THE MACULA DENSA CELLS COMPRISE the sensing component of the tubuloglomerular feedback (TGF) mechanism and respond to changes in tubular fluid composition by transmitting signals to the afferent arterioles thus regulating the preglomerular vascular resistance and filtered load to the tubules (14, 15). This intriguing mechanism has remained under intensive investigation, and the accrued evidence indicates that there are multiple interacting paracrine agents involved in the communication pathway between the macula densa cells and the vascular smooth muscle cells. The macula densa cells are thought to produce and release ATP, adenosine, arachidonic acid metabolites, and nitric oxide. Some of these serve to modulate the sensitivity of the TGF mechanism, and it has remained a formidable challenge to discriminate between the powerful modulators and the specific mediator that respond to the acute changes in distal tubular fluid composition. Perhaps the single most important criterion distinguishing between the mediator and modulators is that there should be a direct relationship between the change in the macula densa stimulus and the change in the release or concentration of the TGF mediator associated with the change in renal vascular resistance (RVR).

Because the TGF mechanism participates in the autoregulatory responses of the arteriolar vasculature to changes in perfusion pressure, it is also recognized that the mediator of the TGF mechanism contributes to the changes in RVR associated with autoregulatory responses (15, 20, 22). Thus one would expect a certain internal consistency in the evidence regarding the mechanism that mediates the TGF mechanism and the mechanism that mediates autoregulatory responses. Considering that the TGF mechanism is a major mediator of renal autoregulatory responses and primarily serves to regulate afferent arteriolar resistance (9, 15, 20), it is surprising that no consensus has emerged regarding the nature of the signaling mechanism that links macula densa function with the changes in affer-