PubMed · 14921070
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[Compound baskir].. https://pubmed.ncbi.nlm.nih.gov/14921070/
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The effect of substances as possible inhibitors of the K+(Na+)/H+ exchanger in the human red cell membrane has been tested on the (ouabain+bumetanide+EGTA)-resistant K+ influx in both physiological (HIS) and low ionic strength (LIS) solution with tracer kinetic methods. It is demonstrated that high concentrations of quinacrine (1 mM) and chloroquine (2 mM) inhibit the residual K+ influx in LIS solution to 60% and 85%, respectively, but activate it in HIS solution. Thus, chloroquine suppressed the 10-fold LIS-induced activation of the flux nearly completely. Amiloride derivatives were able to inhibit the K+ influx in both HIS and LIS solution. EIPA (75 microM) reduced the flux by about 20% and 55% in HIS and LIS solution, respectively. Newly developed drugs (HOE 642, 1 mM; HOE 694, 0.5 mM) designed to inhibit Na+/H+ exchanger isoforms showed an inhibition of the residual K+ influx of 40% and 33% in HIS and 65% and 44% in LIS solution, respectively, without haemolysis. The inhibitory effect of HOE 642 persisted in HIS (24%) and LIS (48%) solutions when Cl- was replaced by CH3SO4-. The K(+)-Cl- cotransport inhibitor DIOA (100 microM) stimulated the residual K+ influx in both solutions. It is, therefore, concluded that the K(+)-Cl- cotransporter does not contribute to the residual K+ influx both in HIS and LIS media. Okadaic acid decreased the residual K+ influx by 40% and 25% in HIS and LIS solution, respectively, showing that the residual K+ influx is affected by phosphatases like other ion transport pathways. The results show that the residual K+ influx can be decreased further by inhibiting the K+(Na+)/H+ exchanger. It remains still unclear to what extent the K+(Na+)/H+ exchanger is inhibited by the different substances used. However, the ground state membrane permeability for K+ is much smaller than assumed so far.
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A 46-year-old female patient with Sjögren's syndrome, hypertension, and stable chronic renal insufficiency (creatinine [CR], 1.9 to 2.1 mg/dL) had a progressive worsening of renal function (CR, 5.0 mg/dL) after 11 months of chloroquine therapy (155 mg/day; cumulative dose of approximately 51 g). Light microscopy revealed nonspecific angionephrosclerosis. Electron microscopy showed accumulations of lamellated myelinoid material and occasionally also of curvilinear bodies, especially in the glomerular podocytes and to a lesser extent in vascular myothelial and endothelial cells. In the tubular system, mainly protein droplets were stored. Activity of alpha-galactosidase A was normal in isolated leukocytes (56 nmol/mg; range, 33.2 to 109 nmol/mg), ruling out Fabry's disease. Clinical, morphological, and biochemical findings were consistent with chloroquine-associated deterioration of renal function that improved considerably after discontinuation of chloroquine treatment. Adverse effects of chloroquine may aggravate preexisting renal disease. Electron microscopy is a worthwhile tool for establishing the correct diagnosis.