MECHANISM OF ACTION OF QUINIDINE ON SQUID AXON-MEMBRANES

Abstract

The mechanism of action of quinidine on squid (Loligo-pealei) axons was examined by means of voltage clamp and internal perfusion techniques. When applied either externally or internally quinidine HCl suppresses both Na and K conductance increases, the effect on the former accounting for the observed decrease in action potential. The K conductance in quinidine undergoes a marked inactivation in a manner dependent upon the membrane potential and time, accounting for the observed prolongation of the terminal falling phase of the action potential. Quinidine methiodide exhibits the effect similar to that of quinidine HCl only when applied internally. The dissociation constants of quinidine in suppressing the Na conducting system are estimated to be 2.4 .times. 10-4 and 4.0 .times. 10-4 M for quinidine HCl and methiodide, respectively. The dissociation constant of quinidine in suppressing the K-conducting system decreases with increasing step depolarization. When applied externally to the intact axons, quinidine HCl is more effective at external pH 8.6 than at 7.3. When perfused internally quinidine HCl is more effective at internal pH 7.0 than at 8.0, and the potency is related to the calculated internal concentration of the charged form rather than that of the uncharged form. Quinidine HCl penetrates the nerve membrane in the uncharged form, is ionized in the axon and blocks the Na and K conductances primarily in the charged form. Quinidine and local anesthetics share some features in the terms of the site of action and active form.