higher in smokers than in controls, respectively. Three days after smoking cessation without nicotine substitution, 11-dehydrothromboxane B2 and 2,3-dinor-6-ketoprostaglandin F1alpha levels were lowered to 75% (P<0.01) and 80% (P<0.05) of the initial values, and after 14 days to 50% (P<0.01) and 60% (P<0.05), respectively. In 3 days leukotriene E4 excretion was dropped to 70% of the initial value (P<0.05), but no further decrease was observed during the study. In individuals using nicotine chewing gum or nicotine patches no significant changes were observed in the analytes during the 2-week follow-up. The increased systemic eicosanoid synthesis observed in smokers may be involved in the harmful cardiovascular effects of smoking. The fact that eicosanoid production remains at pre-cessation level in volunteers who quit smoking but use nicotine substitution may be involved in the risk of cardiovascular complications reported during nicotine replacement therapy.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Eicosanoides/biosíntesis , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Ácidos Polimetacrílicos/farmacología , Polivinilos/farmacología , Cese del Hábito de Fumar , Administración Cutánea , Adulto , Análisis de Varianza , Eicosanoides/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nicotina/análogos & derivados , Dispositivos para Dejar de Fumar TabacoRESUMEN
Smoking is an important risk factor for respiratory and cardiovascular diseases. The role of numerous chemical, partly uncharacterised compounds existing in tobacco smoke is not known. (-)-Nicotine, its stereoisomer (+)-nicotine and main metabolite cotinine are biologically active compounds influencing e.g. catecholamine and eicosanoid systems. The precise mechanisms are not well known. The purpose of the present study consisting of a PhD thesis (11) and five original papers was to investigate the in vitro effects of nicotine isomers and cotinine on eicosanoid production in polymorphonuclear leukocytes, platelets and whole blood in vitro, and to clarify the effects of smoking without and with nicotine substitution on eicosanoid production in vivo and ex vivo. It was found that all the tested compounds modulated blood cell eicosanoid synthesis. Nicotine isomers and cotinine increased PGE2 but decreased TXB2, LTB4 and LTE4 synthesis in vitro. Eicosanoid synthesis in vivo and ex vivo was higher in smokers (n = 60) than in non-smoking controls (n = 20). This may contribute to the harmful cardiovascular effects of smoking. Cessation of smoking without, but not with, nicotine substitution reduced eicosanoid synthesis measured ex vivo as whole blood production or in vivo as urinary excretion of eicosanoid metabolites after 3, 7 and 14 days. Thus long-term nicotine substitution diminishes the beneficial effects of smoking cessation.
Asunto(s)
Células Sanguíneas/efectos de los fármacos , Cotinina/farmacología , Eicosanoides/metabolismo , Nicotina/farmacología , Células Sanguíneas/metabolismo , Eicosanoides/biosíntesis , Eicosanoides/sangre , Eicosanoides/orina , Femenino , Humanos , Masculino , Nicotina/administración & dosificación , Nicotina/química , Fumar , Cese del Hábito de Fumar/métodosRESUMEN
The in vitro effects of nicotinic acid (10-1000 microM), pyridoxine (0.1-500 microM) and pyridoxal-5'-phosphate (0.1-500 microM) and the ex vivo effects of nicotinic acid (2500 mg orally during 12 h) and pyridoxine (600 mg orally daily for seven days) on arachidonic acid metabolism were investigated in calcium ionophore A23187 (calcimycin)-stimulated human whole blood. In vitro nicotinic acid stimulated prostaglandin E2, thromboxane B2 and leukotriene E4 synthesis. Pyridoxine at all concentrations and pyridoxal-5'-phosphate at the highest concentration stimulated prostaglandin E2 and thromboxane B2 production, but had no effect on leukotriene E4 synthesis. Nicotinic acid treatment increased ex vivo prostaglandin E2, thromboxane B2 and leukotriene E4 synthesis to 185%, 165% and 175% of the initial values, respectively. In the pyridoxine-treated subjects, ex vivo prostaglandin E2, thromboxane B2 and leukotriene E4 synthesis was decreased after seven days to 75%, 65% and 45% of the initial values, respectively. In the present study the effects of nicotinic acid on the 5-lipoxygenase pathway in arachidonic acid metabolism were studied for the first time and the drug was found to stimulate this pathway in vitro and ex vivo. In vitro pyridoxine and pyridoxal-5'-phosphate had no effect on the 5-lipoxygenase pathway. The inhibition of leukotriene synthesis by pyridoxine ex vivo might be of therapeutic importance.
