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S Abraham, GN Beatch, BA MacLeod and MJ Walker
Department of Pharmacology & Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, Canada.
Blockade of ventricular sodium conductance (gNa) is believed to play an important role in the beneficial antiarrhythmic effects of class I antiarrhythmic agents. The present study was undertaken to examine the importance of ventricular gNa blockade by assessing the antiarrhythmic profile of tetrodotoxin (TTX), a selective sodium channel blocker. Experiments were performed in pentobarbital-anesthetized and artificially ventilated rats. Two doses of TTX were tested for antiarrhythmic action: a low dose (low TTX, 10 micrograms/kg of bolus + infusion of 10 micrograms/kg/hr) which blocked only neuronal activity, and a high dose (TTXh, 50 micrograms/kg of bolus + infusion of 50 micrograms/kg/hr) which also produced signs of ventricular gNa blockade in normal hearts. To control for the decreases in blood pressure and heart rate caused by TTX, hexamethonium, nitroprusside and propranolol were also used. Only TTXh 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 + propranolol, 4.3; low TTX, 3.9; and TTXh, 0.9. Only TTXh reduced dV/dt max. of the action potential (recorded in vivo by means of 3 M KCl filled microelectrodes) as well as action potential height, and concomitantly prolonged the P-R and QRS intervals of normal hearts. In conclusion, 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 blockade. Thus, TTX provides a useful tool for examining the antiarrhythmic properties of ventricular gNa blockade.
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