Interaction of some antiarrhythmic drugs with the heart sarcolemmal Na+-Ca2+ exchange system

Abstract

The effects of some Class I antiarrhythmics (quinidine, procainamide and lidocaine) and some Class II antiarrhythmics (propranolol, atenolol and acebutolol) on canine cardiac sarcolemmal Na+-Ca2+ exchange activity were studied. Both quinidine (5-100 microM) and procainamide (1-100 microM), unlike lidocaine, inhibited Na+-dependent Ca2+ uptake in sarcolemmal vesicles. The effective concentrations of these agents were well within their respective therapeutic ranges; about 30% inhibition was seen by 10 microM quinidine or procainamide. Propranolol showed a 25% inhibition of the Na+-Ca2+ exchange activity at 100 microM, which concentration is well above its therapeutic range. Acebutolol (0.1-100 microM) had no significant effects, whereas atenolol (10-100 microM), which appeared to inhibit Na+-dependent Ca2+ uptake, also stimulated nonspecific Ca2+ uptake. These results indicate that the cardiac sarcolemmal Na+-Ca2+ exchange system may be one of the sites for the antiarrhythmic actions of quinidine and procainamide.

Mode‐dependent inhibition by quinidine of Na+–Ca2+ exchanger current from guinea‐pig isolated ventricular myocytes

“…Data from sarcolemmal vesicles are suggestive of a greater potency of quinidine against the exchanger (e.g. approximately 30% inhibition at 10 μmol/L quinidine 25 ) than we observed in the present study, but such data may not be directly comparable with results from intact myocytes. In fact, our data and results obtained from rat myocytes and [ 45 Ca 2+ ] measurements 19 are more directly comparable and, considered collectively, both studies are consistent with quinidine showing low potency exchanger inhibition.…”

“…For example, quinidine has been reported to inhibit, in a concentration‐dependent manner, Na + gradient‐dependent [ 45 Ca 2+ ] uptake (reverse mode of the exchanger) by sarcolemmal vesicles from superior mesenteric artery 24 . Data from canine sarcolemmal vesicles have also been suggestive of an inhibitory action of quinidine on the exchanger 25 . Significantly, the agent has been reported to block Na + ‐dependent [ 45 Ca 2+ ] uptake by intact rat myocytes, while exerting little effect on Ca 2+ efflux 19 .…”

Lidocaine Attenuates Mechanical and Metabolic Derangements Induced by Palmitoyl-L-Carnitine in the Isolated Perfused Rat Heart

“…Amphiphilic metabolites including PALCAR, which are preferentially incorpo rated into the phospholipid bilayer of sarcolcmmal membrane, disturb the critical trans port system for ion homeostasis [10,11]. For example, PALCAR inhibits the sarcolemmal Na+,K+-ATPase and hence increases intracel lular Na+ concentration [19,22], According to recent electrophysiological studies with car diac cells using the whole-cell voltage-clamp technique, PALCAR produces activation of a slowly inactivating Na+ current to increase intracellular Na+ concentration [17,18], The increase in intracellular Na+ concentration would accelerate the Na+-C a2+ exchange sys tem, causing intracellular Ca2+ overload [ 18], which is responsible for mechanical and met abolic derangements of the heart [23], In fact, PALCAR induces intracellular Ca2+ accumu lation in the cardiac myocyte [24], Lidocaine inhibits the cardiac Na+ channel [25,26] with out significant action on the Na+-C a2+ ex change system in the sarcolemma [27], The beneficial effect of lidocaine on the PALCARinduced myocardial derangements, therefore, may be due to inhibition of Na+ influx into the cardiac cells. This view can be supported by the fact that tetrodotoxin, a specific inhibi tor of the Na+ channel, attenuates the PAL CAR-induced myocardial derangements [28], The blocking action of lidocaine on the car diac Na~ channel is known to be augmented by depolarization of resting membrane or high frequency of stimulation.…”