Asunto(s)
Araquidonato 5-Lipooxigenasa/metabolismo , Ácido Araquidónico/metabolismo , Niacina/farmacología , Fosfato de Piridoxal/farmacología , Piridoxina/farmacología , Adulto , Sangre/efectos de los fármacos , Sangre/metabolismo , Calcimicina/farmacología , Dinoprostona/biosíntesis , Humanos , Técnicas In Vitro , Ionóforos/farmacología , Leucotrieno E4/biosíntesis , Masculino , Niacina/sangre , Fosfato de Piridoxal/sangre , Piridoxina/sangre , Tromboxano B2/biosíntesisRESUMEN
Female sexual steroids are known to modify the expression of various K+ channels and thus they can alter cardiac repolarization. In the present work, using conventional microelectrode techniques, action potential characteristics were studied in atrial myocardium isolated from virgin, late pregnant, early (1-3 days) post-partum and late (2-3 weeks) post-partum rabbits. No changes in action potential configuration were observed during pregnancy. However, the duration, overshoot and amplitude of action potentials were significantly increased in the early (1-3 days) post-partum period. Resting potential and maximum rate of depolarization remained unchanged. The observed changes were transient, normal action potential characteristics were obtained at weeks 2-3 post-partum. 4-aminopyridine (1 mmol L(-1)). caused a marked lengthening of action potential duration in all preparations obtained from non-pregnant and pregnant rabbits, whereas this 4-aminopyridine-induced prolongation was moderate in those preparations excised from the hearts of early post-partum animals. Action potential configuration was not affected by pinacidil (10 micromol L(-1)) or glibenclamide (5 micromol L(-1)) in non-pregnant or pregnant animals. In preparations obtained from early post-partum rabbits, pinacidil significantly shortened action potential duration, which was reverted by glibenclamide. The lengthening of action potential duration together with the decreased sensitivity to 4-aminopyridine observed in early post-partum animals may probably be caused by reduction of the transient outward K+ current at this stage. The results also suggest that electrophysiological alterations in the early post-partum period may probably be more pronounced than those associated with pregnancy itself.
Asunto(s)
Sistema de Conducción Cardíaco/fisiología , Miocardio/citología , Periodo Posparto/fisiología , 4-Aminopiridina/farmacología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Función Atrial , Electrofisiología , Estrógenos/fisiología , Femenino , Gliburida/farmacología , Atrios Cardíacos/citología , Hipoglucemiantes/farmacología , Fibras Musculares Esqueléticas/química , Fibras Musculares Esqueléticas/fisiología , Miocardio/química , Pinacidilo/farmacología , Canales de Potasio/fisiología , Embarazo , Conejos , Vasodilatadores/farmacologíaRESUMEN
The effects of substituted catechols (3-methylcatechol, 4-methylcatechol, 4-nitrocatechol, and guaiacol) and trihydroxybenzenes (pyrogallol, propyl gallate, 1,2,4-trihydroxybenzene, and 1,3,5-trihydroxybenzene) on the synthesis of prostaglandin (PG)E2 and leukotriene (LT)B4 were tested in human A23187-stimulated polymorphonuclear leukocytes. The effects were related to their peroxyl-radical-scavenging (antioxidant), superoxide-scavenging (antioxidant), and superoxide-generating (prooxidant) properties. In general, compounds with hydroxyl groups in the ortho position increased PGE2/LTB4 ratio, and compounds with hydroxyl groups in the meta position decreased PGE2/LTB4 ratio. Catechols, which have hydroxyl groups in the ortho position, were the most potent peroxyl radical and superoxide anion scavengers. Trihydroxybenzenes (pyrogallol, 1,2,4-trihydroxybenzene, and 1,3,5-trihydroxybenzene) generated superoxide, whereas dihydroxybenzenes did not. Thus, the positions and number of hydroxyl groups seem to be the most important properties determining the action of phenolic compounds on PGE2/LTB4 ratio and their antioxidant/prooxidant activities.
