Negative inotropic effects of tetrodotoxin and seven class 1 antiarrhythmic drugs in relation to sodium channel blockade.
The negative inotropic effect and the effect on action potential configuration were investigated for TTX and 7 class 1 antiarrhythmic drugs (aprindine, AR-LH 31, CCI 22277, disopyramide, mexiletine, quinidine and sparteine) in the isolated guinea-pig papillary muscle contracting at 1 Hz. The ratio of the molar concentration producing 50% reduction of Vmax to that reducing force of contraction by 50% ranged from 0.23 (sparteine) to 2.2 (disopyramide) showing that some of the drugs were more potent Na channel blockers than negative inotropic agents, while the reverse was true for others. With the exceptions of sparteine and AR-LH 31, all the drugs produced a larger negative inotropic effect than TTX at concentrations equieffective in reducing Vmax. Thus, blockade of Na channels can account for only part of the negative inotropic effect of aprindine, CCI 22277, disopyramide, mexiletine and quinidine. Even sparteine and AR-LH 31 showed a negative inotropic property independent of Na channel blockade because, unlike TTX and like all other agents, they retained their negative inotropic activity after inactivation of Na channels by elevated extracellular K concentration (24 mmol/l). Relative negative inotropic effects of lorcainide, Org 6001 and propafenone were similar at 5.9 and 24 mmol/l (K)o. In contrast, the -log molar IC50(Fc) of flecainide, prajmalium bitartrate and tocainide was significantly decreased (by 0.35 to 0.81 log units) if Na channels were inactivated by K depolarization. Ouabain-sensitive Na,K-ATPase was not inhibited by sparteine, while mexiletine and AR-LH 31 produced partial inhibition (each at 1 mmol/l). We conclude that the negative inotropic effect of class 1 antiarrhythmic drugs represents the sum of their Na channel blocking and additional drug-dependent inotropic properties. Quinidine, aprindine and mexiletine appear to be combined Na channel and Ca channel inhibiting agents thus causing a larger negative inotropic effect than TTX. However, a superimposed positive inotropic mechanism may also be operative in some antiarrhythmic drugs (sparteine, AR-LH 31, high concentrations of mexiletine).
P
P
Honerjäger
E
E
Loibl
I
I
Steidl
G
G
Schönsteiner
K
K
Ulm
D000200:Action Potentials / Q000187:drug effects; D000732:Androstanols / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001073:Aprindine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003864:Depression, Chemical; D004206:Disopyramide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D007473:Ion Channels / Q000187:drug effects*; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008801:Mexiletine / Q000494:pharmacology; D008839:Microelectrodes; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D011802:Quinidine / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013034:Sparteine / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology*
D000732:Androstanols; D000889:Anti-Arrhythmia Agents; D007473:Ion Channels; D007546:Isoquinolines; D008801:Mexiletine; D013034:Sparteine; D013779:Tetrodotoxin; D001073:Aprindine; C045061:AR-LH31; C034874:CCI 22277; D012964:Sodium; D000254:Sodium-Potassium-Exchanging ATPase; D004206:Disopyramide; D011802:Quinidine; D011188:Potassium; D002118:Calcium