Veratridine-induced intoxication in the isolated left atrium of the rat: effects of some anti-ischemic compounds.
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 45Ca 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/l) 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Wermelskirchen
D
D
Janssen Research Foundation, Neuss, Federal Republic of Germany.
Wilffert
B
B
Nebel
U
U
Wirth
A
A
Peters
T
T
D000818:Animals; D016279:Atrial Function, Left / Q000187:drug effects; D052160:Benzothiazoles; D002118:Calcium / Q000378:metabolism; D003327:Coronary Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014701:Veratridine / Q000506:poisoning*
D052160:Benzothiazoles; D010880:Piperidines; D011758:Pyrroles; D015222:Sodium Channels; D013844:Thiazoles; C072538:R 59494; D014701:Veratridine; C054551:R 56865; D012964:Sodium; D002118:Calcium