Asunto(s)
Antioxidantes/química , Antioxidantes/farmacología , Ácido Araquidónico/metabolismo , Oxidantes/química , Oxidantes/farmacología , Fenoles/química , Fenoles/farmacología , Calcimicina/farmacología , Catecoles/química , Catecoles/farmacología , Dinoprostona/metabolismo , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Humanos , Técnicas In Vitro , Ionóforos/farmacología , Leucotrieno B4/metabolismo , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Peróxidos/metabolismo , Relación Estructura-Actividad , Superóxidos/metabolismoRESUMEN
Amrinone-a phosphodiesterase III inhibitor-is used in the treatment of acute heart failure. In addition to its hemodynamic effects, amrinone has been shown to inhibit thromboxane synthesis in vitro. We investigated the effects of amrinone on thromboxane, prostaglandin, and leukotriene synthesis in humans. Eight healthy male volunteers took part in this single-blind study in which either amrinone (a 1.5-mg/kg bolus in 30 min and after that 10 microg/kg/min for 1 h 30 min) or placebo (0.9% NaCl) were infused. Amrinone infusion increased systolic blood pressure but had no significant effect on diastolic blood pressure or heart rate. Amrinone did not modulate thromboxane B2 synthesis stimulated by either spontaneous clotting or calcium-ionophore A23187 in whole blood. Amrinone had no effects on prostaglandin E2 or leukotriene E4 production in A23187-stimulated whole blood, nor did it affect urinary excretion of 11-dehydrothromboxane B2 or 2,3-dinor-6-keto-prostaglandin F1alpha, the index metabolites of thromboxane A2 and prostacyclin productions, respectively. We conclude that amrinone has no effects on eicosanoid production in humans at the dose level used in this study, and that the hemodynamic effects noticed are not mediated via cyclooxygenase or lipoxygenase products of arachidonic acid metabolism.
Asunto(s)
Amrinona/farmacología , Ácidos Araquidónicos/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Adulto , Humanos , Leucotrienos/metabolismo , Masculino , Prostaglandinas/metabolismo , Prostaglandinas/orina , Tromboxanos/metabolismo , Tromboxanos/orinaRESUMEN
OBJECTIVE: Regular exercise is recommended for the non-pharmacological treatment of hypertension, but the mechanisms underlying the lowering of blood pressure remain controversial. Therefore, we studied the effects of 22-week-long training on blood pressure, arterial reactivity, and metabolic abnormalities in a model of genetic obesity and moderate hypertension. METHODS: Obese and lean Zucker rats were subjected to treadmill exercise from 8 to 30 weeks of age. Blood pressures were measured by the tail-cuff method, and urine was collected in metabolic cages. At the end of the study, the samples for biochemical determinations were taken, and reactivity of isolated mesenteric and carotid arterial rings was examined in standard organ chambers. RESULTS: The exercise prevented the elevation of blood pressure which was observed in non-exercised obese Zucker rats, and also reduced blood pressure in the lean rats. The relaxations of norepinephrine-preconstricted mesenteric and carotid arterial rings to acetylcholine and nitroprusside were clearly improved by exercise in the obese rats. In the lean rats exercise enhanced vasorelaxation to nitroprusside in the mesenteric and carotid rings, and to acetylcholine in the carotid preparations. The exercise-induced improvement of endothelium-mediated dilatation to acetylcholine was abolished by nitric oxide synthesis inhibition with NG nitro-L-arginine methyl ester, but not by cyclooxygenase inhibition with diclofenac or functional inhibition of endothelium-dependent hyperpolarization by precontractions with KCl. The urinary excretion of the systemic prostacyclin metabolite (2,3-dinor-6-ketoprostaglandin F1 alpha) was increased two-fold by exercise in the obese and lean rats, whereas that of the thromboxane A2 metabolite (11-dehydrothromboxane B2) remained unaffected. Treadmill training reduced blood glucose, cholesterol, and triglycerides, but did not affect the high levels of insulin in obese Zucker rats. CONCLUSIONS: These results suggest that the antihypertensive effect of long-term exercise in experimental obesity related hypertension is associated with improved vasodilatation. This is expressed as enhanced relaxation via endogenous and exogenous nitric oxide, and increased endothelial prostacyclin production. The improved control of arterial tone after training could be attributed to the alleviation of hyperlipidemia and insulin resistance, whereas hyperinsulinaemia per se remained unaffected.
