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A series of studies on the signal responsible for initiating the tubuloglomerular feedback (TGF)-mediated changes in SNGFR have utilized a retrograde perfusion technique that permits close control of macula densa segment tubular fluid composition. The feedback response has been demonstrated to be an approximately linear function of luminal NaCl concentration between 15 and 60 mM, with increasing NaCl concentration resulting in lower nephron filtration rate. Feedback responses could be initiated by NaCl and NaBr solutions but not by NaI, NaNO3, NaF, NaHCO3, NaSCN, or Na acetate. All chloride salts tested, in which chloride was accompanied by a univalent cation, elicited a response. The feedback mechanism thus shows a special requirement for chloride or bromide and not for sodium. With the chloride salts the response varied in magnitude depending on the accompanying cation with the following order of decreasing response, Rb+, Na+, Cs+, NH4+, K+, choline+, and Li+, CaCl2 and MgCl2 did not elicit a feedback response. The feedback response was not influenced by large changes in luminal osmolarity by addition of urea, suggesting either that the feedback sensing site is water impermeable or that water movement does not influence the signal. When electrolyte-free solutions are perfused through the loop of Henle in an orthograde direction, sufficient electrolyte may enter the luminal fluid to transiently influence the feedback mechanism.

Changes in ion concentration can be expected to accompany natural activity in any preparation with infolded membranes or narrow spaces between cells. Such preparations have complex electrical properties because some of the membranes are isolated by the resistance of the solution in narrow extracellular spaces. Analyses of the diffusional and electrical consequences of these structural complexities are intimately related: both require morphometric measurement and theoretical analysis of the the structure. The measured properties of complex tissues, either diffusional or electrical, depend on the properties of many membranes and intra- and extracellular compartments. Fitting a structural theory to one type of experimental data separates some of the measured properties of the tissue into the properties of its components. Fitting electrical data alone give many electrical parameters of the tissue components. Fitting diffusional data alone may give some of the permeability and diffusional parameters of the tissue components. A complete understanding of ion accumulation probably requires a concomitant analysis of elctrical properties.