Physiological and pharmacological correlates of calcium antagonist receptors

We studied voltage-sensitive and Na-dependent Ca²⁺ flux into synaptosomes as well as Na-dependent influx in cardiac sarcolemmal vesicles. Rapid, voltage-sensitive ⁴⁵Ca²⁺ influx into synaptosomes is blocked by cadmium (IC₅₀ 1 μM) and the novel peptide toxin ω-conotoxin GVIA (30% of uptake blocked by 50 pM toxin), but not by dihydropyridine and phenylalkylamine calcium antagonists, even though [³H]dihydropyridines and [³H]phenylalkylamines bind to synaptosomes. The toxin also blocks voltage-sensitive neurotransmitter release from synaptosomes. Sodium-dependent Ca²⁺ flux into synaptosomes and cardiac sarcolemmal vesicles is inhibited by selected antihistamines, neuroleptics, and tricyclic antidepressants. We can elicit neurotransmitter release from synaptosomes by changing the Na gradient; this neurotransmitter release is absolutely Ca²⁺-dependent and blocked by Na⁺/Ca²⁺ exchange inhibitors, thereby suggesting that physiological neurotransmitter release may have a Na⁺/Ca²⁺ exchange component. More potent Na⁺/Ca²⁺ exchange inhibitors may have cardiovascular roles as inotropic agents or antagonists of calcium-related injury to cardiomyocytes during reperfusion or other disease states.