Asunto(s)
Hipertensión/etiología , Obesidad/complicaciones , Esfuerzo Físico/fisiología , Vasodilatación/fisiología , 6-Cetoprostaglandina F1 alfa/análogos & derivados , 6-Cetoprostaglandina F1 alfa/orina , Acetilcolina/farmacología , Análisis de Varianza , Animales , Glucemia/metabolismo , Arterias Carótidas/efectos de los fármacos , Colesterol/sangre , Inhibidores de la Ciclooxigenasa/farmacología , Diclofenaco/farmacología , Endotelio Vascular/efectos de los fármacos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Técnicas In Vitro , Insulina/sangre , Masculino , Arterias Mesentéricas/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Nitroprusiato/farmacología , Obesidad/metabolismo , Obesidad/fisiopatología , Ratas , Ratas Zucker , Tromboxano B2/análogos & derivados , Tromboxano B2/orina , Triglicéridos/sangre , Vasodilatadores/farmacologíaRESUMEN
Bacterial endotoxin (LPS) and fibrinogen degradation product D (FDP-D) are both potent stimulators of interleukin-6 (IL-6) production in liver, however, there are differences in their metabolic effects. The aim of the present study was to compare the role of prostaglandins in the enhancement of IL-6 production by LPS or FDP-D in perfused mouse livers. Indomethacin inhibited the effect of LPS significantly but was ineffective in the case of FDP-D. Accordingly, production of prostaglandins D2 and E2 was not elevated following the addition of FDP-D, while their formation was increased several fold by LPS. At the same time interleukin-1 (IL-1) production in perfused liver rose markedly upon the addition of FDP-D. It is suggested that prostaglandins are not involved in the effects of FDP-D on the liver. The stimulatory effect of FDP-P on IL-6 production might be the consequence of elevated IL-1 levels.
Asunto(s)
Productos de Degradación de Fibrina-Fibrinógeno/farmacología , Interleucina-6/biosíntesis , Hígado/efectos de los fármacos , Hígado/metabolismo , Prostaglandinas/farmacología , Animales , Dinoprostona/biosíntesis , Técnicas In Vitro , Indometacina/farmacología , Interleucina-1/biosíntesis , Masculino , Ratones , Perfusión , Prostaglandina D2/biosíntesisRESUMEN
The effects of (-)-nicotine (0.0005-500 microM), (+)-nicotine (0.0005-50 microM) and (-)-cotinine (0.0005-500 microM) on arachidonic acid metabolism were investigated in Ca2+ ionophore A23187 (calcimycin)-stimulated human whole blood in vitro. (-)-Nicotine and (-)-cotinine stimulated prostaglandin E2 but inhibited thromboxane B2 synthesis, as has been observed previously in A23187-stimulated polymorphonuclear leukocytes and platelet-rich plasma [Saareks, V., Riutta, A., Mucha, I., Alanko, J., Vapaatalo, H., 1993. Nicotine and cotinine modulate eicosanoid production in human leukocytes and platelet rich plasma. Eur. J. Pharmacol., 248, 345-349.]. (+)-Nicotine also stimulated prostaglandin E2 but inhibited thromboxane B2 synthesis. High concentrations of (-)-nicotine and (-)-cotinine and even nanomolar concentrations of (+)-nicotine inhibited leukotriene E4 synthesis. These results indicate that (-)-nicotine and (-)-cotinine stimulate cyclooxygenase but inhibit thromboxane synthase and 5-lipoxygenase in whole blood in vitro. (+)-Nicotine is capable of affecting in the same direction as well.
