PubMed · 14141239
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L E VOYER, R S MERECH. 1964. [WATER-ELECTROLYTE CHANGES].. https://pubmed.ncbi.nlm.nih.gov/14141239/
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In recent years there has been an increase in the use of ACE inhibitors in the paediatric population. We describe a case of hyperchloraemic metabolic acidosis with hypoaldosteronism in a 4-year-old boy with nephrotic syndrome who was receiving ACE inhibitors.
Recently, we presented evidence that sulfite protects transthyretin (TTR) from normal human individuals and heterozygotes with amyloidogenic TTR mutations against the decay of tetramers into monomers. In this paper we demonstrate a stabilizing effect of sulfite on TTR tetramers from a familial amyloidotic polyneuropathy (FAP) patient homozygous for the most-common amyloidogenic TTR-V30 M mutation. We compare the conformational stability of partially sulfonated TTR from a heterozygote for normal TTR and amyloidogenic TTR-V30 M with the stability of untreated TTR from a compound heterozygote for amyloidogenic TTR-V30 M and TTR-T119 M known to have only minor or no problems of FAP. Using a combination of polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate (SDS) gradient PAGE we demonstrate that TTR dimers containing amyloidogenic TTR mutations decay into monomers at pH<7.4. Increasing the pH by some 0.2 units within physiological ranges, i.e., pH 7.0-7.4, and sulfonation of TTR were observed to have additive inhibitory effects on the transition of dimers into monomers. We conclude that mild acidifying episodes in the interstitial volume of tissues at risk for amyloidosis could contribute to the development of FAP. Early and permanent efforts to counteract acidosis by treatment with base could possibly help to delay the onset of the disease. The intake of sulfite could support these efforts.
Expression of the human tandem P domain K+ channel, hTREK1, is limited almost exclusively to the central nervous system, where ambient Po2 can be as low as 20 Torr. We have previously shown that this level of hypoxia evokes a maximal inhibitory influence on recombinant hTREK1 and occludes the activation by arachidonic acid; this has cast doubt on the idea that TREK1 activation during brain ischemia could facilitate neuroprotection via hyperpolarizing neurons in which it is expressed. Using both whole cell and cell-attached patch-clamp configurations, we now show that the action of another potent TREK activator and ischemia-related event, intracellular acidification, is similarly without effect during compromised O2 availability. This occlusion is observed in either recording condition, and even the concerted actions of both arachidonic acid and intracellular acidosis are unable to activate hTREK1 during hypoxia. Conversely, intracellular alkalinization is a potent channel inhibitor, and hypoxia does not reverse this inhibition. However, increases in intracellular pH are unable to occlude either arachidonic acid activation or hypoxic inhibition. These data highlight two important points. First, during hypoxia, modulation of hTREK1 cannot be accomplished by parameters known to be perturbed in brain ischemia (increased extracellular fatty acids and intracellular acidification). Second, the mechanism of regulation by intracellular alkalinization is distinct from the overlapping structural requirements known to exist for regulation by arachidonic acid, membrane distortion, and acidosis. Thus it seems likely that hTREK1 regulation in the brain will be physiologically more relevant during alkalosis than during ischemia or acidosis.