Abstract
Carbonic anhydrase plays important role in life. This study sought to demonstrate the feasibility of detecting carbonic anhydrase activity in the human brain in vivo. After oral administration of [U-13C6]glucose, 13C saturation transfer experiments were performed with interleaved control spectra and carbon dioxide saturation spectra. Proton nuclear Overhauser effect pulses were used to increase signal to noise ratio; no proton decoupling was applied. Results showed that the 13C signal of bicarbonate was reduced by 72% ± 0.03 upon saturating carbon dioxide. The unidirectional dehydration rate constant of the carbonic anhydrase reaction was found to be 0.28 ± 0.02 sec−1 in the human brain. These findings demonstrate the feasibility of measuring carbonic anhydrase activity in vivo in the human brain, which makes it possible to characterize this important enzyme in patients with brain disorders.
Highlights
carbonic anhydrase (CA) inhibitors such as aromatic and heterocyclic sulfonamides have important clinical applications in the treatment of glaucoma[4], epilepsy, and other neurological disorders[13,14]
The bicarbonate signal was appreciably reduced upon radio frequency (RF) saturation of carbon dioxide (b)
All of our experiments were performed using a 13C saturation transfer technique at 7 Tesla, the intense labeled bicarbonate 13C signal observed after administration of uniformly 13C-labeled glucose, and the dramatic change in the bicarbonate signal (72% reduction) observed in conjunction with carbon dioxide saturation, suggests that this technique could be readily extended to lower and more clinically relevant field strengths such as 3 Tesla
Summary
CA inhibitors such as aromatic and heterocyclic sulfonamides have important clinical applications in the treatment of glaucoma[4], epilepsy, and other neurological disorders[13,14]. Considering the fundamental importance of CA, a noninvasive magnetic resonance spectroscopy (MRS) method capable of directly measuring the carbon dioxide–bicarbonate exchange rate catalyzed by CA in humans would clearly be valuable. In vivo enzyme-specific saturation transfer spectroscopy was limited to using 31P MRS for the study of creatine kinase and adenosine triphosphate (ATP) exchange reactions[19]. Using rodent models, previous work from our laboratory demonstrated in vivo 13C saturation transfer effects catalyzed by aspartate aminotransferase, lactate dehydrogenase, malate dehydrogenase, and CA20–23. The present study used 7 Tesla MRS to examine the 13C saturation transfer effect of the carbon dioxide–bicarbonate exchange catalyzed by CA in human subjects. We sought to quantify the pseudo first-order rate constant of this exchange in the dehydration direction (H+ + HCO3− → CO2 + H2O) in the human brain
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