Flunarizine and R 56865 suppress veratridine-induced increase in oxygen consumption and uptake of 45Ca2+ in rat cortical synaptosomes.
The effect of the anti-ischemic compounds flunarizine and R 56865 on the veratridine-induced uptake of Ca2+ and Na+ was observed in cortical synaptosomes in the rat. The veratridine-induced uptake of Na+ and Ca2+ was determined by means of a measurement of synaptosomal oxygen consumption and a method for the uptake of 45Ca2+, respectively. Veratridine (10(-5) M) was found to induce a 3-fold increase in synaptosomal oxygen consumption (uptake of Na+) and uptake of 45Ca2+, both of which were inhibited by tetrodotoxin (10(-5) M). Nitrendipine (10(-5) M) and omega-conotoxin (5 x 10(-7) M) were ineffective on the veratridine-induced response. Nimodipine (10(-5) M) suppressed the veratridine-induced uptake of 45Ca2+ but also diminished the unstimulated uptake of 45Ca2+. The veratridine-induced uptake of Na+ was not influenced by nimodipine. Flunarizine (3 x 10(-6)-10(-5) M), as well as R 56865 (10(-6)-10(-5) M), attenuated the veratridine-induced uptake of both Na+ and 45Ca2+. In conclusion, the veratridine-induced uptake of Na+ and 45Ca2+ was shown to be closely correlated to the activity of Na+ channels but not to voltage-operated Ca2+ channels. Secondly, flunarizine and R 56865 seemed to evoke their effects by interfering with the permeability of Na+ channels. Since veratridine-induced uptake of Na+ and Ca2+ shares some similarities with ischaemia-induced uptake of Na+ and Ca2+, it is proposed, that flunarizine and R 56865 exert their anti-ischaemic effects by reducing ischaemia-induced Na+ and Ca2+ load, probably by inhibiting a TTX-sensitive Na+ channel.
Wermelskirchen
D
D
Janssen Research Foundation, Neuss, Fed. Rep. Germany.
Gleitz
J
J
Urenjak
J
J
Wilffert
B
B
Tegtmeier
F
F
Peters
T
T
D000818:Animals; D052160:Benzothiazoles; D002118:Calcium / Q000378:metabolism*; D002132:Calcium Radioisotopes; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D005444:Flunarizine / Q000494:pharmacology*; D066298:In Vitro Techniques; D010101:Oxygen Consumption / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D011048:Polarography; D051381:Rats; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D014701:Veratridine / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D052160:Benzothiazoles; D002132:Calcium Radioisotopes; D010880:Piperidines; D013844:Thiazoles; D013779:Tetrodotoxin; D014701:Veratridine; C054551:R 56865; D005444:Flunarizine; D002118:Calcium