RESUMEN
PURPOSE: To study potential properties of iodinated radiographic contrast media (IRCM) for intravascular use in in vitro free radical generating reactions. MATERIAL AND METHODS: Superoxide (*O2-) and hydroxyl (*OH) radicals were generated in xanthine oxidase and Fenton reactions. *O2- was assayed by the nitroblue tetrazolium (NBT) method, whereas *OH was assayed by an aromatic hydroxylation (2-hydroxybenzoic acid) method. Total antioxidant status (TAS) of test substances was determined by a colorimetric assay. Finally, acetyl-cholinesterase (AChE) activity was measured in the absence and presence of IRCM. RESULTS: High concentrations (>50 mM) of IRCM inhibited *O2- production, ionic more than non-ionic IRCM. Medium concentrations (25-50 mM) of IRCM reduced *OH production, and both types of IRCM were equally potent. Low concentrations (<25 mM) of non-ionic IRCM displayed higher antioxidant capacity than their ionic counterparts when tested in the TAS assay. Visipaque 320 (iodixanol) was found to have the highest TAS value, followed by Omnipaque 350 (iohexol), Hexabrix 320 (ioxaglate), and Urografin 370 (diatrizoate). CONCLUSION: IRCM have in vitro antioxidant properties in concentrations relevant for their clinical application. These properties may therefore be of potential importance when evaluating IRCM effects in vivo, particularly those concerning cardiovascular and renal function.
Asunto(s)
Acetilcolinesterasa/química , Medios de Contraste/química , Peróxido de Hidrógeno/química , Hierro/química , Especies Reactivas de Oxígeno/síntesis química , Ácidos Triyodobenzoicos/química , Xantina Oxidasa/química , Colorimetría , Interacciones Farmacológicas , Técnicas In Vitro , Oxidación-ReducciónRESUMEN
The aim of the present study was to investigate the role of the Na+/K+/2Cl- co-transporter and the Na+/H+ exchanger on contractile function and electrolyte regulation during hyperosmotic perfusion of the heart. Langendorff perfused rat hearts were subjected to hyperosmolal perfusion in 10-min intervals. Perfusates were made hyperosmotic by adding mannitol to the buffer (370, 450 and 600 mOsmol/kg H2O). Cardiac contractile function was monitored with a balloon in the left ventricle (LV) coupled to a pressure transducer. Cardiac effluent was sampled repeatedly throughout and after hyperosmotic perfusion and analysed for content of Na+, K+, and Cl-. All three hyperosmotic perfusates initially reduced LV developed pressure (LVDP), but for 370 and 450 mOsmol/kg H2O, LVDP recovered to baseline within 4 min of perfusion. With 600 mOsmol/kg H2O, LVDP recovered slowly and was 50% below baseline after 10 min of hyperosmotic perfusion. Inhibition of the Na+/H+ exchanger with 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and 3-methylsulfonyl-4-piperidinobenzoyl-guanidine methanesulfonate (HOE 694) abolished the recovery of LVDP to the 600 mOsmol/kg H2O perfusate, whereas inhibition of the Na+/K+/2Cl- co-transporter had no impact on LVDP. Potassium was taken up by the heart during hyperosmotic perfusion and this uptake was significantly reduced with inhibition of the Na+/H+ exchanger. Intracellular pH was assessed with 31p magnetic resonance spectroscopy and hyperosmolality induced a significant alkalosis that was dependent upon the Na+/H+ exchanger. The rat heart responds to moderate elevations in osmolality with a transient reduction in contractile function, whereas an elevation of 300 mOsmol/kg H2O persistently reduces contractile function. The Na+/H+ exchanger, but not the Na+/K+/2Cl- co-transporter, is of importance in contractile recovery and electrolyte regulation during hyperosmotic perfusion in the rat heart.
Asunto(s)
Canales de Cloruro/fisiología , Corazón/fisiología , Intercambiadores de Sodio-Hidrógeno/fisiología , ATPasa Intercambiadora de Sodio-Potasio/fisiología , Animales , Concentración de Iones de Hidrógeno , Masculino , Contracción Miocárdica , Ósmosis , Perfusión , Ratas , Ratas Sprague-Dawley , Equilibrio HidroelectrolíticoRESUMEN
Intravenous magnesium has proved to be valuable in the treatment of cardiac arrhythmias and eclampsia, but the specific mode of action is not established. In this study the effect of magnesium sulphate (MgSO4) infusion on bleeding time and endogenous prostacyclin (PGI2) production in healthy male volunteers was investigated. Thirty-five males (age 18-30 years) randomized in a double-blind, placebo-controlled, cross-over study were investigated. MgSO4 was given as a bolus (8 mmol, 12 min) followed by continuous infusion (8 mmol in 108 ml saline, 120 min). Control was equal volumes of physiological saline. Heart rate, blood pressure and bleeding time (according to Ivy) were recorded as well as blood concentrations of magnesium and creatinine. Urine PGI2 was analysed as the stable metabolite 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha). Treatment with MgSO4 did not affect bleeding time (MgSO4; 8.4+/-3.5 vs. control 8.0+/-2.7 min) nor the production of PGI2 (MgSO4; 1.2 microg 6-keto-PGF1alpha/g creatinine vs. control; 1.1 microg 6-keto-PGF1alpha/g creatinine). Intravenous infusion of MgSO4 does not affect the PGI2/platelet axis in healthy male volunteers. Studies in patients with endothelium dysfunction and/or concomitant drug therapy are required before the anti-thrombogenic effect of MgSO4 in vivo is discarded.
