BLOCKADE OF 2,4-DINITROPHENOL INDUCED ATP SENSITIVE POTASSIUM CURRENT IN GUINEA-PIG VENTRICULAR MYOCYTES BY CLASS-I ANTIARRHYTHMIC DRUGS

Objective: The aim was to assess the effects of various antiarrhythmic drugs on 2,4-dinitrophenol (DNP) induced outward current (I(DNP)), presumably the ATP sensitive K+ current (I(K,ATP), of isolated cardiac cells and to discuss mechanisms involved in the hypoglycaemia which occurs in patients on these drugs. Methods: The quasi-steady state current-voltage relationship from the isolated guinea pig ventricular cells was measured using whole cell voltage clamp techniques with a ramp pulse programme. The effects of seven different antiarrhythmic drugs on I(DNP) were examined. Action potentials were elicited at a rate of 0.2 Hz by an intracellular current injection. Results: DNP (50 mumol-litre-1) increased the quasi-steady state outward current at potentials positive to about -60 mV. This current (I(DNP)) was completely inhibited by the subsequent application of glibenclamide (I mumol.litre-1), thereby suggesting that the I(DNP) is probably I(K,ATP). Cibenzoline (10 mumol.litre-1, class Ia), disopyramide (30 mumol.litre-1, class Ia), and procainamide (100 mumol.litre-1, class Ia) significantly inhibited the I(DNP) by 95.5(SD 11.3)%, 77.8(21.2)%, and 76.4(23.9)% respectively. Flecainide (class 1c) inhibited the I(DNP) by 66.9(23.9)% at 10 mumol.litre-1 but not at 2 mumol.litre-1. Mexiletine (30 mumol-litre-1, class Ib), pilsicainide (50 mumol.litre-1, class Ic), and E4031 (10 mumol-litre-1, class III) at concentrations as high as approximately fivefold the clinically effective blood levels, did not suppress I(DNP). Except for 10 mumol.litre-1 flecainide, all the concentrations listed above which blocked I(DNP) were within twofold of the clinical blood concentrations ducumented to be effective for suppression of arrhythmias. Cibenzoline, disopyramide, and procainamide, but not flecainide, belong to class Ia antiarrhythmic drugs. All these class la antiarrhythmic drugs "shortened" the action potential duration of guinea pig ventricular cells, an opposite change to that noted for multicellular preparations, eg, guinea pig papillary muscles. Conclusions: Class Ia antiarrhythmic drugs (cibenzoline, disopyramide, and procainamide) inhibit I(DNP) (presumably I(K,ATP)) in guinea pig ventricular cells within a range of therapeutic concentrations. This inhibitory effect of I(K,ATP can probably explain the hypoglycaemia which occurs in some patients receiving these drugs, and the prolongation of the action potential duration alleged to occur in "superfused" papillary muscles.