VARIATIONS OF NaCl concentration in the macula densa region of the tubule between 20 and 60 mM/l cause inverse changes in glomerular filtration rate (GFR) that, for the most part, are the result of a progressive increase in afferent arteriolar resistance and a subsequent fall in glomerular capillary pressure (5). The reductions in capillary pressure and GFR are rapidly inducible and rapidly reversible. They are restricted to the perturbed nephron, although electronic coupling of smooth muscle cells can transmit an attenuated constrictor response to a neighboring nephron. The sensing step at the level of the macula densa cells is linked to some consequence of activation of NKCC2-mediated NaCl uptake (5). It is the premise of this discussion that graded increments in NaCl concentration, normally produced by increments in loop of Henle flow, cause a graded activation of NKCC2. Through a number of intermediate steps, this is followed by the NaCl concentration-dependent appearance of a humoral mediator within the juxtaglomerular interstitium whose interaction with its receptors on afferent arteriolar smooth muscle cells causes progressive vasoconstriction.

A tubuloglomerular feedback (TGF) mediator that fulfills all theoretical requirements for an extracellular paracrine transmitter, analogous to those defined earlier for synaptic transmission, has not been identified to date. On the basis of the available data and their interpretation, different investigators have suggested different agents or combinations of agents as TGF mediators (3, 5). The present essay takes the position that the preponderance of all experimental evidence supports the notion that TGF-mediated vasoconstriction is caused by a single vasoactive mediator and that this mediator is adenosine (4). Strong evidence in support of this notion comes from the recent use of mouse strains with knockout mutations in the adenosine 1 receptor (A1AR) gene generated by two independent groups of investigators (1, 7). Adenosine involved in TGF mediation is likely to act through A1AR, because only this receptor subtype me-