Asunto(s)
Tiempo de Sangría , Sulfato de Magnesio/farmacología , 6-Cetoprostaglandina F1 alfa/orina , Adolescente , Adulto , Presión Sanguínea/efectos de los fármacos , Estudios Cruzados , Método Doble Ciego , Epoprostenol/biosíntesis , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Sulfato de Magnesio/administración & dosificación , Masculino , Placebos , Valores de Referencia , Reproducibilidad de los ResultadosRESUMEN
Manganese (Mn) dipyridoxyl diphosphate (MnDPDP) is the active component of a contrast medium for liver MRI. By being metabolized, MnDPDP releases Mn(2+), which is taken up and retained in hepatocytes. The study examined whether MnDPDP elevates Mn content and enhances proton relaxivity in normal myocardium, but not in ischemic myocardium with reduced coronary flow and impaired metabolism. Isolated guinea pig hearts were perfused at normal flow or low flow, inducing global subtotal ischemia. Ventricular ATP and Mn contents, T(1) and T(2) were measured. At normal flow tissue Mn content increased from the control level of 4.1 to 70.4 micromol/100g dry wt with MnDPDP (3000 microM), while low-flow perfusion with MnDPDP (3000 microM) resulted in a Mn content of 16.6 micromol/100 g dry wt. Prolonged ischemia (35 and 90 min) reduced tissue Mn down to the control level. T(1) shortening closely paralleled myocardial Mn elevations during both normal and low-flow perfusion. The use of a Mn(2+)-releasing contrast agent like MnDPDP may be a promising principle in MRI assessments of myocardial function and viability in coronary heart disease by revealing a differential pattern of changes in T(1) relative to coronary flow, cell Mn uptake and retention, ion channel function and metabolism.
Asunto(s)
Medios de Contraste , Ácido Edético/análogos & derivados , Manganeso/metabolismo , Isquemia Miocárdica/metabolismo , Miocardio/metabolismo , Fosfato de Piridoxal/análogos & derivados , Animales , Circulación Coronaria , Cobayas , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Masculino , Manganeso/farmacocinética , Contracción Miocárdica , Isquemia Miocárdica/fisiopatología , Perfusión , Protones , Función Ventricular Izquierda , Presión VentricularRESUMEN
Perturbations of the extracellular osmotic environment leads to cell volume changes. The aim of the present study was to evaluate the effects of hyperosmolality on cardiac contractile function and in particular the role of ionic mechanisms anticipated to be operative during hyperosmolal exposure. Paced rabbit hearts were perfused in the Langendorff mode and were exposed to 330, 370, 410, 450 and 600 mOsm kg-1 in 10 min. intervals intervened by 15 min. isosmolal buffer perfusion (by adding mannitol). Thereafter, 370 and 600 mOsm kg-1 perfusates were chosen for investigation of the effects of inhibition of the Na-K-2Cl co-transporter (bumetanide 1 microM and 10 microM), the Na+/H+ exchanger (5-(N-ethyl-N-isopropyl amiloride (EIPA) 100 nM) and the Na+/K(+)-ATPase (ouabain 50 nM). After a rapid and transient decrease in left ventricular developed pressure, all perfusates up to 450 mOsm kg-1 increased LVDP. The 600 mOsm kg-1 perfusate initially reduced LVDP by 50%, but LVDP increased to 85% of initial value at the end of the 10 min. perfusion. EIPA attenuated the recovery of LVDP during perfusion with 600 mOsm kg-1, whereas bumetanide did not affect cardiac contractile function. A net uptake of potassium was observed during hyperosmolal perfusion. Inhibition of the Na+/H+ exchanger resulted in a continued release of cardiac water throughout hyperosmolal perfusion. Isolated perfused rabbit hearts tolerate considerable elevations in perfusate osmolality. Our results suggest that the Na+/H+ antiporter is activated on hyperosmolal exposure with a secondary activation of the Na+/K(+)-ATPase. Since inhibition with bumetanide did not affect contractility or electrolyte movements, the Na-K-2Cl co-transporter does not seem to play an important role in cardiac response to hyperosmolality in rabbits.
Asunto(s)
Electrólitos/metabolismo , Contracción Miocárdica , Miocardio/metabolismo , Animales , Proteínas Portadoras/fisiología , Femenino , Masculino , Concentración Osmolar , Perfusión , Conejos , Intercambiadores de Sodio-Hidrógeno/fisiología , Simportadores de Cloruro de Sodio-Potasio , Función Ventricular IzquierdaRESUMEN
Manganese dipyridoxyl diphosphate (MnDPDP) is a contrast agent for magnetic resonance imaging (MRI) of the liver. Aims of the study were to examine if MnDPDP possesses superoxide dismutase (SOD) mimetic activity in vitro, and if antioxidant protection can be demonstrated in an ex vivo rat heart model. Superoxide (*O-2) and hydroxyl radicals (*OH-) were generated in xanthine oxidase and Fenton reactions. Spin adducts with 5,5-dimethyl-1-pyrroline-N-oxide were detected by electron spin resonance spectroscopy. Contractile function and enzyme release were monitored in rat hearts during hypoxia-reoxygenation. Low microM concentrations of MnDPDP and its metabolite Mn dipyridoxyl ethylene-diamine (MnPLED) dismutated *O-2, but showed no activity in Fenton or catalase reactions. MnDPDP 30 microM improved contractile function and reduced enzyme release in rat hearts during reoxygenation. It is concluded that MnDPDP and MnPLED possess SOD mimetic activities and may thereby protect the heart in oxidative stress.