Simultaneous intracellular and extracelular p^H measurement in the heart by ¹⁹F NMR of 6‐fluoropyridoxol

Abstract

6-Fluoropyridoxol (6-FPOL) was evaluated as a simultaneous indicator of intracellular and extracellular pH and, hence, pH gradient in perfused rat hearts. After infusion, 19F NMR spectra rapidly showed two well-resolved peaks assigned to the intracellular and extracellular compartments, and pH was calculated on the basis of chemical shift with respect to a sodium trifluoroacetate standard. To demonstrate use of this molecule, dynamic changes in myocardial pH were assessed with a time resolution of 2 min during respiratory and metabolic alkalosis or acidosis and ischemia. For a typical heart, intracellular pH (pHi) = 7.14+/-0.01 and extracellular pH (pHe) = 7.52+/-0.02. In response to metabolic alkalosis, pHi remained relatively constant and the pH gradient increased. In contrast, respiratory challenge caused a significant increase in pHi. Independent measurements using pH electrodes and 31P NMR confirmed validity of the 19F NMR results.

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“…Aromatic reporter molecules tend to have a much larger chemical shift pH response. Analogs of vitamin B6, for example, 6-FPOL are highly sensitive to pH [11,279,[290][291][292]. We showed that 6-FPOL itself readily enters cells and provides well-resolved resonances reporting both intra-and extracellular pH (pHi and pHe), simultaneously, in whole blood (Fig.…”

“…We showed that 6-FPOL itself readily enters cells and provides well-resolved resonances reporting both intra-and extracellular pH (pHi and pHe), simultaneously, in whole blood (Fig. 9) [279] and the perfused rat heart [290]. Ease of entry into blood cells may be related to facilitated transport, since vitamin B6 is naturally stored, transported, and redistributed by erythrocytes [293].…”

“…Intriguingly, most tumors cells show a single resonance only, suggesting that 6-FPOL does not enter. The somewhat basic pK a ¼ 8.2 is appropriate for investigations of cellular alkalosis, but it is not ideal for studies in the normal physiological range (6.5-7.5) [290].…”

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“…hydroxy-6-methyl-3,4-pyridinedimethanol) are highly sensitive to pH [45,[93][94][95]. Synthesis of 6-FPOL is Deutsch et al [86,87] championed the use of…”

“…6-FPOL accelerated and fell into the intermediate exchange regime readily enters cells and provides well resolved resonances causing severe line broadening. Based on this approach a reporting both intra-and extracellular pH (pHi and pHe), series of fluorinated agents was developed, particularly, simultaneously, in whole blood [45] and the perfused rat using mono-, di-and tri-D, L,-2-amino-3,3-difluoro-2-heart, as confirmed by 31 P NMR and pH electrodes [93]. In methyl propanoic acid (Table 4).…”