Modulation of the extracellular divalent cation-inhibited non-selective conductance in cardiac cells by metabolic inhibition and by oxidants

The effect of metabolic inhibition and oxidative stress on the monovalent r ation-permeable, extracellular divalent ration-inhibited non-selective cond uctance was investigated in ventricular myocytes at 22 degreesC. Under whol e-cell voltage-clamp, with L-type Ca2+ channels blocked by nifedipine, and K+ currents blocked by Cs substitution for K+, removal of Ca-o(2+) and Mg-o (2+) induced a nonselective current (INS., a,) in mouse, rabbit and rat cel ls. Removal of glucose increased INS-(Ca)o in the absence of Ca-o(2+) and M g-o(2+), but failed to induce this current in the presence of the divalent rations. Further inhibition of glycolysis by 2-deoxyglucose (DOG; 10 mm, in zero glucose) or of mitochondrial function by rotenone (10 mum) or NaCN (5 mm) also failed to induce INS-(Ca)o in the presence of Ca-o(2+) and Mg-o(2 +). Even when given together, DOG and rotenone did not induce INS-(Ca)o in the presence of divalent cations. Preactivated INS-(Ca)o aro was increased by the oxidants thimerosal (50 mum), diamide (500 mum) and pCMPS (50 mum). However, none of these drugs nor INS-(Ca)o in the presence of Ca-o(2+). and Mg-o(2+). Exposure of rat myocytes to Ag- induced a current (1 mMs) did el icit INS-(Ca)o resembling INS-(Ca)o (reversing at -5 mV; blocked by 100 muM Gd3+) even in the presence of divalent cations. The data indicate that met abolic inhibition only regulates activated INS-(Ca)o but does not induce th e opening of closed channels, and that small oxidants like Ag+ may induce I NS-(Ca)o activation by accessing at sites unavailable for larger molecules. (C) 2001 Academic Press.