Asunto(s)
Cotinina/farmacología , Dinoprostona/biosíntesis , Leucotrieno E4/biosíntesis , Nicotina/farmacología , Tromboxano B2/biosíntesis , Adulto , Araquidonato 5-Lipooxigenasa/sangre , Ácido Araquidónico/metabolismo , Calcimicina/farmacología , Dinoprostona/sangre , Humanos , Técnicas In Vitro , Ionóforos/farmacología , Leucotrieno E4/sangre , Persona de Mediana Edad , Nicotina/química , Prostaglandina-Endoperóxido Sintasas/sangre , Estereoisomerismo , Tromboxano B2/sangreRESUMEN
Estrogens have a beneficial effect on atherosclerosis and osteoporosis after menopause, but their exact mechanism of action is still unknown. The aim of the present study was to investigate the effects of estradiol and its metabolites catechol estrogens on arachidonic acid metabolism in vitro. Estradiol had no effect on arachidonic acid metabolism up to 33 microM in A23187-stimulated human whole blood. All catechol estrogens (2-hydroxyestradiol, 2-hydroxyestrone, 4-hydroxyestradiol and 4-hydroxyestrone) had similar kinds of actions on arachidonic acid metabolism, being over ten times more potent inhibitors of leukotriene synthesis (IC50 values 0.044-0.16 microM) than thromboxane (IC50 values 0.99-2.1 microM) and prostaglandin E2 synthesis (IC50 values 0.84-5.5 microM). It is suggested that some of the protective actions of estrogens--e.g., on atherosclerosis and osteoporosis--may be related to the inhibition of leukotriene synthesis by catechol estrogens.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Estrógenos de Catecol/farmacología , Leucotrienos/biosíntesis , Araquidonato 5-Lipooxigenasa/sangre , Araquidonato 5-Lipooxigenasa/metabolismo , Ácido Araquidónico/sangre , Ácido Araquidónico/metabolismo , Calcimicina/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Dinoprostona/biosíntesis , Dinoprostona/sangre , Estradiol/sangre , Estradiol/metabolismo , Estradiol/farmacología , Humanos , Ionóforos/farmacología , Leucotrieno E4/biosíntesis , Leucotrieno E4/sangre , Leucotrienos/sangre , Inhibidores de la Lipooxigenasa/farmacología , Prostaglandina-Endoperóxido Sintasas/sangre , Prostaglandina-Endoperóxido Sintasas/metabolismo , Estimulación Química , Tromboxano B2/biosíntesis , Tromboxano B2/sangreRESUMEN
OBJECTIVE: To evaluate the in vivo production of prostacyclin and thromboxane A2 during the initial phase of experimental fat embolism as assessed, respectively, by determinations of urine 2,3-dinor-6-ketoprostaglandin F1alpha and 11-dehydrothromboxane B2 excretion. DESIGN: Randomized, controlled trial. SETTING: Animal laboratory. SUBJECTS: Twenty seven domestic pigs, weighing 24 to 31 kg. INTERVENTIONS: All pigs were anesthetized and mechanically ventilated during the experiment. Eighteen pigs were subjected to an intracaval infusion of 10% allogeneic bone marrow suspension at a dose of 100 mg/kg over 5 mins. Nine pigs received only bone marrow suspension (fat embolism group). Nine pigs were given an intravenous bolus of aspirin (300 mg) 1 hr before the bone marrow suspension infusion. After the induction of fat embolism, intravenous aspirin was administered at a dose of 150 mg/hr for 2 hrs (aspirin-treated group). Nine pigs were infused with saline (control group). MEASUREMENTS AND MAIN RESULTS: In the fat embolism group, cardiac index decreased within 30 mins, while mean arterial pressure remained unchanged. Central venous pressure and pulmonary artery occlusion pressure remained relatively stable over time in the animals with fat embolism. Mean pulmonary arterial pressure and pulmonary vascular resistance increased immediately after the bone marrow suspension infusion from 23 +/- 0.8 (SEM) to 34 +/- 1.3 mm Hg and from 305 +/- 28 to 585 +/- 45 dyne x sec/cm5, respectively; these variables remained increased throughout the study period. Simultaneously, pulmonary shunt in the fat embolism group increased persistently from the baseline of 12.3 +/- 2.8%, and reached its maximum of 26.1 +/- 4.8% at the end of the experiment. Instant and gradual decreases in PaO2 (from 95 +/- 4 to 67 +/- 5 torr [12.6 +/- 0.5 to 8.9 +/- 0.7 kPa]), hemoglobin oxygen saturation (from 97.2 +/- 0.4 to 91.8 +/- 1.8%), and oxygen delivery (from 16.3 +/- 1.0 to 12.6 +/- 0.4 mL/min/kg) were observed in the fat embolism group. In the bone marrow suspension-infused animals, urine 2,3-dinor-6-ketoprostaglandin F1alpha excretion increased transiently from 451 +/- 63 up to 1466 +/- 499 pg/micromol creatinine, while urine 11-dehydrothromboxane B2 excretion increased transiently from 385 +/- 36 up to 2307 +/- 685 pg/micromol creatinine. In the aspirin-treated animals, urinary excretion of these prostanoid metabolites was reduced by 81% and 88%, respectively. The changes in mean pulmonary arterial pressure and PaO2 were ameliorated, and the alterations in pulmonary shunt and SaO2 were abolished in the animals with aspirin treatment. CONCLUSIONS: Pulmonary hypertension, increased pulmonary vascular tone, and increased pulmonary shunt are hallmarks of the present fat embolism model. These hemodynamic responses may, at least partly, be related to the changed balance between prostacyclin and thromboxane A2 production.
