SITE OF ACTION AND ACTIVE FORM OF AMINOPYRIDINES IN SQUID AXON-MEMBRANES

  • 1 January 1983
    • journal article
    • research article
    • Vol. 226  (1) , 174-179
Abstract
Aminopyridines, potent K channel blocking agents, were studied for their site of action and active form in the nerve membrane. Voltage clamped, internally perfused squid giant axons were used. 3,4-Diaminopyridine, one of the most potent aminopyridine derivatives, blocked the K current much faster with internal application than with external application. When applid externally to the internally perfused axon, the onset of 3,4-diaminopyridine block was accelerated by suspending the internal flow. 4-Aminopyridine methiodide, a quaternary derivative of 4-aminopyridine, blocked the K current more effectively by internal application than by external application. These observations support the notion that aminopyridines act on a site more easily accessible from inside the nerve membrane than from outside. The block of the K current caused by internal 4-aminopyridine methiodide, similar to that caused by 4-aminopyridine or 3,4-diaminopyridine, was voltage-, time- and frequency-dependent, becoming less with longer and prolonged depolarization and with repetitive depolarizations. Low internal pH, which accelerated block re-establishment by the tertiary derivative, did not affect the quaternary derivative. When perfused internally at different total concentrations and different internal pH values, 2,3-diaminopyridine exhibited the same degree of block as long as the internally present cationic form concentration was kept constant. Aminopyridines evidently act in the cationic form.