Epithelium Na+ channel

A very large number of derivatives of amiloride synthesized by E.J. Cragoe, Jr. at Merck, Sharp Dohme have made it possible to determine in detail the structure-activity relationships for the Na+/H+ exchanger and the epithelium Na+ channel. The following trends have been observed (Vigne et al., 1984 Frelin et al., 1987) ... 

The presence of a halogen atom at position six of the pyrazine ring is important for activity. Its replacement by -H drastically reduces the ability of the molecule to inhibit both the epithelium Na+ channel and the Na+/H+ exchanger. 

Alkyl group substitutions at ring position five result in a tremendous decrease in inhibitory activity of the epithelium Na+ channel, but greatly... 

Figure 1 presents the structure of amiloride and that of amiloride analogues that are known to be the most potent inhibitors of epithelium Na+ channels and the Na+/H+ exchanger. Other derivatives of guanidinium that are unrelated to amiloride and that have antihypertensive properties also block the Na+/H+ exchanger (Frelin etal., 1986). 

Amiloride-sensitive Na+ channels are probably absent from the pigmented rabbit conjunctival epithelium, since the conjunctival Ix is not sensitive to either mucosal or serosal amiloride up to 1 mM. Conjunctival Ix is, however, inhibited... 

C. Ruckes, U. Blank, K. Moller, J. Rieboldt, H. Lindemann, G. Munker, W. Clauss, and W. M. Weber. Amiloride-sensitive Na+ channels in human nasal epithelium are different from classical epithelial Na+ channels. Biochem Biophys Res Commun 237 488-491 (1997). 

Figure 10-14 Ion and fluid movement in the nonpigmented ciliary epithelium. Na+ enters the nonpigmented ciliary epithelium from the stromal side either by diffusion or by NaVH+ exchange. Na+, the main cation involved in aqueous formation, is transported extraceUularly into the lateral intercellular channel by a Na+-K+-adenosine triphosphatase-dependent transport system. HC03 forms from the hydration of CO2, a reaction catalyzed by carbonic anhydrase. HC03", the major anion involved in aqueous formation, balances a portion of the Na+ being transported into the lateral intercellular channel. Cl" enters the intercellular space by a mechanism that is not understood. This movement of ions into the lateral intercellular space creates a hypertonic fluid, and water enters by osmosis. Because of the restriction on the stromal side of the channel, the newly formed fluid moves toward the posterior chamber. A rapid diffusional exchange of CO2 allows for its movement into the posterior chamber. (Adapted from Cole DF. Secretion of aqueous humor. Exp Eye Res 1977 25(suppl) l6l-176.)...

Regarding the effects of macrolides on water transport, the experiment with electrical properties of cultured canine tracheal epithelium [12] showed that erythromycin added to the submucosal side at concentrations of 10 M and higher dose-dependently decreased short-circuit current, an electrical parameter that reflects net value of actively transported ions across airway epithelium (Table I). Moreover, this effect was not altered by the Na channel blocker amiloride but was abolished by the Cl channel blocker diphenylamine-2-carboxylate or substitution... 

Fig. I. The olfactory epithelium. A. Schematic illustration of the olfactory epithelium showing the major cell types. Inset shows the location of putative 7TM odorant receptors on cilia of ORNs. B. Hypothesized olfactory receptor-transduction mechanisms. Current evidence suggests that odor molecules bind to specific 7 transmembrane receptor (7TMr) proteins located in the cilia of ORNs. These 7 TMrs are thought to be coupled to G-proteins that activate either adenyl cyclase (AC) to generate cyclic AMP (cAMP) or phospholipase C (PLC) to generate phosphatidyl inositol (IP3). These second messengers open channels that admit calcium ( Ca ) or sodium (Na ) into the cilium. These ions lead to membrane depolarization and may modulate intracellular free Ca levels, both of which lead to the generation of action potentials that are conducted along ORN axons to the olfactory bulb.

---