No abstract

Effects of amiloride analogues on Na transport were studied in isolated skins of the frog Rana ridibunda. The pattern of structure-activity relationship of these compounds showed that both the -NH2 group at position 5 and Cl at position 6 of the pyrazine ring of the amiloride molecule were important for their biological activity. The paramount role of the groups at position 5 was further demonstrated by the striking properties of an analogue resulting from dimethylation of that -NH2 group. A stimulation of Na transport, opposite to the effect of amiloride itself, was observed in this instance. The increase in Na transport could already be seen at 10(-6) M and was equivalent to the measured increase in Na influx, reversible, dose-dependent, and additive to the natriferic action of oxytocin. Such characteristics resemble those reported with "external" agents like propranolol and La3+. Furthermore, mutual inhibition was observed between the stimulatory effects of this analogue and those of propranolol or La3+. These results suggest that the analogue may be considered as another "external" agent acting at sites of the external membrane distinct from those activated by cAMP but similar to the Ca sites described by Herrera and Curran (Herrera, F.C., Curran, P.F. 1963. J. Gen. Physiol. 46:999).

In a composite membrane with heterogeneous channels, prevention of net volume flow with hydrostatic pressure differences and/or impermeant osmotic solutes may induce positive isotope interaction (coupling of isotope flows) consequent to circulation of volume flow. The permeability coefficient for net flow will then exceen the tracer permeability coefficient. A permeant osmotic solute will induce either positive or negative isotope interaction, according to whether membrane heterogeneity is more marked for the test solute or the osmotic solute, respectively. Thus membrane heterogeneity may account for phenomena commonly attributed to "single file diffusion". For sufficiently small flows the general flux ratio relationship for homogeneous membranes will continue to apply.