Renal endothelial and macula densa NOS: integrated response to changes in extracellular fluid volume

If, only 20 years ago, anyone had postulated that the absence of nitric oxi de gas (NO) would lead to severe hypertension and destruction of the vascul ar bed of the kidney within weeks, it is not unlikely that smiles of pity w ould have appeared on the faces of fellow researchers. By now, this has bec ome common knowledge, and hundreds of reports have appeared on the regulati on of vascular and renal function by nitric oxide. The amount of informatio n complicates the design of a concept on how NO participates in control of extracellular fluid volume (ECFV) by the kidney. This review analyzes the f unction of endothelial and macula densa NO synthase (NOS) in the regulation of renal function. From this analysis, endothelial NOS (eNOS)-derived NO i s considered a modulator of vascular responses and of renal autoregulation in particular. Increases in renal perfusion pressure and sodium loading wil l increase eNOS activity, resulting in vasodilatation and depression of tub uloglomerular feedback system responsiveness. Endothelium-derived NO seems important to buffer minute-to-minute variations in perfusion pressure and r apid changes in ANG II activity. In contrast, macula densa NOS is proposed to drive adaptations to long-term changes in distal delivery and is conside red a mediator of renin formation. Increases in perfusion pressure and dist al delivery will depress the activity and expression of the enzyme that coi ncides with, and possibly mediates, diminished renin activity. Together, th e opposite responses of eNOS and macula densa NOS-derived NO to changes in ECFV lead to an appropriate response to restore sodium balance. The concept that the two enzymes with different localizations in the kidney and in the cell are producing the same product, displaying contrasting responses to t he same stimulus but nevertheless exhibiting an integrated response to pert urbation of the most important regulated variable by the kidney, i.e., the ECFV, may be applicable to other tissues.