Veratridine-induced intoxication in the isolated left atrium of the rat: Effects of some anti-ischemic compounds

Summary

Veratridine-induced Na⁺ and Ca²⁺ uptake was used as a simulation of ischemia-induced Na⁺ and Ca²⁺ uptake. Therefore, electrically driven (1 Hz) isolated left atria of the rat were intoxicated with veratridine and the ⁴⁵Ca²⁺ uptake was determined. Veratridine (10⁻⁴ mol/l) increased the ⁴⁵Ca²⁺ uptake from 575±13 to 2320±86 dpm/mg ww (n=20). The total tissue content of ⁴⁵Ca²⁺ was elevated from 4328±132 to 5136 ±303 dpm/mg ww (n = 13). The veratridine-induced ⁴⁵Ca²⁺ uptake was completely suppressed by tetrodotoxin (10⁻⁷ and 10⁻⁶ mol/l), whereas amiloride (6·10⁻⁶ mol/1) and phentolamine (10⁻⁶ and 10⁻⁵ mol/l) exhibited no effect on the veratridine-induced ⁴⁵Ca²⁺ uptake. Nifedipine (10⁻⁷ and 10⁻⁶ mol/l) was ineffective on veratridine-induced ⁴⁵Ca²⁺ uptake. Verapamil (10⁻⁵ mol/l) suppressed the veratridine-induced ⁴⁵Ca²⁺ uptake, but the ⁴⁵Ca²⁺ uptake in the absence of veratridine was also suppressed by verapamil (10⁻⁶ and 10⁻⁵ mol/l). The novel anti-ischemic compounds R 56865 (10⁻⁸–10⁻⁵ mol/l) and R 59494 (10⁻⁸ -10-5 mol/l) totally abolished veratridine-induced ⁴⁵Ca²⁺ uptake.

It is speculated that Ca²⁺ enters the cell via a Na⁺ channel which changes its selectivity upon veratridine treatment. Consequently, R 56865 and R 59494 could display their protective effect by either inhibiting the modified Na⁺ channel or preventing the transition of the normal Na⁺ channel to its altered state. As ischemia- and veratridine-induced Na⁺ and Ca²⁺ uptake share some similarities, it is proposed that veratridine-induced ⁴⁵Ca²⁺ uptake of the isolated left atrium of the rat could be used to study the mechanism of action of novel antiischemic drugs.