Asunto(s)
6-Cetoprostaglandina F1 alfa/análogos & derivados , Embolia Grasa/fisiopatología , Tromboxano B2/análogos & derivados , 6-Cetoprostaglandina F1 alfa/orina , Animales , Aspirina/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Embolia Grasa/metabolismo , Epoprostenol/biosíntesis , Estudios de Evaluación como Asunto , Hemodinámica , Hipertensión Pulmonar/etiología , Enfermedades Pulmonares/etiología , Distribución Aleatoria , Porcinos , Tromboxano A2/biosíntesis , Tromboxano B2/orinaRESUMEN
Pregnancy is associated with the reduction of vascular sensitivity to vasoconstrictor compounds. We have examined whether pregnancy in rabbits induces hyposensitivity of the pulmonary vascular system to U-46619. Anesthetized, mechanically ventilated nonpregnant (NP; n = 7) and late-pregnant (P; n = 7) rabbits were studied. The intravenous injection of 0.03, 0.1, and 0.3 microgram/kg U-46619 led to a dose-dependent elevation of mean pulmonary arterial pressure (MPAP) in NP rabbits from a baseline value of 15 +/- 1 to 22 +/- 1 mgHg. There was no significant MPAP response to intravenous administration of U-46619 in P rabbits. The pulmonary arterial pressure response of isolated, ventilated, and buffer-perfused lungs of P rabbits was also blunted (P < 0.001 vs. NP). Pulmonary arterial membrane binding of [125I]BOP, another thromboxane (Tx)A2 analog, indicated 48 +/- 16 fmol receptors/mg protein in P rabbits and 193 +/- 48 fmol receptors/mg protein in NP samples (P < 0.025). Receptor affinity [1/dissociation constant (KD)] was also lower in the tissue of P rabbits (P < 0.01 vs. NP). The urinary excretion of the stable TxA2 metabolite 11-dehydro-TxB2 was lower in P than in NP rabbits (P < 0.02), which made homologous desensitization an unlikely explanation for the changes of vascular TxA2 receptors. These results show that, in late gestation, rabbit pulmonary vascular sensitivity to U-46619 is reduced simultaneously with, and as a possible consequence of, downregulation of specific receptors.
Asunto(s)
Preñez/fisiología , Endoperóxidos de Prostaglandinas Sintéticos/farmacología , Circulación Pulmonar/efectos de los fármacos , Tromboxano A2/análogos & derivados , Tromboxano A2/farmacología , Vasoconstrictores/farmacología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Animales , Arterias/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Ácidos Grasos Insaturados/metabolismo , Femenino , Hemodinámica/efectos de los fármacos , Técnicas In Vitro , Embarazo , Conejos , Receptores de Superficie Celular/metabolismo , Valores de Referencia , Tromboxano A2/metabolismo , Orina/químicaRESUMEN
Percutaneous transluminal angioplasty is an acute, local stimulus to platelets which activation is regarded as an important factor for a later restenosis. The balance between the production of prostacyclin and thromboxane A2 is of (patho)physiological importance due to their opposite actions on vascular tone and platelet reactivity. In this study we investigated the influence of percutaneous transluminal angioplasty of the peripheral arteries on prostacyclin and thromboxane A2 productions in vivo by measuring the excretions of their urinary index metabolites, 2,3-dinor-6-ketoprostaglandin F1 alpha and 11-dehydrothromboxane B2, respectively, in 10 patients. We found a twofold increase in thromboxane A2, but no significant change in prostacyclin, production after peripheral transluminal angioplasty which shifted prostacyclin/thromboxane A2 balance to the direction of thromboxane A2 formation. This gives theoretical support to the use of thromboxane A2 synthase inhibitors and receptor antagonists as well as prostacyclin analogues in combination with peripheral percutaneous transluminal angioplasty to prevent thrombosis and restenosis.
