EFFECT OF RUTHENIUM RED ON VOLTAGE-SENSITIVE CA++ CHANNELS

The organometallic dye, ruthenium red (RR) inhibited Ca++ influx, omeg a-conotoxin GVIA-sensitive Ca++ binding and Ca++ dependent neurotransm itter release in a qualitatively similar manner in rat and chicken syn aptosomes and in mammalian neuromuscular preparations, but had no effe ct on Ca++-dependent processes mediated by the dihydropyridine-sensiti ve Ca++ channel. These effects are specific for the RR complex, as RuC l3 affected neither Ca++ influx, omega-conotoxin GVIA binding nor neur otransmitter release, but did, however, in contrast to RR, displace [H -3]nitrendipine from synaptosomes. RR, in a manner similar to omega-co notoxin MVIIC and omega-agatoxin IVA (AgalVA), also effectively inhibi ted the response of the rat diaphragm to nerve stimulation and blocked AgalVA-sensitive Ca++ influx in the rat brain, suggesting a significa nt interactionat the P-type voltage-sensitive Ca++ channel. These effe cts of RR suggest that this amino complex affects both the N and the P domain of the Ca++ channel in the chicken brain and both the N- and P -type Ca++ channel which is intimately coupled to the Ca++ influx and neurotransmitter release in rat synaptosomes. Its ability to block all of the Ca++ influx in mammalian brain preparations and to inhibit com pletely the nerve-stimulated rat neuromuscular junction certainly indi cates a significant action at the P-type voltage-sensitive Ca++ channe l, similar to omega-conotoxin MVIIC or AgalVA. RR should prove to be a valuable synthetic, inexpensive tool with which to probe the neuropha rmacology of the mammalian neurotransmitter-linked voltage-sensitive C a++ channels.