Competitive blocking of apical sodium channels in epithelia

Apical sodium-selective channels in frog skin, when blocked by amiloride or triamterene, exhibit fluctuations in current, the spectra of which are Lorentzian. These effects have been modeled previously with two-state and three-state models by Lindemann and Van Driessche. A recent observation by Hoshiko and Van Driessche that corner frequencies are lowered by increasing the apical sodium concentration cannot be accounted for by these models. We explore the possibility that sodium (S) and amiloride (A) compete for a site at the mouth of the channel. A new three-state channel model (sodium-occupied, open/unoccupied, open/amiloride-blocked) is analyzed. Its corner frequency is of the form fc = fco [1 + (A/KA)/(1 + S/KS)], consistent with the observed sodium dependence of the corner frequency. The minimum frequency, fco, and the inhibition constants, KA and KS, are expressed in terms of the rate constants of the model. To account for sodium self-inhibition, we postulate that two sodium ions in the channel may result in clogging--a fourth state. The two corner frequencies are calculated; so are the plateau values of the noise power. The noise power shows a maximum as a function of blocker concentration, as observed previously using triamterene. The four-state model predicts the observed suppression by small amounts of blocker of the low-frequency sodium (clogging) noise.