Blockade of ventricular sodium conductance (gNa) is believed to play an important role in the beneficial antiarrhythmic effects of dass I antiarrhythmic agents. The present study was undertaken to examine the importance of ventricular gNa blockade by as-sessing the antiarrhythmic profile of tetrodotoxin (TTX), a selective sodium channel blocker. Experiments were performed in pentobarbiWanesthetized and artificially ventilated rats. Two doses of TTX were tested for antiarrhythmic action: a low dose (low TTX, 10 pg/kg of bolus+ infusion of 10 pg/kg/hr) which Mocked only neuronal activity, and a high dose (TTXh, 50 pg/kg of boius+ infusion of 50 pg/kg/hr) which also produced signs of ventricular gNa blockade in normal hearts. To control for the decreases in Mood pressure and heart rate caused by lTX, hexamethonium, nitroprusside and propranold were also used. Only lTXh possessed antiarrhythmic activity in rats subjected to myocardial ischemia (produced by ligation of the left anterior descending coronary artery). Arrhythmia scores (mean, n= 9) were: saline, 3.8; hexamethonium, 3.8; nitroprusside, 3.2; nitroprusside+ proprandd, 4.3; low TTX, 3.9; and TTXh, 0.9. Only lTXh reduced dV/dt max. of the action potential (recorded in vivo by means of 3 M KC1 filled microelectrodes) as well as action potential height, and concomitantly prolonged the PR and QRS intervals of normal hearts. In condusion, our study demonstrated that drugs which produced hypotension, bradycardia and loss of autonomic function were not antiarrhythmic. On the other hand, the marked antiarrhythmic activity of TTXh appeared to depend upon ventricular gNa Mockade. Thus, TTX provides a useful tool for examining the antiarrhythmic properties of ventricular gNa Mockade.

The mechanism underlying the antiarrhythmic effect of class I agents is most probably related to their ability to block the fast inward depolarizing sodium current in ventricular cells (Bigger and Hoffman, 1985). It has been advocated that these compounds exert their activity by reversibly binding to a single site associated with the cardiac sodium channel (Grant et al., 1984). Using radioligand binding techniques, Sheldon et al.(1987) have shown that several type I antiarrhythmic drugs inhibit [3H] batrachatoxin binding to cardiac myocytes, thus strongly suggesting that these drugs bind to specific sites associated with the sodium channel. However, many class I antiarrhythmics have blocking actions on other channels as well (Bigger and Hoffman, 1985). In addition, other mecha-