Genistein inhibits osmotic activation of Na(+) /H( +) exchange in human platelets.
The osmotic shrinkage is an important activator of the Na(+)/H( *) exchanger. The intracellular signaling mechanisms by which shrinkage changes intracellular pH have not been fully elucidated. In human platelets, the removal of calcium did not prevent the osmotic activation of the exchanger. The increase of pH(i) after an hyperosmotic stress was reduced by W-7 (63 micromol l(-1)), and by ML-7 (25 micromol l(-1)), inhibitors of responses mediated by calmodulin or by myosin light chain kinase, but the high concentrations needed suggested that non-specific effects could be involved. Although the exchanger was quiescent during preincubation in hypertonic sodium free solutions, some steps of the signal transduction chain that links the shrinkage to the exchanger activation suffers a modification. Therefore, upon exposure to isotonic sodium-containing media, the rate of recovery from acid loads was increased. The presence of genistein (100 micromol l( -1)) during the preincubation inhibited this activation of Na(+)/H( +) exchanger. We propose that shrinkage induce activation of tyrosine kinases, which in turn leads to the activation of Na(+)/H(+) exchanger and contributes to the restoration of cell volume in human platelets.
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Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina. cicme@atlas.med.unlp.edu.ar
D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D009995:Osmosis / Q000187:drug effects*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013312:Stress, Physiological; D013997:Time Factors
D002147:Calmodulin; D004791:Enzyme Inhibitors; D017923:Sodium-Hydrogen Exchangers; D019833:Genistein; D009219:Myosin-Light-Chain Kinase