Asunto(s)
Angioplastia de Balón , Claudicación Intermitente/metabolismo , Claudicación Intermitente/cirugía , Tromboxano A2/orina , 6-Cetoprostaglandina F1 alfa/análogos & derivados , 6-Cetoprostaglandina F1 alfa/orina , Anciano , Anciano de 80 o más Años , Angiografía , Arterias/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tromboxano A2/análogos & derivados , Tromboxano B2/análogos & derivados , Tromboxano B2/orinaRESUMEN
Although theophylline has been used in the treatment of asthma for decades, it is not a first line choice any more. It is a well-known bronchodilator, but was recently discovered also to be an anti-inflammatory, immunomodulatory and bronchoprotective agent. Therefore we wanted to establish the role of theophylline on prostaglandin and leukotriene production, which plays a part in the pathogenesis of asthma. Theophylline was infused (bolus 5 mg/kg in 15 min and infusion 0.4 mg/kg/h for 1 h 45 min) into healthy volunteers. Thromboxane B2, prostaglandin E2 and leukotriene E4 were measured from the A23187-stimulated whole blood samples and stable metabolites of thromboxane A2; prostacyclin and leukotriene E4 were measured from urine. Theophylline increased prostaglandin E2 production and decreased leukotriene E4 production ex vivo in whole blood, thus increasing the prostanoid/leukotriene ratio. It did not change thromboxane B2 production stimulated by either spontaneous clotting or A23187 in the whole blood. Theophylline had hardly any effect on in vivo thromboxane, prostacyclin and leukotriene E4 production measured as urinary metabolites, 11-dehydro-thromboxane B2, 2,3-dinor-6-keto-prostaglandin F1alpha and leukotriene E4, respectively. Serum theophylline concentrations were at the lower level of normal therapeutic range during the infusion. The increase in PGE2 and the decrease in LTE4 synthesis ex vivo may offer a new explanation for the mode of antiasthmatic action of theophylline. It is notable that this phenomenon occurs at low serum theophylline concentrations. These results confirm the idea that theophylline has an anti-inflammatory and bronchoprotective action and support the use of theophylline as a therapeutic agent in asthmatic patients.
Asunto(s)
Leucotrienos/metabolismo , Prostaglandinas/metabolismo , Teofilina/farmacología , Adulto , Presión Sanguínea/efectos de los fármacos , Broncodilatadores/farmacología , Calcimicina/farmacología , Dinoprostona/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Infusiones Intravenosas , Leucotrieno E4/metabolismo , Leucotrieno E4/orina , Masculino , Teofilina/administración & dosificación , Teofilina/sangre , Tromboxano B2/análogos & derivados , Tromboxano B2/sangre , Tromboxano B2/metabolismo , Tromboxano B2/orinaRESUMEN
Prostacyclin (PGI2) and thromboxane A2 (TXA2) play an important role in the pathophysiology of various cardiovascular diseases. The balance between PGI2 and TXA2 regulates the interaction between platelets and the vessel wall in vivo. In this study we measured PGI2 and TXA2 synthesis by analysing their urinary index metabolites 2,3-dinor-6-keto-PGF1 alpha and 11-dehydro-TXB2, respectively, in acute (10 patients) and chronic (10 patients) lower limb ischaemia. Both PGI2 and TXA2 synthesis were increased about two-fold in patients with acute lower limb ischaemia compared to chronic lower limb ischaemia. However, the PGI2/TXA2 ratio was more or less the same in acute and chronic lower limb ischaemia. In patients with acute lower limb ischaemia caused by thrombotic occlusion, PGI2 and TXA2 formation were about two times higher than in patients with acute lower limb ischaemia caused by embolic occlusion. Elevation of PGI2 and TXA2 synthesis in acute lower limb ischaemia may reflect increased platelet-vascular wall interactions without changing the PGI2/TXA2 ratio.
