In vivo ⁷Li NMR studies on shift reagent infused rats

Abstract

Lithium (Li⁺) is used widely in the treatment and prophylaxis of bipolar disorder. The mechanism of action remains unknown. There have been many studies of intracellular lithium and its fluxes in the human red blood cells (RBCs) with a view towards understanding the maintenance of Li⁺ levels inside the cells and the mechanism of Li⁺ therapeutic action. Such information is valuable for excitable cells such as neurons, the likely site of therapeutic effects, and muscle, the site of common side effects. As intracellular Li⁺ may be responsible for both muscle irritability and pathological changes in the electrocardiogram, there is a need to discriminate intra‐, and extracellular Li⁺ components. To date there is no other human cell for which either intracellular Li⁺ levels or its fluxes have been measured. The muscle tissue with a large concentration of lithium should serve as a suitable model for infusion studies in an in vivo set up. In addition to the intrinsic importance of muscle as a site of side effects of Li⁺ therapy, muscle as an excitable cell may be a better model for the brain than the RBCs. In this study, using the shift reagent thulim(III) 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetrakis(methylene phosphonate) (TmDOTP^5‐), two distinct resonances were observed in the head tissue of rats. Based on earlier results that the brain lithium signal is significantly small compared to the rest of the tissue in the head, the unshifted resonance was attributed as largely due to intracellular Li⁺; the shifted resonance was attributed to Li⁺ present outside the cells (plasma or interstitial). Our study demonstrates that TmDOTP^5‐ infused in animals treated with lithium can discriminate the intra‐ and extracellular Li⁺ in tissue in vivo.

Key words:

• Shift reagents
• infusion
• intra/extracellular lithium
• tissue lithium
• plasma Li⁺ levels
• ⁷Li NMR spectroscopy