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 cation-permeable, extracellular divalent cation-inhibited non-selective conductance was investigated in ventricular myocytes at 22 degrees C. Under whole-cell voltage-clamp, with L-type Ca2+ channels blocked by nifedipine, and K+ currents blocked by Cs+ substitution for K+, removal of Ca2+(o)and Mg2+(o) induced a non-selective current (I(NS-(Ca)o)) in mouse, rabbit and rat cells. Removal of glucose increased I(NS-(Ca)o)in the absence of Ca2+(o) and Mg2+(o), but failed to induce this current in the presence of the divalent cations. Further inhibition of glycolysis by 2-deoxyglucose (DOG; 10 mM, in zero glucose) or of mitochondrial function by rotenone (10 microM) or NaCN (5 mM) also failed to induce I(NS-(Ca)o)in the presence of Ca2+(o) and Mg2+(o). Even when given together, DOG and rotenone did not induce I(NS-(Ca)o) in the presence of divalent cations. Preactivated I(NS-(Ca)o) was increased by the oxidants thimerosal (50 microM), diamide (500 microM) and pCMPS (50 microM). However, none of these drugs nor NEM (1 mM) did elicit I(NS-(Ca)o)in the presence of Ca2+(o) and Mg2+(o). Exposure of rat myocytes to Ag+ induced a current resembling I(NS-(Ca)o) (reversing at -5 mV; blocked by 100 microM Gd3+) even in the presence of divalent cations. The data indicate that metabolic inhibition only regulates activated I(NS-(Ca)o)but does not induce the 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.
Macianskiene
R
R
Laboratory of Cardiac Cellular Research, Centre for Experimental Surgery and Anaesthesiology, Katholieke Universiteit Leuven, Campus Gasthuisberg, Leuven, B-3000, Belgium.
Matejovic
P
P
Sipido
K
K
Flameng
W
W
Mubagwa
K
K
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D002413:Cations, Divalent / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002586:Cesium / Q000737:chemistry / Q000494:pharmacology; D003847:Deoxyglucose / Q000378:metabolism / Q000494:pharmacology; D005110:Extracellular Space / Q000737:chemistry; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology; D066298:In Vitro Techniques; D051379:Mice; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D010084:Oxidation-Reduction; D018408:Patch-Clamp Techniques; D011817:Rabbits; D051381:Rats; D012402:Rotenone / Q000378:metabolism / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D016276:Ventricular Function
D020746:Calcium Channels, L-Type; D002413:Cations, Divalent; D013438:Sulfhydryl Compounds; D012402:Rotenone; D002586:Cesium; D003847:Deoxyglucose; D009543:Nifedipine; D005947:Glucose