Polyol and water accumulation in muscle of galactose-fed rats.

Skeletal muscle contains high levels of aldose reductase that catalyzes the reduction of galactose to the polyol galactitol. Galactitol and water were measured in muscle of rats fed a high galactose diet with or without addition of the aldose reductase inhibitor sorbinil. Galactitol, measured in isolated samples of muscle by HPLC, reached steady-state levels (5.9 +/- 1.0 mg/g tissue) within 3 days. Muscle water, determined in vivo by magnetic resonance imaging, increased (51 +/- 5%, P < 0.02) to steady-state levels within 7 days. Both the increased galactitol and water remained constant for the 4-month duration of this study. Aldose reductase activity also remained constant. Sorbinil prevented both the increase in galactitol and the increase in water. These results suggest that the increase in water is due to the osmotic effects of galactitol accumulation and demonstrate that galactitol and water accumulation neither up-regulate nor down-regulate aldose reductase expression in skeletal muscle.

Triple-quantum-coherence-filtered imaging of sodium ions in vivo at 4.7 tesla.

The tissue distribution of sodium ions which generate triple-quantum coherence (TQC) in vivo is determined from images. A technique for filtering conventional sodium images, so that signal is obtained only from sodium ions which have a correlation time appropriate for producing TQC, is described. The utility of TQC-filtered sodium images is demonstrated in a study of tumors implanted in a nude rat model, where the intensity of the TQC signal from sodium ions in the growing margin of the tumor is observed to be 200-250% greater than that from surrounding tissue.

Pharmacokinetics of CuDIPS in mice.

Pharmacokinetic evaluation of Cu(II)2(3,5-diisopropylsalicylate)4(H2O)2 (CuDIPS), a copper complex with anticancer activity in mice, showed rapid absorption into the circulation after subcutaneous (SC) injection of a 0.50mumol, 0.75 mumol or 1.0 mumol dose. A direct relationship was observed between peak plasma copper concentration (one or two hours) and dose. Rate of plasma release also appeared to be dose related. The lowest dose of CuDIPS had no effect on plasma zinc levels; higher doses produced significant increases, but only at one hour. Rapid absorption into the blood (apparent peak in concentration, Tmax, at 0.5 hours) was also found in studies to determine distribution of 67Cu after SC injection of 67Cu and 14C double-labeled CuDIPS (50 mumol/kg body weight). Distribution to other tissues and organs occurred less rapidly with apparent peak 67Cu concentrations at three hours after administration in femur (bone marrow) and intestine, and at six hours in spleen and thymus.

19F 2-FDG NMR imaging of the brain in rat.

Images of the rat head reflecting glucose utilization were obtained using 2-fluoro-2-deoxy-D-glucose (2-FDG) and 19F nuclear magnetic resonance (NMR) imaging. Spatial heterogeneity of glucose utilization in the rat head was clearly demonstrated showing significantly higher glucose utilization in the brain as compared to the surrounding tissues. Although the potential adverse effects of the high doses of 2-FDG (400 mg/kg) needed to perform the study preclude immediate application of this technique to clinical quantitative glucose utilization studies, the present study shows potential for future development of glucose utilization imaging by NMR.

F-19 MR imaging of glucose metabolism in the rabbit.

Noninvasive metabolic magnetic resonance (MR) imaging reflecting glucose metabolism in the aldose-reductase-sorbitol (ARS) pathway was performed in the rabbit head; after administration of the fluorinated glucose analogue 3-fluoro-3-deoxy-D-glucose (3FD-glucose), fluorine-19 images were generated. Images of 3FD-glucose showed significant 3FD-glucose uptake by adipose tissue, indicating its buffering effects in case of excess loads of glucose. Images of 3-fluoro-3-deoxy-D-sorbitol (3FD-sorbitol) demonstrated the spatial distribution of aldose reductase activities and significant sorbitol accumulation in the lens. Images of 3-fluoro-3-deoxy-D-fructose (3FD-fructose) showed preferential uptake of fructose by muscle tissue. The extremely low toxicity of 3FD-glucose indicates promise for its clinical application in metabolic imaging.

Fluorine-19 NMR imaging of glucose metabolism.

Metabolic imaging reflecting glucose metabolism in the glycolytic and aldose reductase sorbitol (ARS) pathways was performed noninvasively in rat using fluorinated glucose analogs, 2-fluoro-2-deoxy-D-glucose (2-FDG) or 3-fluoro-3-deoxy-D-glucose (3-FDG), and fluorine-19 (19F) nuclear magnetic resonance (NMR) imaging. 19F images of 2-FDG-6-phosphate, a main metabolite of 2-FDG in the glycolytic pathway, showed high glucose utilization in the brain, spinal cord, and heart. Images of 3-fluoro-3-deoxy-D-sorbitol (3-FDSL), a main metabolite of 3-FDG in the ARS pathway, demonstrated the heterogeneous nature of the spatial distribution of aldose reductase activities, being highest in the brain and lens. The extremely low toxicity of 3-FDG indicates promise for clinical application of 3-FDG NMR imaging.