Asunto(s)
Epoprostenol/biosíntesis , Extremidades/irrigación sanguínea , Isquemia/metabolismo , Tromboxano A2/biosíntesis , 6-Cetoprostaglandina F1 alfa/análogos & derivados , 6-Cetoprostaglandina F1 alfa/orina , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Creatinina/orina , Epoprostenol/análisis , Epoprostenol/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trombosis , Tromboxano A2/análisis , Tromboxano A2/metabolismo , Tromboxano B2/análogos & derivados , Tromboxano B2/orinaRESUMEN
A corticotropin-releasing hormone (CRH) test was performed on 7 patients with central diabetes insipidus (DI) and on 7 healthy subjects. The test was repeated on the patients with DI after 3 days of oral treatment with captopril at a dose of 100 mg daily. No significant difference in the responses of plasma ACTH and cortisol to CRH between the patients and the controls was found. The short-term captopril treatment resulted in a significant decrease of both basal and CRH-stimulated ACTH and cortisol levels in the patients with DI. CRH did not induce any changes in the stable metabolite of prostaglandin E2 13, 14-dihydro-15-keto-prostaglandin E2 (PGE2-M) in the patients with DI before or after the captopril treatment. The results obtained suggest that vasopressin is not an obligatory factor for a normal ACTH response to CRH. Angiotensin II (A II) is involved in the regulation of ACTH. This study confirmed our previous data showing the lack of any specific effect of CRH on PGE2 production.
Asunto(s)
Hormona Adrenocorticotrópica/sangre , Captopril , Hormona Liberadora de Corticotropina/farmacología , Diabetes Insípida/sangre , Dinoprostona/análogos & derivados , Hidrocortisona/sangre , Adulto , Inhibidores de la Enzima Convertidora de Angiotensina , Captopril/administración & dosificación , Diabetes Insípida/tratamiento farmacológico , Dinoprostona/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Vasopresinas/fisiologíaRESUMEN
1. We have used anaesthetized, acutely instrumented non-pregnant (NP) and late pregnant (P) New Zealand white rabbits to examine the possible role of nitric oxide (NO) in the pregnancy-induced fall of vascular tone and arterial pressure. Systemic, renal and pulmonary vascular resistance, as well as plasma concentrations of cyclic GMP (PcGMP) were compared before and after the inhibition of NO synthesis by N(G)-nitro-L-arginine methyl ester (L-NAME). 2. P rabbits had lower baseline total peripheral resistance (TPR), mean arterial pressure (MAP) and higher PcGMP than NP controls (all P < 0.05 or less). L-NAME (1, 10, 50 mg kg1, i.v.) resulted in dose-dependent elevation of TPR in both groups. However, the absolute, as well as percentage increases in TPR were greater (P < 0.05) in NP than in P rabbits. 3. Cardiac output (CO) was reduced more (P < 0.01) by NO inhibition in NP than P rabbits. Therefore, despite the smaller increase in TPR, the elevation of MAP was greater (P < 0.001) in P than NP rabbits. After L-NAME, NP rabbits developed more severe bradycardia and a greater increase of pulmonary vascular resistance which might have contributed to the more pronounced reduction of CO. 4. PcGMP increased in both groups following L-NAME, but more (P < 0.01) in NP than P rabbits. 5. Infusion of acetylcholine (ACh, 0.02 micromol l-1 kg-1) reduced MAP and TPR more (both P < 0.05) in NP than P rabbits and L-NAME reduced the ACh-induced depressor response only in NP rabbits. 6. These results suggest that the low vascular tone and arterial pressure in pregnant rabbits is not mediated by NO.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico/farmacología , Resistencia Vascular/efectos de los fármacos , Acetilcolina/farmacología , Animales , GMP Cíclico/sangre , GMP Cíclico/fisiología , GMP Cíclico/orina , Relación Dosis-Respuesta a Droga , Femenino , Óxido Nítrico/antagonistas & inhibidores , Embarazo , ConejosRESUMEN
We infused noradrenaline (0.025 micrograms/kg/min for 60 min, n=7) and dopamine (3.0 micrograms/kg/min for 60 min, n=6) into healthy male volunteers to study the effects of these catecholamines on in vivo thromboxane A2, prostacyclin and leukotriene E4 production measured as urinary excretions of 11-dehydro-thromboxane (TX) B2, 2,3-dinor-6-keto-prostaglandin (PG) F1alpha and leukotriene (LT) E4, respectively. Plasma noradrenaline and dopamine concentrations were 2.9+/-0.3 and 233+/-17 nmol/l at the endo fo the noradrenaline and dopamine infusions, respectively. Noradrenaline decreased thromboxane production and increased leukotriene production almost two fold. It had hardly any effect on prostacyclin production. Dopamine had no significant effects on any of the variables, however, it had a tendency to increase prostacyclin and leukotriene production. The results indicate that noradrenaline is a more important modulator of arachidonic acid metabolism than dopamine in vivo.